Permanent and Semi-Permanent Dermal Fillers

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ASERNIP S
Australian Safety
and Efficacy
Register of New
Interventional
Procedures - Surgical
Systematic Review
Permanent and Semi-Permanent
Dermal Fillers
ASERNIP-S REPORT NO. 55
February 2009
Australian Safety & Efficacy Register of
New Interventional Procedures – Surgical
The Royal Australasian College of Surgeons
- ASERNIP-S REVIEW OF PERMANENT AND SEMI-PERMANENT DERMAL FILLERS. FEBRUARY 2009 -
Permanent and Semi-Permanent Dermal Fillers
ISBN 978-0-9806299-4-1
Published February 2009
This report should be cited in the following manner:
Sturm L, et al. Permanent and Semi-Permanent Dermal Fillers. ASERNIP-S Report
No. 55. Adelaide, South Australia: ASERNIP-S, February 2009.
Copies of these reports can be obtained from:
ASERNIP-S
PO Box 553,
Stepney, SA 5069
AUSTRALIA
Ph: 61-8-8363 7513
Fax: 61-8-8362 2077
E-Mail: [email protected]
http://www.surgeons.org/asernip-s
- ASERNIP-S REVIEW OF PERMANENT AND SEMI-PERMANENT DERMAL FILLERS. FEBRUARY 2009 -
The Systematic Review of Permanent and Semi-Permanent
Dermal Fillers
was ratified by:
The ASERNIP-S Advisory Committee in
December 2008
and
The Council of the Royal Australasian College of Surgeons in
February 2009
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Table of Contents
Executive Summary .............................................................................................................. vi
The ASERNIP-S Classification System ............................................................................. ix
The ASERNIP-S Review Group ........................................................................................ xi
Abbreviations and Acronyms............................................................................................. xii
1. Introduction........................................................................................................................ 1
Objective ............................................................................................................................. 1
The skin............................................................................................................................... 1
The ageing process ............................................................................................................ 1
HIV-associated lipodystrophy syndrome....................................................................... 1
Non-surgical therapies for facial augmentation ............................................................ 3
Topical therapies ........................................................................................................... 3
Injectable agents ............................................................................................................ 3
Dermal fillers ................................................................................................................. 4
Types of dermal fillers....................................................................................................... 4
Temporary fillers ........................................................................................................... 5
Semi-permanent fillers.................................................................................................. 5
Permanent fillers ........................................................................................................... 5
How dermal fillers work ................................................................................................... 9
Demand for cosmetic procedures ................................................................................. 10
Australian cosmetic industry .......................................................................................... 10
Summary ........................................................................................................................... 11
2. Methodology..................................................................................................................... 12
Literature search protocol .............................................................................................. 12
Inclusion criteria.......................................................................................................... 12
Literature search strategies ............................................................................................. 14
Databases searched and search terms used ............................................................. 14
Selection of studies .......................................................................................................... 16
Data extraction and appraisal of study methodology................................................. 16
Data analysis ..................................................................................................................... 17
3. Studies included in the review........................................................................................ 18
Literature search results .................................................................................................. 18
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Description of studies ..................................................................................................... 19
Critical appraisal............................................................................................................... 23
Facial augmentation for ageing ................................................................................. 23
Facial augmentation for HIV-associated lipoatrophy............................................ 27
4. Results................................................................................................................................ 32
Efficacy outcomes for ageing......................................................................................... 32
Permanent vs. temporary fillers ................................................................................ 32
Permanent fillers ......................................................................................................... 33
Semi-permanent vs. temporary fillers ...................................................................... 36
Semi-permanent fillers................................................................................................ 40
Safety outcomes for ageing ............................................................................................ 40
Permanent vs. temporary fillers ................................................................................ 40
Permanent fillers ......................................................................................................... 42
Semi-permanent vs. temporary fillers ...................................................................... 45
Semi-permanent fillers................................................................................................ 46
Efficacy outcomes for HIV-associated lipoatrophy ................................................... 47
Permanent vs. semi-permanent vs. temporary fillers............................................. 47
Permanent fillers ......................................................................................................... 53
Semi-permanent fillers................................................................................................ 54
Safety outcomes for HIV-associated lipoatrophy....................................................... 64
Permanent vs. semi-permanent vs. temporary fillers............................................. 64
Permanent fillers ......................................................................................................... 67
Semi-permanent fillers................................................................................................ 68
Ongoing and unpublished trials..................................................................................... 76
5. Discussion ......................................................................................................................... 78
Limitations of the evidence ............................................................................................ 78
Efficacy outcomes ........................................................................................................... 79
Ageing ........................................................................................................................... 80
HIV-associated lipoatrophy....................................................................................... 80
Safety outcomes ............................................................................................................... 82
Ageing ........................................................................................................................... 82
HIV-associated lipoatrophy....................................................................................... 83
Other considerations....................................................................................................... 84
Future research................................................................................................................. 86
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6. Conclusions and Recommendations............................................................................. 88
Classification and recommendations ............................................................................ 88
Safety............................................................................................................................. 88
Efficacy......................................................................................................................... 88
Clinical and research recommendations .................................................................. 89
Acknowledgments ........................................................................................................... 89
References ............................................................................................................................. 91
Appendix A – Excluded studies .................................................................................. 101
Appendix B – Study profile tables .............................................................................. 104
Appendix C – Treatment data ..................................................................................... 128
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List of Tables
Table 1. Classification of dermal fillers by composition .................................................. 5
Table 2. Classification of injectable semi-permanent and permanent dermal fillers.... 6
Table 3. Databases searched............................................................................................... 14
Table 4. NHMRC hierarchy of evidence .......................................................................... 16
Table 5. Summary of included studies .............................................................................. 19
Table 6. Dermal fillers for ageing - number of injections or treatments ..................... 21
Table 7. Dermal fillers for HIV-associated lipoatrophy – number of injections or
treatments .............................................................................................................................. 22
Table 8. Semi-permanent vs. temporary fillers for ageing – observer ratings of
appearance............................................................................................................................. 37
Table 9. Semi-permanent vs. temporary fillers for ageing – patient satisfaction ........ 38
Table 10. Semi-permanent vs. temporary fillers for ageing – would recommend
treatment................................................................................................................................ 39
Table 11. Semi-permanents filler for ageing - patient satisfaction ................................ 40
Table 12. Semi-permanent vs. temporary fillers - adverse event reporting: oedema
(swelling), erythema (bruising) and eccymosis (bruising) ............................................... 46
Table 13. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated
lipoatrophy - changes in skin thickness ............................................................................ 48
Table 14. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated
lipoatrophy – observer ratings of appearance.................................................................. 49
Table 15. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated
lipoatrophy - patient satisfaction........................................................................................ 50
Table 16. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated
lipoatrophy – quality of life outcomes .............................................................................. 52
Table 17. Permanent fillers for HIV-associated lipoatrophy – quality of life outcomes
................................................................................................................................................. 54
Table 18. Semi-permanent fillers for HIV- associated lipoatrophy - changes in skin
thickness ................................................................................................................................ 57
Table 19. Semi-permanent fillers for HIV- associated lipoatrophy - observer ratings
of appearance........................................................................................................................ 58
Table 20. Semi-permanent fillers for HIV- associated lipoatrophy - patient
satisfaction............................................................................................................................. 60
Table 21. Semi-permanent fillers for HIV-associated lipoatrophy - quality of life and
other psychological outcomes ............................................................................................ 63
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Table 22. Permanent vs. semi-permanent vs. temporary fillers - adverse event
reporting: oedema (swelling) and eccyhmosis (bruising)................................................ 66
Table 23. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event
reporting: oedema (swelling) and ecchymosis (bruising) and erythema (redness)...... 72
Table 24. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event
reporting: other events ........................................................................................................ 75
Table 25. Ongoing and unpublished studies – Ageing ................................................... 76
Table 26. Ongoing and unpublished studies – HIV-associated lipoatrophy............... 77
List of Figures
Figure 1. Process for selection of studies retrieved from the literature databases...... 18
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Executive Summary
Objective
The objective of this systematic review is to assess the safety and efficacy of
injectable semi-permanent and permanent dermal fillers in comparison with other
injectable methods of facial augmentation for age-related wrinkle reduction, and for
aesthetic improvement of human immunodeficiency virus (HIV)-associated facial
lipoatrophy, through a systematic review of the literature.
Methods
Search strategy – Studies were identified by searching EMBASE, CINAHL, PubMed,
The Cochrane Library and Current Contents from inception to July 2008. The
Clinical Trials Database (US), NHS Centre for Research and Dissemination
Databases (UK), National Research Register (UK), Meta Register of Controlled
Trials, and the Australian Clinical Trials Registry were also searched in July 2008.
Additional articles were identified through reference sections of the retrieved studies.
Study selection – Systematic reviews, randomised controlled trials (RCTs), nonrandomised comparative studies and case series of at least 40 patients reporting the
use of injectable semi-permanent and permanent dermal fillers for age related lines
and wrinkles, and for HIV-associated facial lipoatrophy were included for review.
Efficacy outcomes included changes in skin thickness, observer ratings of
appearance, success of treatment, patient/practitioner satisfaction and quality of life.
Safety outcomes included mortality, allergic reactions, granuloma formation, palpable
lumpiness, abscess formation and infections.
Data collection and analysis – Data from the included studies were extracted by an
ASERNIP-S researcher using standardised data extraction tables developed a priori
and checked by a second researcher. Statistical pooling was not appropriate due to
the study and result heterogeneity.
Results
A total of 20 studies were included in this review: four RCTs, one pseudo-RCT, two
non-randomised comparative studies, and 13 case series. The comparator used in the
comparative studies was often a temporary filler, which by their nature do not last as
long as permanent or semi-permanent fillers and have different mechanisms of
action.
For age related lines and wrinkles, and for HIV-associated facial lipoatrophy patients,
permanent and semi-permanent dermal fillers increased skin thickness or improved
subjective ratings of appearance and resulted in high patient satisfaction.
Long term efficacy data were scarce, but appeared good in the few studies that
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reported it.
There was great variation in the level of adverse event reporting for both
interventions. In general, many adverse events were transient and mild in nature with
the majority being associated with the injection process and resolving within a matter
of days. Lumps were reported many of the studies included in the review but
received little follow-up. Long term safety was limited and hence could not be
determined.
Classification and Recommendations
On the basis of the evidence presented in this systematic review, the ASERNIP-S
Review Group agreed on the following classifications and recommendations
concerning the safety and efficacy of semi-permanent and permanent dermal fillers.
Classifications
Evidence rating
The evidence-base in this review for the use of permanent and semi-permanent
dermal fillers for age-related lines and wrinkles is poor, and for HIV-associated
lipoatrophy is average.
The review was limited by the lack of a valid comparator for long term outcomes.
The included studies were of variable quality, and did not employ similar study
protocols. This variation prevented statistical pooling and limited the conclusions
which could be drawn.
Efficacy
The treatment of age related lines and wrinkles, and the effects of HIV-associated
lipoatrophy with permanent and semi-permanent dermal fillers is more efficacious
than with temporary fillers in those studies that compared them. Case series evidence
suggests that permanent and semi-permanent dermal fillers achieve their objective,
which is to decrease the visible (objective or subjective) effects of age related changes
for HIV-associated facial lipoatrophy, with high patient satisfaction.
Safety
From the limited data included in this systematic review, the safety of permanent and
semi-permanent dermal fillers appear at least as safe as temporary fillers in the short
term in those studies that compared them. Long term safety could not be
determined.
Clinical and Research Recommendations
It is recommended that further research be done into:
•
Long term efficacy of permanent and semi-permanent dermal fillers
•
Long term safety of permanent and semi-permanent dermal fillers, including the
nature and outcomes of lumps
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•
Facial changes around permanent and semi-permanent dermal fillers, and
whether the face can adequately accommodate them long term
•
Potential gender differences in response to permanent and semi-permanent
dermal fillers
•
Short and long term quality of life outcomes after permanent and semipermanent dermal filler treatment
•
The development, and/or validation of assessment tools for use in cosmetic
intervention studies
•
The development of training standards to aid physicians with injection
techniques and product placement
Important note
The information contained in this report is a distillation of the best available evidence
located at the time the searches were completed as stated in the protocol.
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The ASERNIP-S Classification System
Evidence Rating
The evidence for ASERNIP-S systematic reviews is classified as Good, Average or
Poor, based on the quality and availability of this evidence. High quality evidence is
defined here as having a low risk of bias and no other significant flaws. While high
quality RCTs are regarded as the best kind of evidence for comparing interventions,
it may not be practical or ethical to undertake them for some surgical procedures, or
the relevant RCTs may not yet have been carried out. This means that it may not be
possible for the evidence on some procedures to be classified as good.
Good
Most of the evidence is from a high quality systematic review of all relevant
randomised trials or from at least one high quality RCT of sufficient power. The
component studies should show consistent results, the differences between the
interventions being compared should be large enough to be important, and the
results should be precise with minimal uncertainty.
Average
Most of the evidence is from high quality pseudo-RCTs, or from non-randomised
comparative studies without significant flaws, such as large losses to follow-up and
obvious baseline differences between the comparison groups. There is a greater risk
of bias, confounding and chance relationships compared to high-quality RCTs, but
there is still a moderate probability that the relationships are causal.
An inconclusive systematic review based on small RCTs that lack the power to detect
a difference between interventions and RCTs of moderate or uncertain quality may
attract a rating of average.
Poor
Most of the evidence is from case series, or studies of the above designs with
significant flaws or a high risk of bias. A poor rating may also be given if there is
insufficient evidence.
Safety and Efficacy Classification
Safety
At least as safe compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is at least as safe as the comparator.
Safety cannot be determined
This grading is given if the evidence is insufficient to determine the safety of the
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new intervention.
Less safe compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is not as safe as the comparator.
Efficacy
At least as efficacious compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is at least as efficacious as the comparator.
Efficacy cannot be determined
This grading is given if the evidence is insufficient to determine the efficacy of
the new intervention.
Less efficacious compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is not as efficacious as the comparator.
Research Recommendations
It may be recommended that an audit or a controlled (ideally randomised) clinical
trial be undertaken in order to strengthen the evidence base.
Clinical Recommendations
Additional recommendations for use of the new intervention in clinical practice may
be provided to ensure appropriate use of the procedure by sufficiently qualified/
experienced centres and on specific patient types (where appropriate).
* A comparator may be the current ‘gold standard’ procedure, an alternative procedure, a non-surgical
procedure or no treatment (natural history)
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The ASERNIP-S Review Group
ASERNIP-S Director
Professor Guy Maddern
ASERNIP-S
Royal Australasian College of Surgeons
Stepney SA 5069
Protocol Surgeon
Mr. Rodney Cooter
1st Floor Waverley House
360 South Terrace
Adelaide SA 5000
Advisory Surgeon
Mr. Keith Mutimer
206 New Street
Brighton VIC 3168
Other-specialty Surgeon
Mr. John Graham
St Vincents Medical Centre
Suite 4, Level 2, 20 Dalley Street
Lismore NSW 2480
ASERNIP-S Researcher
Ms. Lana Sturm
ASERNIP-S
Royal Australasian College of Surgeons
Stepney SA 5069
Conflict of Interest
No conflicts of interest were declared.
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Abbreviations and Acronyms
ABCD
Adult AIDS Clinical Trails Group Assessment of Body Change
and Distress (questionnaire)
AFT
Autologous fat transfer
AIDS
Acquired immune deficiency syndrome
ANRS
Agence Nationale de Recherche sur le SIDA
ASERNIP-S
Australian Safety and Efficay Register of New Interventional
Procedures - Surgical
BDI
Beck Depression Inventory
CaHA
Calcium hydroxylapatite
CI
Confidence interval
CT
Computed tomography
DEAE
Dextran particles
EMA
Ethylmethacrylate
ePTFE
Expanded polytetrafluoroethylene
FDA
Food and Drug Administration
FFAS
Facial Fold Assessment Scale
FSTV
Facial soft tissue volume
GAIS
Global Aesthetic Improvement Score
HA
Hyaluronic acid
HAART
Highly active antiretroviral therapy
HEMA
Hydroxyethylmethacrylate
HIV
Human immunodeficiency virus
LIS
Liquid injectable silicone oil (polydimethylsiloxane oil)
MBSRQ-AS
Multidimensional Body-Self Relations Questionnaire – Appearance
Scales
MOS-HIV
Medical Outcomes Study-HIV
NHMRC
National Health & Medical Research Council
NLF
Nasolabial folds
NR
Not reported
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NRTI
Nucleoside reverse transcriptase inhibitor
NS
Not significant
PAAG
Polyacrylamide gel
PI
Protease inhibitor
PICO
Patient population, intervention, comparator intervention and
outcomes
PLA
Polylactic acid
PMMA
Polymethylmethacrylate
PTFE
Polytetrafluoroethylene
PVA
Polyvinyl alcohol
PVOH
Polyvinylhydroxide
PVP
Polyvinylpyrrolidone
RCT
Randomised controlled trial
RNA
Ribonucleic acid
SD
Standard deviation
SF-36
Short Form 36-item health survey
TCT
Total cutaneous thickness
TGA
Therapeutic Goods Administration
VAS
Visual analogue scale
WSRS
Wrinkle Severity Rating Scale
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1. Introduction
Objective
To assess the safety and efficacy of semi-permanent and permanent dermal fillers in
comparison with other methods of facial augmentation for age-related wrinkle
reduction and for aesthetic improvement of human immunodeficiency virus (HIV)associated facial lipoatrophy through a systematic review of the literature.
The skin
The skin has two main layers, the epidermis and dermis. The epidermis gives rise to
the outer barrier layer of dead cells, the stratum corneum, through terminal
differentiation of keratinocytes, which are the predominant cell type. Below the
epidermis is the dermis. This layer contains the blood vessels, lymphatics, nerves, and
deeper portions of the hair follicles and glands that originate from the epidermis. The
dermis is composed largely of extracellular matrix and gives skin its strength and
elasticity (Hotta 2004). Below the dermis is a subcutaneous layer of fatty tissue that
gives contour to the skin.
The ageing process
The process of ageing leads to visible changes in facial contour as there is a loss of
subcutaneous volume. Diminished dermal vasculature and blood flow, combined
with a reduction of dermal extracellular matrix (including collagen, hyaluronic acid
and elastin), lead to progressive thinning of the dermis. This results in a loss of
elasticity and underlying atrophy of the natural fat pads. The soft tissue that encircles
bony skeleton slowly collapses so that these bony landmarks are more visible
(Chisholm 2005). This is exacerbated by the effects of gravity, which results in
sagging of the soft tissues relative to their substructure (Mandeville & Rubin 2004).
The full fibrous tissue associated with youthful appearance is replaced by less dense,
less supple and less supportive tissue (Chisholm 2005).
Among the most noticeable changes in the face as it ages, is the development of
wrinkles (rhytids) and furrows, and the increased visibility of blood vessels. Critical
changes in the perioral area can include vertical rhytids, increased prominence of
nasolabial folds (crease that runs from nose to the corner of the mouth), ptosis of the
oral commissures (sagging of lines from the corners of the mouth), thinning of the
lips, and flattening of the upper lip with less definition of the Cupid’s bow (Chisholm
2005). Transverse forehead lines become prominent and can be accompanied by a
lowering of the eyebrows.
HIV-associated lipodystrophy syndrome
With the long-term use of highly active antiretroviral therapy (HAART), infection
SECTION 1 INTRODUCTION
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with human immunodeficiency virus (HIV) has been transformed (in the Western
world) to a chronic disease associated with a variety of metabolic complications
(Gkrania-Klotsas & Klotsas 2007). These include hyperlipidaemia, insulin resistance,
diabetes mellitus, and body fat changes (Samaras 2008).
Body fat changes, commonly referred to as lipodystrophy, are known to occur in
20% to 80% of HIV-infected patients receiving antiretroviral therapy (Grinspoon &
Carr 2005). The mechanisms of antiretroviral-associated lipoatrophy in patients with
HIV infection remain poorly understood.
The clinical features of lipodystrophy vary, and can present in different ways:
•
Peripheral lipoatrophy - the loss of subcutaneous fat, resulting in hollowing of
the cheeks, wasting of extremities or flattening of the buttocks (Gkrania-Klotsas
& Klotsas 2007).
•
Central lipohypertrophy - manifesting mainly as increased abdominal girth (and
less frequently as an enlarged dorso-cervical fat pad). The increase in abdominal
girth is caused by increased amounts of visceral adipose tissue (Saint-Marc et al.
2000). The development of increased amounts of visceral adipose tissue is an
acknowledged risk factor for cardiovascular disease, diabetes, hypertension and
related conditions (Montague & O'Rahilly 2000).
•
A combination of the above. Although some patients develop both lipoatrophy
and lipohypertrophy, this is not universal (Falutz 2007). The presence of
lipoatrophy does not correlate with that of lipohypertrophy (Bacchetti et al.
2005).
•
Unilateral or bilateral breast enlargement due to increased glandular fatty tissue
(Falutz 2007).
These body-shape changes should not be confused with the wasting syndrome of
acquired immune deficiency syndrome (AIDS), as they occur more frequently among
patients responding to HIV therapy and are not accompanied by substantial loss of
lean tissue mass (Gkrania-Klotsas & Klotsas 2007).
Body fat changes were initially ascribed to protease inhibitors (PIs), but it is now
clear that nucleoside reverse transcriptase inhibitors (NRTIs) also contribute to
lipodystrophy syndrome (Baril et al. 2005). The development of body-shape changes
and metabolic toxicities is partially related to the individual drugs included in the
various HAART regimens (Falutz 2007), in association with other risk factors. These
include non-HIV-related factors such as gender (Martinez et al. 2001) and body
composition prior to infection, as well as disease-specific factors such as the nadir
level of CD4+ lymphocytes and duration of HIV infection (Lichtenstein et al. 2001).
Lipoatrophy, especially of the buccal fat pads (cheeks), can affect the quality of life
and body image of patients, as it potentially contributes to stigmatisation, and a
perception of being recognisable as a person infected with HIV (Oette et al. 2002;
SECTION 1 INTRODUCTION
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Power et al. 2003). As a result of this, the presence of lipoatrophy has been
demonstrated to negatively affect a patient’s adherence to drug treatment regimes
(Corless et al. 2005; Duran et al. 2001).
Non-surgical therapies for facial augmentation
Facial rejuvenation and augmentation techniques include topical therapies as well as
injectable agents. These products and procedures can be used alone or in
combination, depending on the desired result.
For any procedure, practitioners must use caution when using products derived from
animal sources. There is a risk of delayed-type hypersensitivity reactions with animal
products, and the use of injectable bovine collagen requires a sensitivity test to be
performed on each potential recipient in the weeks prior to use. Skin tests are
positive in approximately 3% of cases, and 1.2 % of patients with non-reactive skin
tests may eventually develop an immune response (Mandeville & Rubin 2004).
Additionally, personal, cultural, religious and ethical issues may preclude some
patients from receiving animal (as well cadaver) derived products.
Topical therapies
Products and non-surgical procedures aimed at skin rejuvenation for age-related
defects include:
•
Topical therapies, such as moisturisers (Rawlings et al. 2004), retinoids (Cho et al.
2005), bleaching agents, hydroxy acids (Tung et al. 2000) and growth factors
(Ehrlich et al. 2006).
•
Energy-based therapies, such as laser and radiofrequency (Doshi & Alster 2005;
Railan & Kilmer 2005).
•
Light-based therapies, both visible and infrared (Hedelund et al. 2006; Goldberg
& Cutler 2000).
Other topical procedures include chemical peels (Fulton & Porumb 2004) and microdermabrasion (Koch & Hanasono 2001), which address superficial rhytids and
variations in pigmentation by debriding the superficial layers of the epidermis.
Dermabrasion and laser resurfacing address deeper rhytids by ablating into the
papillary dermis and stimulating even regrowth of the epidermis (Ang & Barlow
2002; Gold 2003). However, these techniques are only appropriate for correcting
age-related deficiencies in the most superficial layers of the skin, as they rely on the
removal of all the layers of the epidermis (Railan & Kilmer 2005). Deeper lines and
furrows are not significantly improved by these methods as they do not augment the
skin.
Injectable agents
Injectable agents for facial rejuvenation fall into two categories; paralytic agents for
the treatment of dynamic rhytids, and dermal-filling agents for the treatment of static
SECTION 1 INTRODUCTION
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rhytids or volume defects (Mandeville & Rubin 2004). Injectable muscle relaxants,
such as botulinum toxin A, work by paralysing the wrinkle-causing muscles to create
an improved appearance. The results are only temporary and the treatment does not
address the depressions typically caused by tissue loss. Botulinum toxin type A is
most commonly used for rejuvenation of the upper third of the face (Narins &
Bowman 2005) and is often used in conjunction with other facial rejuvenation
techniques (Coleman & Carruthers 2006).
Dermal fillers
Injectable dermal fillers and synthetic dermal implants have been developed to
address volume loss and contour defects and appear to be useful in the lower third of
the face (Narins & Bowman 2005). Dermal fillers are injected or inserted into the
skin to give the face a fuller look, as opposed to the pulled, flat, two-dimensional
look that is sometimes associated with facelift surgery (rhytidectomy) (Klein & Elson
2000; de Maio 2004). Facelifts, which eliminate loose skin folds in the neck and
rhytids in the cheeks by the removing tissue and tightening or ‘lifting’ of the skin, do
not augment or ‘fill’ the skin (Senglemann & Tull 2006).
Dermal fillers can complement surgical and topical treatments to give a greater and
longer lasting aesthetic result (de Maio 2004). A combination of filler materials can
be injected or inserted to give a natural contour to the face (de Maio 2004; Godin et
al. 2006).
Types of dermal fillers
Dermal fillers can be temporary, semi-permanent or permanent and can be classed
on the basis of biodegradability or their mechanism of action (Table 1). Permanence
of fillers refers to a lack of degradation of the in vivo material over time rather than to
a permanent cosmetic result. Permanent aesthetic results are seldom possible because
of continued tissue volume loss and other factors associated with the ageing face
(including continued HAART therapy in the case of HIV-infected patients).
The longevity of the effects of dermal filler products vary and are generally based on
their composition and level of biodegradability within the tissues. Permanent and
semi-permanent dermal fillers were developed as an alternative to biodegradable
dermal fillers to increase the durability of the aesthetic effect, with a lower risk, less
expense and a faster recovery time (Senglemann & Tull 2006).
Fillers that are placed superficially can be injected without anaesthesia, whereas
deeper implants, such as those used for lip augmentation, usually require nerve
blockade (Narins & Bowman 2005). Autologous fat transfer (AFT) requires local or
general anaesthesia or deep sedation depending on the volume of fat harvested and
the harvesting location. Harvesting is done using cannulae and syringes under
negative pressure. Other materials, such as expanded polytetrafluoroethylene
(ePTFE), are inserted in the tissues through small incisions under local anaesthesia.
SECTION 1 INTRODUCTION
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Table 1. Classification of dermal fillers by composition
Temporary biodegradable
(< 1 year)
Semi-permanent biodegradable
(1 - 2 years)
Permanent non-biodegradable
(> 2 years)
Autologous fat transfer (AFT)
Calcium hydroxylapatite (CaHA)
Collagen implant – porcine
Acellular dermis - cadaver
Dextran particles (DEAE)
Silicone oil (polydimethylsiloxane oil) (LIS)
Collagen – human, bovine, porcine
Hydroxyethylmethacrylate (HEMA)
Polyacrylamide gel (PAAG)
Cultured fibroblasts - human
Polylactic acid (PLA)
Polymethylmethacrylate (PMMA)
Fascia autograft - human
Polyvinyl alcohol (PVA)
Expanded polytetrafluoroethylene (ePTFE)
Hyaluronic acid (HA) – avian,
bacterial
Polytetrafluoroethylene (PTFE)
Adapted from Moretti & Greenwood (2006) and Broder & Cohen (2006).
Temporary fillers
Most biological materials such as collagen, hyaluronic acid (HA) gels and humanderived products last temporarily, persisting generally for less than 12 months before
being resorbed into the tissues (Rohrich et al. 2003; Carruthers 2006). To maintain
the visible filling effect produced by these materials, patients must receive regular
reapplications. Temporary fillers can be appealing to patients who want to
experiment with soft tissue augmentation, but do not necessarily want to commit to
their new look.
Semi-permanent fillers
To achieve a longer visible filling effect, slowly resorbable substances such as
polylactic acid (PLA), calcium hydroxylapatite (CaHA), hydroxyethylmethacrylate
(HEMA) and dextran (DEAE) have been used (Morhenn et al. 2002). These
substances slowly biodegrade and typically persist for one to two years in the tissues.
In some cases, multiple injections may initially be required to get the desired effect.
Over time, this may need to be repeated because the visible effect deteriorates as the
filler breaks down.
Permanent fillers
To address the issue of materials being resorbed over time, non-biodegradable
materials have emerged as dermal filler materials. Liquid injectable silicone (LIS),
certain polyacrylamide gels (PAAG), polymethylmethacrylate (PMMA) and
polytetrafluoroethylene (PTFE) are non-resorbable and remain in the tissues
permanently (Carruthers 2006; Morhenn et al. 2002). Used correctly, permanent
fillers offer certain advantages over non-permanent ones, particularly as they do not
require touch-up sessions once the expected result has been achieved (Haneke 2004).
However, permanent dermal fillers are much more technique sensitive than
temporary fillers.
Table 2 provides a summary and taxonomy of the semi-permanent and permanent
dermal fillers available in Australia and the US.
SECTION 1 INTRODUCTION
5
Table 2. Classification of injectable semi-permanent and permanent dermal fillers
Type of Filler
Product Name
Mode of Action
Longevity
Aust TGA
Approval*
US FDA
Approval†
SUSPENSION OF INSOLUBLE POLYMER FRAGMENTS OR MICROSPHERES AND A RESORBABLE LIQUID
SILICONE PARTICLES
100 – 600 µm irregular shaped, solid
silicone particles suspended in a
polyvinylpyrrolidone (PVP) carrier
Bioplastique™
Bioplasty Inc, St Paul, MN, USA
Injected into subcutaneous tissue (below dermis).
Collagen encapsulates and localises the particles. Particles
remain in tissue and produce a local foreign body host response,
ending in fibrosis, which contributes to the filling effect.
Not for fine wrinkles.
No allergy test needed.
Permanent
No
No
POLYMETHYLMETHACRYLATE
(PMMA) MICROSPHERES
30-42 µm smooth particles of PMMA
suspended in bovine collagen
Arte-Fill®
Artes Medical, Inc, San Diego, CA,
USA.
Superceeded products:
Artecoll & Arteplast
Injected into sub-dermis (at junction of dermis and subcutaneous
fat).
Collagen encapsulates and localises the particles. Collagen
degraded in 1-3 months and replaced by body’s own connective
tissue. Particles remain in tissue and produce a local foreign body
host response.
Final result takes up to 1 – 2 years.
Not for fine wrinkles.
Allergy test recommended.
Permanent
No
Yes
P020012
Approved
27/10/2006
POLYVINYLHYDROXIDE (PVOH)
PARTICLES IN POLYACRYLAMIDE
GEL (PAAG)
5 – 80 µm porous PVOH
microspheres suspended in PAAG
Evolution™
ProCytech Labs, Bordeaux, France
Gel is phagocytosed. Microparticles surrounded by fibrous
capsule. After 9 months implant is totally infiltrated by
macrophages, fibroblasts and giant cells.
No allergy test needed.
Permanent
No
No
HYDROXYETHYLMETHACRYLATE
(HEMA) AND ETHYLMETHACRYLATE (EMA) PARTICLES IN
HYALURONIC ACID (HA) GEL
Smooth, non-spherical acrylic hydrogel
(HA) particles (copolymer of
hydroxyethylmethacrylate (HEMA) and
ethylmethacrylate (EMA)) and crosslinked hyaluronic acid
DermaLive® 45 – 65 µm
DermaDeep® 80 – 110 µm
Dermatech, Paris, France
DermaLive injected into deeper layers of dermis (junction of
dermis and hypodermis).
DermaDeep injected into subperiosteal layer or hypodermis.
Hyaluronic acid is completely broken down over months. Particles
produce a local foreign body host response.
No skin test required.
Semi-Permanent
No
No
6
Table 2. Classification of injectable semi-permanent and injectable permanent dermal fillers (continued)
Type of Filler
Product Name
Mode of Action
Longevity
Aust TGA
Approval*
US FDA
Approval†
Injected into deep dermis or subcutaneous space.
Local foreign body host response.
Polylactic acid is completely broken down within months. New
collagen growth can last for up to 2 years or longer.
No skin test necessary.
Semi-Permanent
Sculptra
ARTG No:
151888
Product Id:
241585
Sponsor Name:
Sanofi-Aventis
Australia Pty Ltd
Yes
P030050 (HIV
lopoatrophy)
Approved
3/8/2004
Semi-Permanent
No
Yes
P050037 (HIV
lipoatrophy)
P050052
(ageing)
Approved
22/12/2006
SUSPENSION OF SLOWY DEGRADABLE POLYMER MICROSPHERES AND A RESORBABLE LIQUID
POLYLACTIC ACID (PLA)
MICROSPHERES
1 – 50 µm PLA microspheres in
mannitol/ carbomethoxycellulose gel
Sculptra®
Dermik Laboratories, Berwyn, PA
CALCIUM HYDROXYLAPATITE
(CaHA) PARTICLES
25 - 45 µm calcium hydroxylapatite
(CaHA) microspheres suspended in
cellulose gel.
Radiesse®
BioForm Medical, Inc. Franksville,
Wisconsin
(formerly Radiance FN)
Injected subcutaneously (sub-dermis).
Product incorporated by tissues and then replaced by collagen.
CaHA broken down into calcium and phosphate.
Good for deeper folds.
No skin test necessary.
DEXTRAN PARTICLES IN HA
40 – 60 µm dextran micro beads
suspended HA gel
Reviderm® Intra
Rofil Medical International, Breda, The
Netherlands
After injection, there is in an initial macrophage response followed
by fibroblast proliferation and new collagen formation.
Semi-Permanent
No
No
80-120 µm micro particles with a
positively charged surface suspended
in cross linked hyaluronic acid
Matridex®
BioPolymer GmbH & Co. KG
Stimulates new collagen production.
Semi-Permanent
No
No
Biodegradable cross-linked HA gel with
positively charged dextranomer beads
ReDexis® (formerly HylaDex)
Prollenium Medical Technologies Inc,
ON, Canada
Positively charged dextranomer beads attract body’s own
collagen and elastin to injection site. Results in filling through
cross-linked HA and collagen regeneration. HA broken down, but
microspheres remain permanently.
Semi-Permanent
No
No
7
(Also known as New-Fill™)
Table 2. Classification of injectable semi-permanent and injectable permanent dermal fillers (continued)
Type of Filler
Product Name
Mode of Action
Longevity
Aust TGA
Approval*
US FDA
Approval†
HOMOGENOUSLY BUILT POLYMER GEL (SILICONE GEL , POLYACRYLAMIDE HYDROGEL – NO PARTICLES/SPHERES)
LIQUID SILICONE
Injectable liquid silicone -poly
dimethylsiloxane
Silikon™ 1000, Alcon Laboratories Inc,
Fort Worth, TX, USA
PMS 350®, Vikomed, Meinerzhagen,
Germany
VitreSil® 1000 & SilSkin® 1000, RJ
Development Corp. Peabody, MA, USA
Adatosil® 5000, Bausch & Lomb Inc
Injected into sub-dermis.
Each micro-droplet induces its own fibroblastic response resulting
in augmentation by forming a fibrous capsule around each
silicone particle.
No skin test needed.
Permanent
No
No
POLYACRYLAMIDE GEL (PAAG)
Polyacrylamide gel: 95% sterile water
and 5% hydrophilic, cross-linked
polyacrylamide polymer
Aquamid® Contura, Soeberg, Denmark
(aka Formacryl (Russia), Interfall
(Ukraine), Royamid (Sweden),
BioFormacryl, Argiform, Kosmogel)
Phigel®
Outline™, Original (2 years), Ultra (5
years) & Fine Line (1 year), ProCytech
Labs, Bordeaux, France
Beautical 2® (2 years) &
Beautical 5® (5 years), Rofil Medical
International, Breda, The Netherlands
Eutrophill®, Mediform
Aquamid injected subcutaneously.
Permanent filler where the volume of the implant is given by water
not from a solid product. Body accepts the gel readily and forms a
thin membrane around the implant which helps to keep it in place;
as the gel is very elastic it moves with all facial expressions.
Aquamid marketed under different names in different countries.
Similar products available with different polyacrylamide/water
ratio.
Permanent
No
No
Polyalkylimide gel (based on
polyacrylamide gel): 96% sterile water
and 4% hydrophilic, cross-linked
polymer (poly-Alkyl-Imide)
Bio-Alcamid®
Polymekon, Biotech Industrie, Milan,
Italy
Injected into subcutaneous tissue.
Product becomes covered by thin collagen capsule which
completely surrounds the gel, isolating it from the host tissues.
Does not become integrated into surrounding tissues and can be
removed. Volume of the implant given by water not from a solid
product.
Permanent
No
No
Based on polyacrylamide gel: 92%
sterile water and 8% polyvinyl alcohol
Bioinblue®
Polymekon, Biotech Industrie, Milan,
Italy
As for polyacrylamide gel
Semi-Permanent
No
No
*As found on Australian Therapeutic Goods Administration website: www.tga.gov.au
†
As found on US Food and Drug Administration website: www.fda.gov
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How dermal fillers work
Dermal fillers can be classed by their mechanism of action as either volumisers (fillers) or
stimulators (sculptors) (Thioly-Bensoussan 2006; Carruthers 2006). When injected into
the skin, volumisers increase facial volume and fill out the skin directly. Volumisers are
normally of minimal viscosity and are injected into the upper layers of the dermis to fill
superficial lines (Carruthers 2006). They do not initiate a chronic immune response and
hence cause little foreign body reaction in the tissues. Volumisers include silicone,
collagen, certain PAAGs and HA.
Stimulators can also directly create volume, but primarily, they stimulate the tissues to
create a foreign body reaction over a limited time. This stimulates long-term or
permanent collagen deposition. Stimulators include PLA, DEAE, CaHA, HEMA and
PMMA. Fillers such as PLA and DEAE cause a foreign body reaction for a limited time
before they are absorbed, whereas PMMA is non-biodegradable and stimulates collagen
deposition indefinitely (Carruthers 2006). Stimulators are intended for deeper lines and
furrows, and are generally injected into the deep dermis or upper subcutaneous tissue
(Thioly-Bensoussan 2006). Some fillers contain both volumising and stimulating
components and fall into both categories.
The majority of stimulators consist of microparticles suspended in a carrier gel. The
carrier gel provides some distance between the particles and holds them in place so they
do not move during the initial phases of wound healing. According to their chemical
composition, size, shape, surface structure and surface charge, different microparticles
demonstrate different biocompatibility (Marler et al. 2000). According to the chemical
composition and surface charge of the microparticle, the tissue reacts either with protein
attachment and consequent encapsulation with fibrous tissue, or with an attempt to
phagocytose the particle (Morhenn et al. 2002). Microparticle size determines whether it
is phagocytosable, and hence biodegradable. Small particles (< 60 µm) are phagocytosed,
whereas larger particles remain in the tissue (Ersek & Beisang, 1991). Macrophages
containing phagocytosed particles may migrate toward distant organs such as the spleen,
the lymph nodes or liver (Morhenn et al. 2002; Tomazic-Jezic et al. 2001).
Smooth-walled microparticles become enveloped by a fibrous capsule that holds them in
place. A monolayer of macrophages then surrounds the surface of the microparticle.
Fibroplasia is initiated and results in fibroblast adhesion and collagen synthesis, resulting
in augmentation (Laeschke 2004). There is no chronic inflammation, and the
microparticle becomes embedded in the ‘new’ collagen.
Microparticles with rough surfaces and irregular shape encourage tissue ingrowth and
create a foreign body reaction (Lemperle et al. 2004). Activated macrophages and tissue
monocytes release cytokines, such as angiogenic growth factors, to induce the invasion of
capillaries into the granulation tissue. Collagen is then synthesised, which forms a
scaffold for cellular reconstruction and remodelling in this tissue.
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Demand for cosmetic procedures
The number of people undergoing cosmetic procedures continues to grow. In the US,
nearly 11.7 million surgical and non-surgical cosmetic procedures were performed in
2007 (American Society of Aesthetic Plastic Surgery 2007). In 2007, a study by the
American Society of Aesthetic Plastic Surgery found that the overall number of cosmetic
procedures performed in the US increased 457% since 1997. This study also found that
the most frequently performed procedure in the US was botulinum toxin injections and
the most popular surgical procedure was liposuction (American Society of Aesthetic
Plastic Surgery 2007). Almost 54% of cosmetic procedures in the US in 2007 were
performed in office-based facilities; 28% in freestanding surgicentres; and 17% in
hospitals (American Society of Aesthetic Plastic Surgery 2007). Americans spent just over
$13 billion on cosmetic procedures; $8.3 billion of this being on surgical procedures, and
$4.7 billion on non-surgical procedures (American Society of Aesthetic Plastic Surgery
2007). No figures are available for facial augmentation procedures alone. There are no
accurate figures on how many procedures are performed each year.
Although it has been estimated that lipoatrophy occurs in 20 to 80% of people receiving
antiretroviral therapy (Grinspoon & Carr 2005), exact statistics regarding the numbers of
people living with facial lipoatrophy are not known. It is therefore difficult to comment
on the demand for dermal filler treatment for HIV-associated lipodystrophy. As the
development of HAART as an effective therapy for HIV an AIDS continues to
substantially reduce the death rate and increase life expectancy in those areas where these
drugs are widely available (Lohse et al. 2007), the number of people living with this
condition could be expected to increase, and therefore increase the number of people
seeking treatment . In Australia, it has been estimated that approximately 17,000 are
currently living with HIV and AIDS (up to 30 June 2007) (NCHECR, 2007) suggesting
that 20 – 80% of these people could seek treatment.
Australian cosmetic industry
In Australia, the cosmetic industry is largely self-regulated and there is little research on
clinical standards and skills required to perform cosmetic procedures (Health Care
Complaints Commission 1999). Additionally, there are no figures on the number of
cosmetic procedures conducted in Australia or their complication rates. Cosmetic and
plastic surgery are considered elective procedures and are not, with very few exceptions,
covered by Medicare or private health insurance plans.
Anyone with a medical degree can perform cosmetic surgery in Australia (Australian
Society of Plastic Surgeons 2006). The outcome of dermal filler products can be
influenced by the experience of the practitioner, indication and injection technique
(Haneke 2004; Narins & Bowman 2005). The relationship between a potential consumer
and service provider can be a direct one, without mediation or quality control by a
referring doctor. Consumers considering cosmetic procedures could potentially be at risk
in this unregulated field of medicine.
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Summary
Many people wish to improve the appearance of their face. Facial rejuvenation therapies,
which are minimally invasive and provide a long-lasting visible improvement, are very
appealing to people who want to improve their appearance. Topical therapies rejuvenate
the superficial layers of the skin, but do not address the lines and furrows associated with
the loss of subcutaneous volume that occur with either the ageing process or the effects
of HIV-associated lipoatrophy.
Dermal fillers address volume loss to give the face a fuller, more youthful appearance.
They have become a popular means of addressing volume loss and contour defects
resulting from ageing, photo-damage, disease, trauma and/or scarification (Senglemann et
al. 2006). Fillers that are biodegradable are resorbed over time by the tissues and require
repeat applications. Semi-permanent and permanent dermal fillers have emerged as
alternatives, to give patients a longer lasting or permanent effect. However, the potential
side effects and complications associated with these fillers have not been well
documented, may be difficult to manage, and can last as long as the filler. Thus, the aim
of this review is to assess the safety and efficacy of semi-permanent and permanent
dermal fillers, compared with other facial augmentation techniques, for the management
of lines and rhytids on the ageing face and for volume loss resulting from HAART
therapy for HIV infection.
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2. Methodology
Literature search protocol
Inclusion criteria
Articles were selected for inclusion in this systematic review on the basis of the following
criteria.
Participants
Humans recieving either injectable semi-permanent or permanent dermal fillers in the
face to reduce the visibility of lines, wrinkles and fat loss associated with ageing or with
HIV-associated facial lipoatrophy were included.
Studies reporting on patients with facial reconstruction, injury, scarring, disease (except
HIV-associated facial lipoatrophy), or a history of previous facial filling within three
months of the study were excluded.
Index intervention
Semi-permanent and permanent injectable dermal fillers.
Comparative intervention
Non-surgical, injectable methods of skin augmentation.
Outcomes
Studies that report at least one of the following outcomes were included:
Efficacy
Rhytid assessment factors which included, but were not limited to:
•
Dermal thickness measurements
•
Visual aesthetic changes
•
Photographic comparisons
Patient satisfaction factors which included, but were not limited to:
•
Patient satisfaction
•
Pain
•
Palpable lumpiness
Safety
Periprocedural and postprocedural mortality.
Periprocedural and postprocedural morbidity, which included, but was not limited to:
•
12
Granuloma formation
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•
Allergic reactions
•
Toxic/adverse effects
•
Histopathology
•
Migration, dislocation or resorption of filler
Types of studies
Systematic reviews, randomised controlled trials, pseudo-randomised controlled trials,
non-randomised comparative studies, and case series (with pre- and post- test outcomes)
with a total sample size of at least 40 patients were included for review.
Study design
Systematic reviews were defined as those studies that met all the following criteria as
defined by Cook et al. (1997):
1. Focused clinical question
2. Explicit search strategy
3. Use of explicit, reproducible and uniformly applied criteria for article selection
4. Critical appraisal of the included studies
5. Qualitative or quantitative data synthesis.
RCTs published after the search dates of the most recent systematic review were also
included.
RCTs and pseudo-randomised controlled trials were considered eligible for inclusion and
critical appraisal. A study was deemed to be an RCT if the author(s) explicitly stated
(usually by some variant of the term ‘random’ to describe the allocation procedure used)
that the groups compared in the trial were established by random allocation (Higgins &
Green 2008). Studies in which the method of allocation was known but was not
considered strictly random (for example, alternation, date of birth and medical record
number) were classified as pseudo-randomised controlled trials (Higgins & Green 2008).
When overlapping patient groups were reported in studies, only the paper quoting the
most complete data set was used.
Background information
Where appropriate; additional relevant published material in the form of letters,
conference material, commentary, editorials and abstracts were included as background
information.
Language restriction
Searches were restricted to studies reported in the English language.
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Literature search strategies
Databases searched and search terms used
Searches are shown in Table 3. Initial searches were conducted in August 2007. The
searches were updated in July 2008.
Table 3. Databases searched
Database
Platform
Cochrane Library
Current Contents
EMBASE
MEDLINE
CINAHL
PubMed
Clinical Trials Database (US)
NHS CRD (UK) NHS HTA (UK)
National Research Register (UK)
Current Controlled Trials (mRCT)
Ovid
Ovid
Ovid
Webspirs
Entrez
Edition and date searched
Initial search
Updated search
Issue 2, 2006
2007 to 2008
Searched 21 August 2007
2007 to 2008
Week 1 1980 to 21 August 2007 2007 to 2008
1966 to 21 August 2007
1982 to 21 August 2007
August 2007 to 7 July 2008
1953 to 21 August 2007
August 2007 to 7 July 2008
Searched 29 August 2007
10 July 2008
Searched 29 August 2007
10 July 2008
Issue 2, 2006
10 July 2008
Searched 29 August 2007
10 July 2008
Search terms
In The Cochrane Library the search terms used were:
dermal filler
soft tissue augmentation
For MEDLINE, EMBASE, CINAHL, Entrez-PubMed and Current Contents Connect
the following search terms were used:
1. (Artecoll OR Artefill OR Arteplast)
2. Bioplastique
3. (DermaLive OR DermaDeep)
4. (New Fill OR Newfill OR Sculptra)
5. (Radiesse OR Radiance FN)
6. Reviderm
7. Matridex
8. (Hylan dex OR Hylandex OR Hyla dex OR Hyladex OR ReDexis)
9. (Silikon OR Silskin OR VitreSil OR PMS 350 OR Adatosil)
10. (Aquamid OR Formacryl OR Interfall OR Royamid OR Bioformacryl OR
Argiform OR Kosmogel OR Beautical OR Phigel)
11. Eutrophill
12. (Bio Alcamid OR Bio Alkamid OR Bioalcamid)
13. Bioinblue
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14. Isalogen
15. Amazingel
16. (Permacol OR Fibroquel)
17. (Metacrill OR Bioplasty OR Aphrodite Gold)
18. (Outline OR Evolution)
19. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13
OR 15 OR 16 0R 17 OR 18.
20. Polyalkylimide
21. (calcium hydroxylapatite OR CaHA)
22. (sephadex OR Dextran OR DEAE)
23. (hydroxyethylmethacrylate OR HEMA)
24. (poly-L-lactic acid OR polylactic acid OR PLA)
25. (polyvinyl alcohol OR PVA)
26. (porcine dermal collagen)
27. (liquid silicon* OR injectable silicon* OR silicon* OR polydimethylsiloxane OR
LIS)
28. (polyacrylamide OR PAAG)
29. (polymethylmethacrylate OR PMMA)
30. 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29.
31. 30 AND (facial fill* OR facial volume OR cosmetic OR aesthetic OR facial
contouring OR facial implant* OR permanent fill* OR dermal fill* OR soft tissue
augmentation OR skin fill* OR soft tissue fill* OR dermal implant*)
32. 19 OR 31.
33. explode “bone”/all SUBHEADINGS
34. explode “teeth”/all SUBHEADINGS
35. explode “incontinence”/all SUBHEADINGS
36. 32 NOT (33 or 34 or 35)
The NHS CRD databases were searched using the above terms. The National Research
Register, Clinicaltrials.gov, Meta-Register and the Australian Clinical Trials Registry were
also searched using the above search terms for RCTs in progress.
Note: * is a truncation character that retrieves all possible suffix variations of the root
word e.g. surg* retrieves surgery, surgical, surgeon, etc. In Cochrane the truncation
character is *; in Current Contents, EMBASE, CINAHL and MEDLINE (Ovid) it is $.
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# is a wildcard symbol that substitutes for one required character in Current Contents,
EMBASE, CINAHL and MEDLINE (Ovid).
Selection of studies
One reviewer applied the inclusion criteria to identify those studies potentially eligible for
selection and appraisal based on their abstracts; these studies were retrieved as full text.
The selection criteria were then applied fully to the retrieved studies to identify those to
be appraised and included in the review. Full publications subsequently found not to
meet the inclusion criteria were excluded and reasons for exclusion are documented.
The bibliographies of all publications retrieved were manually searched for relevant
references that may have been missed in the database search (pearling).
Data extraction and appraisal of study methodology
Data from all included studies was extracted by one reviewer and checked by a second
reviewer using standardised data extraction tables that were developed a priori. The
studies included in the review were classified according to the National Health & Medical
Research Council (NHMRC) hierarchy of evidence (NHMRC 2000) (Table 4). Any
differences were resolved through discussion.
Table 4. NHMRC hierarchy of evidence
Level of Evidence
I
II
III-1
III-2
III-3
IV
(NHMRC 2000)
Study Design
Evidence obtained from a systematic review of all relevant randomised controlled trials.
Evidence obtained from at least one properly designed randomised controlled trial.
Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or
some other method).
Evidence obtained from comparative studies (including systematic reviews of such studies) with
concurrent controls and allocation not randomised, cohort studies, case-control studies, or
interrupted time-series with a control group.
Evidence obtained from comparative studies with historical control, two or more single arm studies,
or interrupted time series without a parallel control group.
Evidence obtained from case-series, either post-test or pre-test/post-test.
If systematic reviews were eligible for inclusion in the review, the methodology of these
secondary studies were evaluated with respect to the following factors:
•
Did the review ask a focused research question that incorporates the elements of the
patient population, intervention, comparator intervention and outcomes (PICO)?
•
Were the inclusion and exclusion criteria of included studies clearly stated?
•
Did the review use a clear and comprehensive search strategy?
•
Did the review assess the validity of included studies, and if so which validity criteria
were used?
•
Was the analysis or synthesis of the results appropriate?
•
Did the review include a summary of its main results, including a discussion of its
strengths and limitations?
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Where primary studies were eligible for inclusion in the review, the following criteria
were used to appraise their methodology, where applicable:
•
Were the objectives of the study clearly defined?
•
Were the inclusion and exclusion criteria clearly described?
•
Was there a clear description of the interventions used?
•
Were the characteristics of patients included in the study clearly described?
•
Were patients randomly assigned to intervention groups, and if so was the method of
randomisation described?
•
Was the randomised assignment of patients to intervention groups concealed from
both patients and staff administering the study until recruitment was complete?
•
Was an attempt made to blind both patients and staff responsible for measuring
outcomes of the intervention to the interventions patients received?
•
Was the number of patients who withdrew or dropped out of the study reported, and
were the characteristics of these patients described?
•
Were the main outcomes of interest adequately reported?
•
Were point estimates and measures of variability presented for the primary outcome
measures?
Non-randomised studies were assessed for other features of study design or execution
that may have introduced bias, such as comparability of patient groups at baseline,
method of patient selection and comparability of outcome assessment. Case series were
assessed in relation to patient selection and whether patients were selected consecutively
or retrospectively.
Data analysis
If the data were suitable for statistical pooling, meta-analyses of the main outcomes were
performed. If possible, the data were stratified into clinically relevant groups. Otherwise,
data for the main outcomes were reported narratively.
17
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3. Studies included in the review
Literature search results
Details of the searching and retrieval process are shown in Figure 1.
Figure 1. Process for selection of studies retrieved from the literature databases
Potentially relevant citations identified as a result of initial electronic searches (August 2007)
n = 214
Citations excluded after
application of inclusion criteria
n = 171
Studies retrieved for more detailed evaluation
n = 43
Citations excluded after detailed
evaluation
n = 30
Studies initially included in systematic review
n = 13
Randomised controlled trials n = 1
Pseudo-randomised controlled trilas n = 1
Non-randomised comparative studies n =1
Case series n = 10
Potentially relevant additional citations identified as a result of updated electronic searches (July
2008) n = 82
Citations excluded after
application of inclusion criteria
n = 56
Studies retrieved for more detailed evaluation
n = 26
Citations excluded after
application of inclusion criteria
n = 19
Additional studies included in systematic review
n=7
Randomised controlled trials n = 3
Non-randomised comparative studies n = 1
Case series n = 3
SECTION 3 INCLUDED STUDIES
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Description of studies
Excluded studies are given in Appendix A. A total of 20 studies were included in this review
(Table 5): four RCTs, one pseudo-RCT, two non-randomised comparative studies, and 13
case series. There were a total of 3853 participants in the included studies. The profiles for
these studies are given in Appendix B. Table 6 and Table 7 detail the number of injections or
treatments given to patients for ageing and HIV-associated facial lipoatrophy, respectively, in
those studies that reported these data. Appendix C details the injection technique used for
each study, the facial areas addressed, and the volume of product injected into each area.
Table 5. Summary of included studies
Study
Ageing
PERMANENT FILLERS VS.
Cohen et al. 2006 (USA)
Study type
Level
of E
Interventions
N
Follow-up
(years)
RCT
II
PMMA (Artecoll*)
Collagen (Zyderm II/Zyplast)
128
123
4–5
0.5
Case series
Case series
Case series
Case series
IV
IV
IV
IV
PMMA (Artecoll*)
Silicone particles (Bioplastique)
Liquid silicone (Silikon)
PAAG (name not specified)
145‡
40
608
1306
5
1
3
0.3 – 6
CaHA (Radiesse)
HA 1 (Juvederm 24)
HA 2 (Juvederm 24HV)
HA 3 (Perlane)
CaHA (Radiesse) (one side of face)
Collagen (Cosmoplast) (other side)
70§
33║
33
69¶
117
117
1.3
1.3
1.3
1.3
0.5
0.5
40
64
1.5
0.5
15
20
24
115**
26††
8
130
91
24
54
0.5
0.5
0.5
1
1
1
1
1
1
1
50
77
2
6.8‡‡
TEMPORARY FILLERS
PERMANENT FILLERS
Cohen et al. 2007† (USA)
Mladick 1992 (USA)
Fulton et al. 2005 (USA)
Reda-Lari 2008 (Kuwait)
SEMI-PERMANENT FILLERS
Moers-Carpi et al. 2007
(Germany)
VS. TEMPORARY FILLERS
Smith et al. 2007 (USA)
RCT
II
RCT
II
SEMI-PERMANENT FILLERS
Jacovello et al. 2006 (Argentina)
Case series
IV
CaHA (Radiesse)
Sklar & White 2004 (USA)
Case series
IV
CaHA (Radiance FN)
HIV-associated lipoatrophy
PERMANENT FILLERS, SEMI-PERMANENT FILLERS VS. TEMPORARY FILLERS
Guaraldi et al. 2005 (Italy)
Pseudo-RCT
III-1
PAAG (Aquamid)
PLA (New-Fill)
AFT
Negredo et al. 2006 (Spain)
III-2
PAAG (Aquamid)
Non-randomised
comparative
PLA (New-Fill)
AFT
Orlando et al. 2007 (Italy)
III-2
PAAG (Aquamid)
Non-randomised
comparative
PLA (Sculptra)
AFT + PLA (Sculptra)
AFT
PERMANENT FILLERS
De Santis et al. 2008 (Italy)
Case series
IV
PAAG (Aquamid)
Jones et al. 2004 (USA)
Case series
IV
Liquid silicone (Silikon 1000 or
VitreSil 1000)
Continued over page
SECTION 3 INCLUDED STUDIES
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Table 5. Summary of included studies continued
Study
Study type
Level
of E
Interventions
N
Follow-up
(years)
SEMI-PERMANENT FILLERS
Carey et al. 2007 (Australia)
RCT
II
Cattelan et al. 2006 (Italy)
Lafaurie et al. 2005 (France)
Mest & Humble 2006 (USA)
Valantin et al. 2003 (France)
Silvers et al. 2006 (USA)
Case series
Case series
Case series
Case series
Case series
IV
IV
IV
IV
IV
PLA (Sculptra) Immediate§§
PLA (Sculptra) Deferred§§
PLA (New-Fill)
PLA (New-Fill)
PLA (name not specified)
PLA (New-Fill)
CaHA (Radiesse)
50
50
50
94
99¶¶
50
100
0.5║║
0.5║║
1
1
1
1.9
1.5
AFT, autologous fat transfer; CaHA, calcium hydroxylapitite; Level of E, Level of evidence; NA, not applicable; RCT, randomised controlled trial;
PAAG, polyacrylamide gel; PLA, polylactic acid; PMMA, polymethylmethacrylate.
*
In Cohen & Holmes (2004), the original publication, Artecoll was used for all patients. Cohen et al. (2006) is the follow-up publication. In this
article, the product is referred to as Arte-Fill because this is now the manufacture name of the product. As Artecoll was used for all patients
in the original study, and because Arte-Fill has a slightly different composition, the name Artecoll was used for this review.
†
Same study patients as Cohen et al. (2006). Original PMMA patients followed up. Patients initially in the Collagen group who crossed over
to PMMA at 6 months also followed up. Original PMMA study patients n = 100; Cross over patients n = 45. Authors grouped patients
together, resulting in duplication of some results.
‡
142 patients included for efficacy, and 145 for safety.
§
5 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described.
║
2 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described.
¶
4 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described.
**
10 patients dropped out of follow-up (after the first intervention). Data for these patients not included in the analyses.
††
1 patient dropped out of follow-up (after the first intervention). Data for this patient not included in the analyses.
‡‡
Patients were followed up a mean of 58.9 weeks since their first treatment and 27.1 weeks since their last treatment.
§§
Bilateral PLA at weeks 0, 2, 4 and 6. Deferred group had the same, but delayed by 24 weeks. Therefore, the Deferred group had no
treatment during the study period.
║║
Study reported to follow patients for 96 weeks, but only reported 24 week outcomes.
¶¶
1 patient had a single treatment and was discontinued (was not HIV positive). The data for this patient were not included in the analyses. 1
patient dropped out after a third treatment before complete correction.
SECTION 3 INCLUDED STUDIES
20
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Table 6. Dermal fillers for ageing - number of injections or treatments
PERMANENT FILLERS VS. TEMPORARY FILLERS
Cohen et
N
Intervention
Number of treatments (mean)*
al. 2006
Glabella
NLF
Upper lip
Mouth Corners
Level II
128
PMMA (Artecoll†)
2.0
2.3
1.7
2.1
123
Collagen (Zyderm II/
2.0
2.0
1.8
2.2
Zyplast)
P-value
0.97
0.32
0.71
0.61
PERMANENT FILLERS
Cohen et
N
Intervention
Number of treatments
al. 2007
100
PMMA (Artecoll†)
As for Cohen et al. 2006
Level IV
NR
45
PMMA (Artecoll†)
Cross over patients
Fulton et al. N
Intervention
Percentage of patients treated in number of lip augmentation sessions‡
2005
2
3
>3
Level IV
608
Liquid silicone
73%
51%
31%
(Silikon)
SEMI-PERMANENT FILLERS
Sklar &
N
Intervention
Percentage of patients treated in 2 sessions for each facial area§
White 2004
Cheek║
Lips
Mouth
Above
NLF
Tear
Chin
upper lip (n = 5)
trough
Level IV
(n = 15)
(n = 11)
(n = 52)
(n = 2)
(n = 9)
(n = 15)
64
SEMI-PERMANENT
MoersN
Carpi et al.
70
2007
33
Level II
33
Smith et al.
2007
Level II
69
N
117
117
CaHA (Radiance FN)
37%
40%
27%
17%
0%
60%
50%
VS. TEMPORARY FILLERS
Intervention
CaHA (Radiesse)
HA 1 (Juvederm 24)
HA 2 (Juvederm
24HV)
HA 3 (Perlane)
Intervention
CaHA (Radiesse) one
side of face
Collagen
(Cosmoplast) other
side of face
P-value
Number of treatments¶
2
2
2
2
Baseline injection
only N (%)
61 (52.1%)
Number of injection sessions**
Two injection
Three injection
sessions N (%)
sessions N (%)
51 (43.6%)
5 (4.3%)
38 (32.5%)
70 (59.8%)
9 (7.7%)
0.017
NR
NR
CaHA, calcium hydroxylapitite; NA, not applicable; NR, not applicable; PMMA, polymethylmethacrylate; HA, Hyaluronic acid; NLF, nasolabial folds
*
During the 4 weeks after initial treatment, up to 2 additional treatments were permitted.
†
In Cohen & Holmes (2004), the original publication, Artecoll was used for all patients. Cohen et al. (2006) is the follow-up publication. In this
article, the product is referred to as Arte-Fill because this is the name that it is now manufactured under. As Artecoll was used for all patients
in the original study, and because Arte-Fill has a slightly different composition, the name Artecoll was used for this review.
‡
It was unclear how these percentages were calculated as they do not add up to 100%. One month after initial treatment, there was a followup visit where reinjection could occur. Desired augmentation was gradually achieved with a series of treatments at monthly intervals.
§
The number of patients receiving less or more than 2 treatments was not reported.
||
Includes zygoma and buccal regions.
¶
Patients received an initial treatment and a touch-up treatment 4 months later. Only nasolabial folds treated.
**
After initial treatment patients were allowed up to 2 touch up treatments at 2 week intervals.
SECTION 3 INCLUDED STUDIES
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Table 7. Dermal fillers for HIV-associated lipoatrophy – number of injections or treatments
PERMANENT FILLER
Guaraldi et
N
al. 2005
20
Level III-1
24
15
VS. SEMI-PERMANENT FILLER VS. TEMPORARY FILLER
N
130
91
24
Intervention
PAAG (Aquamid)
PLA (New-Fill)
AFT
P-value
Intervention
PAAG
PLA
PLA after AFT
54
AFT
Negredo et
al. 2006
Level III-2
N
115§
26║
8
P-value
Intervention
PAAG (Aquamid)
PLA (New-Fill)
AFT
P-value
PERMANENT
De Santis
et al. 2008
Level IV
Jones et al.
2004
Level IV
FILLERS
Orlando et
al. 2007
Level III-2
N
50
Intervention
PAAG (Aquamid)
N
Intervention
77
Liquid silicone (Silikon
1000 or VitreSil 1000)
SEMI-PERMANENT
Carey et al. N
2007
50
Level II
Cattelan et
al. 2006
Level IV
Lafaurie et
al. 2005
Level IV
Mest &
Humble
2006
Level IV
N
50
N
94
PLA (New-Fill)
Intervention
PLA (New-Fill)
N
Intervention
99¶¶
PLA (name not
specified)
Intervention
N
99¶¶
6 (2 – 11)
5 (2 – 8)
1†
NR
N sets of injections* (mean ± SD)
7±3
5±3
75% patients 5 ± 3 PLA infiltrations after 1 AFT procedure
17% patients 4 ± 1 PLA infiltrations after 2 AFT procedures
8% patients 6 ± 2 PLA infiltrations after 3 AFT procedures
80% patients 1 procedure
20% patients 2 procedures
NR
Number of sessions‡, n (maximum allowed)
2
3
NR
NR
Average number of procedures for each patient
6
Number of treatments per patient by pre-treatment lipoatrophy score¶
(mean ± SD)
1 (mild)
2 (moderate)
3 (severe)
P-value
(n = 37)
(n = 30)
(n = 10)
3.2 ± 1.2
5.6 ± 1.9
8.6 ± 2.3
< 0.0001**
FILLERS
Intervention
PLA (Sculptra)
Immediate
PLA (Sculptra)
Deferred
Intervention
50
N sets of injections*, n (range)
PLA (name not
specified)
N treatments††
4
0
Number of injection sessions per patient by pre-treatment lipoatrophy
score,‡‡ n (injection sessions)
6
7
8
9
7 (4)
13 (4)
14 (4)
16 (6)
§§
Number of injections per cheek per patient , median (range)
5 (1 - 7)
Median number of treatments║║ by pre-treatment James Scale¶ class
1 (mild)
2
3
4 (severe)
3
4
5
6
1
1(1)***
Number of treatments║║ for completed patients, n (%)
2
3
4
5
6
2 (2)
16 (16)
17 (17)
20 (20)
43 (44)
Continued over page
SECTION 3 INCLUDED STUDIES
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Table 7. Dermal fillers for HIV-associated lipoatrophy – number of injections or treatments continued
Valantin et
al. 2003
Level IV
Silvers et
al. 2003
Level IV
N
Intervention
50
N
PLA (New-Fill)
Intervention
100
CaHA (Radiesse)
3
4 (8)
1
4 (4)
Number of sets of injections per patient†††, n (%)
4
5
26 (52)
20 (40)
Number of injections per patient‡‡‡ n (%)
2
3
18 (18)
78 (78)
AFT, autologous fat transfer; NR, not reported; PAAG, polyacrylamide gel; PLA, polylactic acid; PMMA, polymethylmethacrylate.
*
PLA and PAAG administered as a set of injections every 4 weeks. The number of injections was not fixed. Number of injections was
dependent on physician’s opinion and patient’s desire of aesthetic result.
†
Two patients required an additional surgical procedure due to asymmetric absorption of the fat graft.
‡
Two weeks after initial treatment, all patients received another treatment session. After another 2 weeks, only patients in the PLA group
received another treatment session. This constituted the first round of injections. Patients were evaluated after 1 year to determine whether a
second round of injections was necessary. At the 1 year follow-up 17/20 (85%) of the PLA group; 5/65 (8%) of the PAAG group, and 7/8 (88%)
of the AFT group required a second round of injections.
§
10 patients dropped out of follow-up (after the first intervention) and were not included in the analyses.
║
1 patient dropped out of follow-up (after the first intervention) and was not included in the analyses.
¶
Developed by James et al. 2002. Measured on a scale of 1, mild; to 4, severe.
**
The number of treatments and volume of silicone injected significantly increased with severity of lipoatrophy score.
††
Bilateral injections at weeks 0, 2, 4 and 6.
‡‡
Injections were given to patients at baseline, day 30, day 45 and day 60. If necessary, additional treatments were allowed at day 75 and day
90 (16 (32%) patients with a baseline lipoatrophy score of 9 underwent these additional treatments). To maintain satisfactory results 28/50
(56%) patients required at least a set of 2 or more injections of PLA within 18 months after the end of follow-up.
§§
Injections given every 2 weeks. The number of sets of injections was left to the patient’s and surgeon’s discretion. New injections were allowed
during follow-up but could not be performed in the first 3 months following the last injection.
|| ||
Treatment sessions were conducted 3 weeks apart (with an allowed variability of 10 days).
¶¶
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the analyses. 1 patient
dropped out after third treatment before complete correction.
***
This patient had a single treatment and was discontinued (was not HIV positive).
†††
Injections given at baseline, week 2, week 4 and week 6. If ultrasound evaluation at week 6 indicated a total cutaneous thickness < 8 mm, a
fifth set of injections could be given.
‡‡‡
Injections given at baseline followed with touch up injections at 1 month, 6 months, and 18 months from initial injection, as deemed
appropriate by investigators.
Critical appraisal
Facial augmentation for ageing
Permanent fillers vs. temporary fillers
Randomised controlled trials
A single RCT compared the safety and efficacy of a permanent PMMA filler (Artecoll), with
a temporary collagen filler (Zyderm II/Zyplast) (Cohen et al. 2006).
The method of randomisation was not described in this study, but was found in Thaler and
Ubogy (2005), which reported the results of one of the eight study centres. Randomisation
was reported as being done by an off-site computer. No details regarding allocation
concealment were reported. Patients and evaluators were blinded to treatments groups, while
injecting physicians were not. Each of the three evaluators rated photographs independently.
It was stated that inter-rater reliability for observer Facial Fold Assessment Scale ratings was
evaluated using intraclass correlation, but no values were reported.
Intention-to-treat analysis, power calculations and the study period were not reported. Losses
to follow-up were reported, but reasons for these losses were not given. Efficacy was
measured by three masked observers using a validated assessment scale. Neither the scale
used by investigators to measure success of treatment nor the scale used to measure patient
SECTION 3 INCLUDED STUDIES
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satisfaction were validated.
It was not reported if there were any significant differences in baseline characteristics
between groups, with only age and gender being reported. Inclusion criteria and exclusion
criteria were reported in detail.
This study was a US Food and Drug Administration trial, and was sponsored by Artes
Medical, the manufacturer of Artecoll. In Thaler & Ubogy (2005) it was reported that both
authors had a financial interest in Artes Medical.
Permanent fillers
Case series
Four case series were included for review. These studies investigated the use of PMMA in
the nasolabial folds (Cohen et al. 2007), liquid silicone for lip augmentation (Silikon) (Fulton
et al. 2005), silicone particles for facial lines and wrinkles (Bioplastique) (Mladick 1992), and
PAAG for augmentation of the malar area (cheeks) (Reda-Lari 2008).
The methodological detail in three of these studies was generally scant (Fulton et al. 2005;
Mladick 1992; Reda-Lari 2008). In addition to this, one of these studies was not written in
the style of a traditional scientific article, describing what should be done, instead of exactly
what had been done (Mladick 1992). One study (Cohen et al. 2007) was a follow-up study of
an RCT (Cohen et al. 2006), and grouped patients that had crossed over from a temporary
filler treatment (Collagen) to PMMA. Although it was stated that 45/145 (31%) belonged to
the initial collagen group, patients were most often grouped collectively. This resulted in
duplication of reporting of safety outcomes.
Patients were selected retrospectively in three studies (Fulton et al. 2005; Mladick 1992; RedaLari 2008), and prospectively in one study (Cohen et al. 2006). Losses to follow-up and
statistical analyses were not reported in three studies (Mladick 1992; Fulton et al. 2005; RedaLari 2008).
The study period in which the studies were conducted reported as being in the last three years in
one study (Fulton et al. 2005), and was not reported in three other studies (Cohen et al. 2005;
Mladick 1992; Reda-Lari 2008).
Cohen et al. (2007) used the same methods to determine safety and efficacy as employed in
the original RCT. The three other studies did not report whether the outcome measures used
had been validated (Fulton et al. 2005; Mladick 1992; Reda-Lari 2008).
Age and gender were reported as demographic characteristics by three studies (Cohen et al.
2007; Fulton et al. 2005; Reda-Lari 2008). Cohen et al. (2007) reported potential selection bias,
as there was a significant difference between aesthetic improvement (at six months) between
the patients that participated in this study compared with those chose not to participate (p =
0.09). Demographic characteristics were not reported in two studies (Mladick 1992; RedaLari 2008).
Cohen et al. (2007) reported that inter-rater agreement between the three blinded observers
SECTION 3 INCLUDED STUDIES
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was high. The three other studies did not report any elements of blinding or independent
evaluation of results (Fulton et al. 2005; Mladick 1992; Reda-Lari 2008).
One study reported that patients were excluded if there were insufficient data on their
treatment (Cohen et al. 2007). One study reported clear exclusion criteria but no inclusion
criteria (Reda-Lari 2008). Two other studies did not report either inclusion or exclusion
criteria (Fulton et al. 2005; Mladick 1992).
One study reported being sponsored by the manufacturer of the study product (Cohen et al.
2007). Another study reported that the author had no financial interest in, and received no
compensation from, the manufacturers of the products mentioned in the article (Reda-Lari
2008). One study reported no significant interest with commercial supporters (Fulton et al.
2005).
Semi-permanent vs. temporary fillers
Randomised controlled trials
Two prospective, multicentre studies investigated semi-permanent fillers vs. temporary fillers
(Moers-Carpi et al. 2007; Smith et al. 2007). Moers-Carpi et al. (2007) compared CaHA
treatment with HA in the nasolabial folds in different groups of patients. Smith et al. (2007)
on the other hand, compared CaHA to collagen in the same patient (ie one nasolabial fold
treated with CaHA, and the other with collagen). The reporting of methodological detail in
these studies was average.
The method of randomisation was described as being done at the time of injection in one
study (Moers-Carpi et al. 2007), and by computer generated randomisation codes by the other
study (Smith et al. 2007). Allocation concealment, intention-to-treat analysis and power
calculations were not reported by either study.
The study period was reported by one study (Moers-Carpi et al. 2007), but not by the other
(Smith et al. 2007).
It was reported in Moers-Carpi et al. (2007) that 205 patients were initially treated with
CaHA, but it was unclear how many patients were in each treatment group at each time
point. In addition to this, the effect of initial treatment was not assessed before the four
month touch up treatments were given.
It was reported by one study that each study centre had one consistent blinded evaluator
throughout the study (Moers-Carpi et al. 2007). The other study reported that three blinded
evaluators assessed photographs in random order, and that patients had their eyes covered
during injection procedures (Smith et al. 2007).
Losses to follow-up were reported by both studies. It was reported by one study that four
patients were lost to follow-up and that no further data were available for these patient
(Smith et al. 2007). The other study lost between seven and 11 patients during the follow-up
visits, but it was unclear from the other study where the losses to follow-up occurred (ie in
which treatment group) and why (Moers-Carpi et al. 2007).
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Inter-rater reliability was not reported by one study (Moers-Carpi et al. 2007). Smith et al.
(2007) reported that intraobserver and interobserver agreement was assessed using weighted
kappa. In addition to this, it was reported that confirmatory analysis was performed for each
evaluator’s scores independently, and that similar results were found for each evaluator as
reported for the median scores of the three evaluators.
Both studies reported using validated scales for aesthetic improvement or wrinkle severity
classification. In addition to this, one study reported using two unspecified patient
satisfaction surveys (Moers-Carpi et al. 2007).
Baseline characteristics were reported as age and gender by one study (Moers-Carpi et al.
2007) and age, gender and ethnicity by the other study (Smith et al. 2007). Moers et al. (2007)
did not report whether patients were well matched at baseline.
One study reported extensive inclusion criteria and exclusion criteria (Moers-Carpi et al.
2007), but the other study only reported inclusion criteria (Smith et al. 2007).
Both studies reported that support and funding was provided by the manufacturer of the
study material, and that authors received financial compensation for presentations about it to
the medical community.
Semi-permanent fillers
Case series
Two retrospective case series were included for review, and investigated semi-permanent
fillers containing CaHA (Radiesse in Jacovello et al. 2006; and Radiance FN in Sklar & White
2004). The methodological detail reported in these studies was generally scant. In addition to
this, one of these studies was not written in the style of traditional scientific article,
describing what should be done, instead of exactly what had been done (Sklar & White
2004).
The method of patient allocation and recruitment were not reported in one study (Jacovello
et al. 2006). In the other study, consecutive patients were selected retrospectively (Sklar &
White 2004).
Losses to follow-up and statistical analyses were not reported in either study. Both studies
did not report whether the outcome measures used had been validated (Jacovello et al. 2006;
Sklar & White 2004).
The study period in which the studies were conducted was reported by one study (Jacovello
et al. 2006), and not reported in the other study (Sklar & White 2004).
Demographic characteristics were not reported in one study (Sklar & White 2004). Age,
gender and ethnicity were reported by the other study (Jacovello et al. 2006).
One study did not report inclusion or exclusion criteria (Sklar & White 2004). The other
study reported no inclusion criteria, but did report exclusion criteria (Jacovello et al. 2006).
One study reported no significant interest with commercial supporters (Sklar & White 2004).
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The other study reported receiving financial support from BioForm Medical Inc
(manufacturer of Radiesse) for the preparation of the article, but also reported that none of
the authors had any financial interest in BioForm Medical (Jacovello et al. 2006).
Facial augmentation for HIV-associated lipoatrophy
Permanent vs. semi-permanent vs. temporary fillers
Two studies investigated permanent vs. semi-permanent vs. temporary fillers for HIVassociated facial lipoatrophy (Guaraldi et al. 2005; Negredo et al. 2006). One study
investigated permanent, semi-permanent and temporary fillers for HIV-associated facial
lipoatrophy from baseline and did not compare the interventions (Orlando et al. 2007). The
core investigators and study centres of Guaraldi et al. (2005) and Orlando et al. (2007) were
the same.
Pseudo-randomised controlled trials
One study compared a permanent PAAG filler with a semi-permanent PLA filler with
temporary filling with AFT for HIV-associated facial lipoatrophy (Guaraldi et al. 2005). The
reporting of methodology in this study was generally inadequate.
Randomisation of consecutive patients was reported to be done selectively, according to the
level of a patient’s residual subcutaneous fat. If enough residual subcutaneous fat was
present, a patient received AFT. Patients without enough subcutaneous fat were randomised
to PLA or PAAG. It was reported that the study groups were well-matched with regard to
baseline demographics and HIV history, but there was a significant difference in
morphological appearance (which was used to determine selective randomisation into
treatment group).
Allocation concealment, blinding, intention-to-treat analysis, and losses to follow-up were
not reported.
The Adult AIDS Clinical Trails Group Assessment of Body Change and Distress (ABCD)
questionnaire was used to assess body image, but it had not been validated at the time of the
study (it was in press). Skin thickness measurements, as conducted by ultrasound, had not
been validated. Independent reviewers compared pre- and post-treatment standardised
pictures, but the number of reviewers and the level of agreement between reviewers was not
reported.
Facial aesthetic satisfaction was measured on a visual analogue scale, the magnitude of which
was unspecified. PLA and PAAG were injected by the same individuals, but in different
teams. All ultrasound measurements were performed by the same single operator.
Inclusion and exclusion criteria, as well as demographic and HIV history characteristics, were
reported.
Non-randomised comparative studies
One prospective non-randomised controlled trial compared a permanent PAAG filler, a
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semi-permanent PLA filler and temporary filling via AFT (Negredo et al. 2006). Another
prospective non-randomised controlled trial compared the effects of a permanent PAAG
filler, a semi-permanent PLA filler and temporary filling via AFT from baseline and did not
compare between products (Orlando et al. 2007). This study also had a patient group that
received PLA after AFT.
Orlando et al. (2007) reported that the interventional techniques used for the study were
described in Guaraldi et al. (2005). It was unclear whether there was any patient overlap
between these studies.
The study by Negredo et al. (2006) aimed to reduce the obvious signs of facial lipoatrophy,
and did not aim to provide optimal correction due to the high cost of the dermal filling
products. The study by Orlando et al. (2007) was not aimed at comparing the different fillers,
but was designed to assess long term psychometric outcomes after treatment. In both
studies, consecutive patients were selectively allocated to AFT if there was fat accumulation
in the abdomen, hump, or breast areas. If not, patients received either PLA or PAAG
treatment. In Negredo et al. (2006) the selection of product was determined by product
availability (PLA and PAAG were donated by the manufacturer of each product). In Orlando
et al. (2007), patients were able to choose which filler they received.
Losses to follow-up were reported by one study (Negredo et al. 2006), but the reason for
these losses were only given in one case (death following leukoencephalopathy). Patients lost
to follow-up were not included in the analysis of the results, even though they had received
an initial round of treatment. The other study did not report losses to follow-up (Orlando et
al. 2007).
Elements of blinding were reported in one study (Negredo et al. 2006), with two independent
blinded assessors not involved in the study evaluating photographs. Inter-rater reliability was
not reported. No blinding was reported in the other study (Orlando et al. 2007).
It was not reported whether the outcome measures used by Negredo et al. (2006) to measure
patient limitation and patient satisfaction in the study were validated. It was reported that the
facial lipoatrophy ordinal scale used to determine the level of lipoatrophy was established by
the study team and had not been validated. Orlando et al. (2007) used the Adult AIDS
Clinical Trials Group Assessment of Body Change and Distress (ABCD) questionnaire to
measure body image, which had been validated in 2006 by the study authors. Depression was
measured by the validated Beck Depression Inventory (BDI). Skin thickness measurements,
as conducted by ultrasound, and facial aesthetic satisfaction as measured on a visual analogue
scale, had not been validated.
Both studies reported the period during which the studies were conducted. Both studies
reported demographic and HIV history characteristics, but it was unclear whether there were
any baseline differences between the groups for either study. Both studies reported inclusion
and exclusion criteria
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Permanent fillers
Case series
One case series study investigated the safety and efficacy of a permanent PAAG filler for
consecutive patients with HIV associated lipoatrophy (De Santis et al. 2008). This study had
common authors and common study location to Guaraldi et al. (2005) and Orlando et al.
(2007). In addition to this, a patient photograph in Guaraldi et al. (2005) was duplicated in De
Santis et al. (2008). It was unclear whether patient overlap occurred.
Another case series study evaluated the safety and efficacy of permanent liquid silicone oil
for the treatment of HIV-associated facial lipoatrophy (Jones et al. 2004). This study reported
outcomes for a subset of patients from four centres that had complete correction with
silicone injections, and was affected by selection and attrition bias. Correction of patients
was considered complete when, one month after a treatment, the patient and physician
believed the patient resembled his or her pre-lipoatrophy state.
The methodological detail reported within both studies was scant. The study period and
losses to follow-up were not reported in either study. De Santis et al. (2008) did not report
any detail regarding the administration of the dermal filling product or what statistical
analyses were used.
The outcome measures used in De Santis et al. (2008) were the same as for Orlando et al.
(2007), with the ABCD questionnaire and BDI being validated, and the ultrasound
measurements and visual analogue scale (VAS) not being validated. Very little detail
regarding any of the outcome measures was reported. The outcome measures used by Jones
et al. (2004) were not validated.
Inclusion and exclusion criteria were reported for both studies. Jones et al. (2004) reported
that patients who had received prior injections with temporary fillers could not begin silicone
injections until three months after their last injection of temporary filling product. The
authors of this study classified New-Fill as a temporary product that would dissipate within
three months.
Two of the authors of Jones et al. (2004) reported working for, and receiving products from
the manufactures of the products included in the study.
Semi-permanent fillers
Randomised controlled trials
One RCT reported safety and efficacy of immediate vs. deferred PLA (Carey et al. 2007). The
immediate group had bilateral injections of PLA at weeks zero, two, four and six; and the
deferred group had the same treatment, but it was delayed by 24 weeks (ie the deferred group
had no treatment during the time the immediate group was treated). This study was generally
well reported.
The method of randomisation was reported to be done by a single statistician and patients
were stratified by age, facial lipoatrophy severity, current PI use, current NRTI use, and
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surgeon. The method of allocation concealment was not reported.
A power calculation was performed and 50 patients were chosen per arm to give 80% power
to detect a difference in the proportion of patients with a clinically relevant improvement in
cheek volume to 10% in the placebo arm versus 35% in the treatment arm.
The study was not blind. The study used intention-to-treat analyses and primary efficacy
analyses adopted a last-value-carried-forward approach for participants lost to follow-up.
All baseline computed tomography (CT) scans, linear measurements, and soft tissue volumes
quality were reviewed at a single radiology site to ensure adherence to protocol.
The quality of life tools used in the study were validated. Patient and physician assessment of
lipodystrophy was made using a validated facial lipodystrophy scale. Skin thickness
measurement techniques and antiretroviral adherence reporting were not validated.
The period in which the study was conducted was reported. There were no losses to followup although one person withdrew before treatment. Inclusion and exclusion criteria were
well described.
Case series
Four case series studies investigated the use of semi-permanent PLA fillers for HIVassociated facial lipoatrophy (New-Fill in Cattelan et al. 2006; Lafaurie et al. 2005; Valantin et
al. 2003; product name not specified in Mest & Humble 2006). One case series investigated a
semi-permanent CaHA filler (Radiesse) for HIV-associated facial lipoatrophy (Silvers et al.
2006).
Patients were selected consecutively in two studies (Cattelan et al. 2006; Lafaurie et al. 2005),
and patient selection was not reported, or was unclear, in the other three studies (Valantin et
al. 2003; Mest & Humble 2006; Silvers et al. 2006). Three studies were prospective (Cattelan
et al. 2006; Lafaurie et al. 2005; Silvers et al. 2006), and recruitment was not reported in two
studies (Valantin et al. 2003; Mest & Humble 2006).
Power calculations were reported by one study (Valantin et al. 2003). Valantin et al. (2003)
reported that they chose a sample size to allow 90% power to determine the percentage of
responders with a precision of 20%, assuming a response rate of 20%, with a type one error
of 0.05.
Losses to follow-up were reported by four studies (Lafaurie et al. 2005; Mest & Humble
2006; Valantin et al. 2003; Silvers et al. 2006), and reasons for all of these losses were reported
by all studies except one (Valantin et al. 2003). One study reported no losses to follow-up,
but recorded six patients not completing treatment, with reasons stated (Silvers et al. 2006).
One study did not report losses to follow-up (Cattelan et al. 2006).
The period during which the studies took place was reported by four studies (Cattelan et al.
2006; Lafaurie et al. 2005; Mest & Humble 2006; Valantin et al. 2003), but not by one study
(Silvers et al. 2006).
One study reported that analyses were performed using an intent-to-treat population, which
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was defined as all patients who received treatment as planned (Silvers et al. 2006).
Quality of life and other psychological data were measured by four studies (Cattelan et al.
2006; Lafaurie et al. 2005; Mest & Humble 2006; Valantin et al. 2003), of which only two used
validated questionnaires (Cattelan et al. 2006; Lafaurie et al. 2005).
Scales and scores used to calculate degrees of lipoatrophy were used by four studies (Cattelan
et al. 2006; Lafaurie et al. 2005; Mest & Humble 2006; Silvers et al. 2006). Of these, the scale
used in two studies had been previously validated (Mest & Humble 2006; Silvers et al. 2006).
The scale used by Lafaurie et al. (2005) was an adapted version of a previously validated scale.
The scale used by Cattelan et al. (2006) had not been validated.
Methods used to determine skin thickness were not validated in five studies (skin callipers,
Mest & Humble 2006 and Silvers et al. 2006; ultrasound, Cattelan et al. 2006 and Valantin et
al. 2003; 3-dimensional photographs, Lafaurie et al. 2005). One study used unvalidated
methods for calculating standard facial thickness values of individuals who were not infected
with HIV (Valantin et al. 2003).
One study did not detail the statistical analyses used to determine safety and efficacy (Silvers
et al. 2003).
In one study, two independent assessors ranked photographs of patients taken throughout
treatment, but there was only low to moderate agreement between them (Lafaurie et al. 2005).
The same practitioners (eg dermatologists, plastic surgeons and/or radiologists) were used
throughout treatment in five studies (Cattelan et al. 2006; Lafaurie et al. 2005; Mest & Humble
2006; Valantin et al. 2003; Silvers et al. 2006), although it was difficult to determine in one
case whether there was more than one physician (Mest & Humble 2006).
Demographic and HIV history characteristics were well reported in four studies (Cattelan et
al. 2006; Lafaurie et al. 2005; Valantin et al. 2003; Mest & Humble 2006). Only patient gender
and age were reported in one study (Silvers et al. 2006).
Inclusion and exclusion criteria were reported by four studies (Cattelan et al. 2006; Lafaurie et
al. 2005; Mest & Humble 2006; Valantin et al. 2003), while only inclusion criteria were
reported by the other study (Silvers et al. 2006).
One study reported no financial disclosures and that funding was independent of the study
device (Cattelan et al. 2006). In another study, the product was provided by the manufacturer
(Lafaurie et al. 2005). One study reported that the authors were consultants for the product
manufacturer, but that they had no financial interest in the manufacture of the material (Mest
& Humble 2006).
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4. Results
The results are presented in two main sections; the use of dermal fillers for ageing,
and the use of dermal fillers for HIV-associated lipoatrophy. The results are then
categorised into safety and efficacy outcomes, and then by the level of evidence.
The various outcomes of the included studies have been grouped together as closely
as possible. It should be noted that the tools and methods used among the studies to
measure efficacy and safety outcomes in many cases were not uniform.
Efficacy outcomes for ageing
Permanent vs. temporary fillers
One RCT by Cohen et al. (2006) compared the efficacy of PMMA to collagen at one,
three, and six months in the glabella, nasolabial folds, upper lip, mouth corners and
overall. No 12 month data for collagen exists as patients in the collagen group were
offered PMMA injections at the six-month follow-up.
Observer ratings of appearance
Randomised controlled trials
Masked observer ratings using a Facial Fold Assessment Scale (Lemperle et al. 2001)
showed a significant difference in favour of collagen one month after injection in the
glabella (p = 0.004), but no significant differences in the other three facial areas or
overall. After three months, masked observer ratings showed a statistically significant
improvement for PMMA in the nasolabial folds (p < 0.001), mouth corners (p =
0.001) and overall (p < 0.001) when compared with the collagen control. After six
months, PMMA was found to be better than collagen in the nasolabial folds and
overall (p < 0.001 for both). At this time, patients who had previously been
randomly assigned to the collagen group were offered PMMA injections, resulting in
12 month comparisons not being available. Efficacy data for PMMA alone was
provided for the 12 month up. The results showed significant improvement in Facial
Fold Assessment Scale ratings from baseline for each of the four facial areas treated
with PMMA, and the overall average (p = 0.047 to p < 0.001).
Unmasked investigator ratings showed a significant difference in favour of collagen
in the glabella and mouth corners one month after injection when compared with
PMMA (p = 0.034 and 0.041 respectively). After three months, PMMA was
significantly better than collagen in the nasolabial folds, upper lip, mouth corners and
overall (p < 0.001 for all). After six months, PMMA was significantly better than
collagen for all of the treated areas, and overall (p < 0.001 for all). The results for
PMMA alone at 12 months’ follow-up showed significant improvement in Facial
Fold Assessment Scale ratings from baseline for each of the four facial areas and the
overall average (p < 0.001 for all).
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After four to five years, 69/128 (54%) PMMA patients were available for follow-up.
Of these 69 patients, 26 had undergone surgical procedures during the four to five
years after initial treatment (it was unclear whether this also included other injectable
treatments). Of the 43 patients who had not undergone any surgical procedures
following PMMA treatment, masked observer Facial Fold Assessment Scale ratings
indicated a 1.2 point improvement when compared to baseline photographs (p <
0.001). For all 69 patients, investigators found a 1.7 point improvement from
baseline (p < 0.001).
Patient satisfaction
Randomised controlled trials
Masked patients reported no difference in satisfaction between the two groups for all
four facial areas treated at one month. At three months, patients who had received
PMMA were reported as being more satisfied for all of the facial areas treated (p =
0.038 for glabella; p < 0.001 for all other areas). At six months, patients who had
received PMMA were reported as having more satisfaction for all of the facial areas
treated than the collagen group (p < 0.001 for all other areas).
Success of treatment
Randomised controlled trials
Unmasked investigators compared the level of success (on a scale of one, completely
successful to five, not at all successful) of PMMA to collagen in four facial areas at
one, three, and six months after treatment.
At one month, PMMA was found to be more successful than collagen for the mouth
corners only (p = 0.011). At three months, PMMA was found to be more successful
than collagen in all areas (p < 0.001) except the glabella, where there was no
significant difference. At six months, PMMA was found to be more successful in all
of the treated areas (p < 0.001). Of the 116 collagen patients who completed the six
month follow-up evaluation, 106 (91%) were treated with PMMA. No statistical
analyses were reported.
After four to five years, 69/128 (54%) PMMA patients were followed up. Of these
patients, 61 (89%) were categorised by investigators (using the Facial Fold
Assessment Scale) as being very or completely successful, and 67 (98%) were
categorised as being at least moderately successful. Of these patients, 26 (38%) had
undergone surgical procedures between the initial PMMA treatment and the four to
five year follow-up. It was unclear whether this included other dermal filling
procedures. No statistical analyses were reported.
Permanent fillers
Four case series studies reported on the use of permanent dermal fillers for
rejuvenating age-related facial changes in the face (Cohen et al. 2007; Fulton et al.
2005; Mladick 1992; Reda-Lari 2008).
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Observer ratings of appearance
Case series
Cohen et al. (2007) was a follow-up study of Cohen et al. (2006), and grouped patients
that had crossed over from collagen treatment to PMMA with the original PMMA
patients. It was reported that 45/145 (31%) patients belonged to the initial collagen
group. Cohen et al. (2007) reported blinded observer assessment ratings using a Facial
Fold Assessment Scale (Lemperle et al. 2001) of the nasolabial folds of 119 patients
who had PMMA treatment five years earlier. Blinded observer Facial Fold
Assessment Scale assessment of nasolabial folds of 113 patients showed a 0.2 point
improvement from six months to five years (p = 0.002), and a 1.0 point
improvement from baseline (p < 0.001). Interrater agreement was high (intraclass
correlation coefficient 0.845). It was further reported that investigator Facial Fold
Assessment Scale scores improved by 1.7 points at five years compared with baseline
(n = 122) (p < 0.001). In a paired analysis of the cross over patients (n = 45), the
PMMA induced improvement assessed at five years was significantly greater than the
collagen induced improvement at six months (0.91 points vs. 0.01 points) (p <
0.001).
An unspecified number of patients from the study group had undergone 44
subsequent cosmetic procedures since PMMA treatment. In patients that had not any
subsequent cosmetic procedures, there was significant improvement in blinded
observer ratings from baseline to five years (p < 0.001). There was no difference in
change in blinded observer efficacy ratings between those patients who had
undergone subsequent cosmetic procedures to those who had not at five years
relative to six months. Of the subsequent cosmetic procedures, it was reported that
16/44 (36.4%) procedures had probably impacted results, and 28/44 (63.6%) had
possibly impacted results. When grouped into subgroups of whether these
procedures had or had not impacted the results, the groups did not significantly
differ from each other.
Cohen et al. (2007) also reported investigator Facial Fold Assessment Scale ratings for
122 patients. There was a 1.67 point improvement from baseline at five years (p <
0.001).
Over-correction
Over-correction refers to the injection of too much product into an area, and can
result in visibility of the substance under the skin, or lumpiness at the site.
Case series
In the case series by Mladick (1992), over-correction occurred four times (7% of
injections) after silicone particle injections in three of 40 (8%) patients. Two (5%)
patients had over-correction bulges in the infraoral depression areas after silicone
particles were injected into each side. One patient had a nasoglabellar bulge after
silicone particles were injected under frown lines. These bulges were corrected by
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needle aspiration.
Reda-Lari (2008) reported that two patients of 1306 (0.2%) were psychologically
dissatisfied with the result of PAAG treatment as they believed they had been overcorrected. The product was removed.
Filler displacement
Case series
Reda-Lari (2008) reported that displacement of PAAG occurred in 43/1306 (3%)
patients. In these patients, the product was displaced to the perioral area in 18/43
(42%) cases and to the buccal area in 25/43 (58%) cases. Treatment consisted of
local corticosteroid injection in some cases (number of cases not reported). In more
severe cases, the product was removed.
Changes in skin thickness
Case series
Fulton et al. (2005) reported changes in lip thickness measurements for patients who
received liquid silicone for lip augmentation. The quadrants of both upper lips of
25/608 (4%) patients were measured using a micrometer 30 days after each session
and then averaged. At baseline, the average lip thickness was 4.1 mm. After one, two
and three sessions, the average lip thickness was 5.6 mm, 7.8 mm and 9.2 mm
respectively. No statistical analyses were reported.
Patient satisfaction
Case series
Cohen et al. (2007) reported that after five years, 111/123 (90%) patients described
themselves as ‘very satisfied’ or ‘satisfied’ with the cosmetic outcome from baseline
(an unspecified number of patients from the study group had undergone 44
subsequent cosmetic procedures since PMMA treatment). No statistical analyses
were reported.
Mladick (1992) reported that patient satisfaction after silicone particle injections was
rated as good (> 3 on a scale of one, poor; two, acceptable; three, good; four, very
good; five, excellent) for all areas. No statistical analyses were reported.
Reda-Lari (2008) reported that 1241/1306 (95%) patients were satisfied with the
aesthetic results immediately after PAAG injections. It was reported that most of the
remaining patients were dissatisfied because they felt the augmentation was
insufficient. It was reported that patient satisfaction decreased over time, and that of
the patients that were monitored for longer than one year, satisfaction was 85%
(number of patients not reported). Two of 1306 (0.2%) patients were dissatisfied as
they felt they had been over-corrected.
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Practitioner satisfaction
Case series
Mladick (1992) reported surgeon satisfaction for each of the facial areas treated with
silicone particles. On a scale of scale of one (poor) to five (excellent), the average
satisfaction score was above four (very good) for all of the treated areas, except the
mouth, which had a rating of 3.9. No statistical analyses were reported.
Success of treatment
Case series
Cohen et al. (2007) reported that investigators regarded the cosmetic effect in
111/123 (90%) as ‘completely successful’ or ‘very successful’ from baseline (an
unspecified number of patients from the study group had undergone 44 subsequent
cosmetic procedures since PMMA treatment). No statistical analyses were reported.
Semi-permanent vs. temporary fillers
Two RCTs investigated the use of semi-permanent fillers vs. temporary fillers
(Moers-Carpi et al. 2007; Smith et al. 2007).
Observer ratings of appearance
Randomised controlled trials
Moers-Carpi et al. (2007) used a Global Aesthetic Improvement Scale (Narins et al.
2003) (scale of one, very much improved to five, worse) to determine changes in
appearance of nasolabial folds after treatment (Table 8). It was reported that
significantly more patients in the CaHA group were considered improved or better
(Global Aesthetic Improvement Scale rating ≤ 3) than patients in any of the HA
groups at eight and 12 months after initial treatment (p < 0.001 for HA 1, 2 and 3).
Sixteen months after treatment, the number of patients considered improved or
better was significantly higher in the CaHA group compared with HA 1 and HA 3 (p
< 0.001 and p = 0.03 respectively), but not for HA 2.
Moers-Carpi et al. (2007) also calculated mean Wrinkle Severity Rating Scale (WSRS)
scores (on a scale of one, no visible folds, to five, severe folds) and WSRS scores
from baseline. It was reported that the results from these ratings over time showed
no statistical significance for any product (specific data were not reported in the
study).
Smith et al. (2007) used a Facial Fold Assessment Scale (Lemperle et al. 2001) to
measure the median blinded observer ratings of appearance after CaHA had been
injected into the nasolabial fold on one side of a patient’s face and collagen had been
injected into the contralateral nasolabial fold (Table 8). At three and six months after
treatment, significantly more nasolabial folds injected with CaHA were improved
from baseline than nasolabial folds injected with collagen (p < 0.0001 for both time
points). Similar results were found when nasolabial folds were assessed from baseline
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using a Global Aesthetic Improvement Scale (Narins et al. 2003). More nasolabial
folds were improved with CaHA than Collagen at three and six months after
treatment (no statistical analyses were reported).
Table 8. Semi-permanent vs. temporary fillers for ageing – observer ratings of appearance
Moers–Carpi et
al. 2007
Level II
N
70
33
33
Smith et al.
2007
Level II
Intervention
12 months after initial
treatment (n = 198†) (%)
16 months after initial
treatment (n = 194†) (%)
HA 1 (Juvederm 24)
96
2
88
5
62
0
P-value‡
< 0.001
< 0.001
< 0.001
HA 2 (Juvederm 24 HV)
71
53
P-value‡
< 0.001
< 0.001
CaHA (Radiesse)
69
HA 3 (Perlane)
N
P-value‡
Intervention
117║
117║
N
117║
117║
117║
117║
Total improved* (%)
8 months after initial
treatment (n = 195†) (%)
CaHA (Radiesse) one
side of face
Collagen
(Cosmoplast) other
side of face
P-value
Intervention
CaHA (Radiesse) one
side of face
Collagen
(Cosmoplast) other
side of face
P-value
CaHA (Radiesse) one
side of face
Collagen
(Cosmoplast) other
side of face
P-value
50
NS
72
64
48
< 0.001
< 0.001
0.03
Number of patients with improvement from baseline§, n (%)
3 months after end of treatment
6 months after end of treatment
102 (87)
96 (82)
32 (27)
32 (27)
< 0.0001
< 0.0001
Number of patients with improvement from baseline¶, n (%)
Very much Much
Improved
No change Worse
improved
improved
3 months after end of treatment
23 (20)
47 (40)
42 (36)
5 (4)
0 (0)
1 (1)
6 (5)
22 (19)
68 (59)
21 (18)
NR
NR
17 (14)
35 (30)
41 (35)
24 (20)
0 (0)
1 (1)
5 (4)
21 (18)
69 (59)
21 (18)
NR
NR
NR
NR
NR
NR
NR
6 months after end of treatment
NR
CaHa, calcium hydroxylapatite; HA, hyaluronic acid; NR, not reported
*
Measured using Global Aesthetic Improvement Scale (Narins et al. 2003) with 1, very much improved to 5, worse. It was reported that
patients for whom there was no difference between the products were excluded from the Global Aesthetic Improvement Scale analysis.
It was unclear whether or where this occurred.
†
Compared with CaHA.
‡
Details of losses to follow-up (if any) not reported.
§
Measured using Facial Fold Assessment Scale (Lemperle et al. 2001) on a scale of 0, no wrinkles to 5, very deep wrinkle, redundant
fold.
║
It was stated that 115 and 113 patients were available at the 3 and 6 month follow-ups respectively, but 117 used in results.
¶
Calculated using Global Aesthetic Improvement scale (Narins et a. 2003) on a scale of: very much improved, optimal cosmetic result
for the implant in this patient; to worse, the appearance is worse than the original condition.
In addition to this, Smith et al. (2007) reported that at three months after treatment,
CaHA was superior to collagen (as assessed by the Facial Fold Assessment Scale) in
99/117 (84%) patients compared with 4/114 (3%) patients (p < 0.0001). At six
months CaHA was superior to collagen in 92/117 (79%) patients compared with
6/117 (5%) patients (p < 0.0001). A similar result was achieved when aesthetic
improvement was determined using a Global Aesthetic Improvement Scale. CaHA
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was found to be superior to collagen in 98/117 (83%) patients compared with
16/117 (3%) patients at three months, and in 88/117 (75%) patients compared with
25/117 (3%) patients at 6 months (no statistical analyses were reported).
Patient satisfaction
Randomised controlled trials
Moers-Carpi et al. (2007) reported that CaHA generally scored better than HA 1 and
2 in relation to whether the treatment was beneficial to patients, whether it made
patients feel attractive, whether it increased emotional well being, and whether it
made patients feel more confident, eight, 12 and 16 months after treatment (Table 9).
Table 9. Semi-permanent vs. temporary fillers for ageing – patient satisfaction
Moers–Carpi et
al. 2007
Level II
N
70
33
Intervention
CaHA (Radiesse)
HA 1 (Juvederm 24)
P-value‡
33
HA 2 (Juvederm 24 HV)
P-value‡
69
HA 3 (Perlane)
P-value‡
Beneficial*
8 months after initial
treatment (n = 195†)
(%)
12 months after initial
treatment (n = 198†)
(%)
16 months after initial
treatment (n = 194†)
(%)
100
53
< 0.001
90
0.031
97
NS
100
19
< 0.001
78
< 0.001
85
0.001
95
10
< 0.001
74
0.004
82
0.026
86
50
< 0.001
77
NS
86
NS
86
19
< 0.001
63
0.01
75
NS
Feel more attractive*
70
33
CaHA (Radiesse)
HA 1 (Juvederm 24)
P-value‡
33
HA 2 (Juvederm 24 HV)
P-value‡
69
HA 3 (Perlane)
P-value‡
82
10
< 0.001
55
0.013
75
NS
Better emotional well being*
70
33
CaHA (Radiesse)
HA 1 (Juvederm 24)
P-value‡
33
HA 2 (Juvederm 24 HV)
P-value‡
69
HA 3 (Perlane)
P-value‡
86
50
< 0.001
61
0.008
77
NS
83
16
< 0.001
53
0.003
66
0.029
79
47
0.002
61
NS
73
NS
80
19
< 0.001
50
0.004
66
NS
77
10
< 0.001
48
0.01
64
NS
More confidence*
70
33
CaHA (Radiesse)
HA 1 (Juvederm 24)
P-value‡
33
HA 2 (Juvederm 24 HV)
P-value‡
69
HA 3 (Perlane)
P-value‡
77
10
< 0.001
35
< 0.001
64
NS
CaHA, calcium hydroxylapatite; HA, hyaluronic acid
*
Patients were asked yes/no questions, and yes answers are tabulated.
†
Compared with CaHA
‡
Details of losses to follow-up not reported
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Smith et al. (2007) reported that at the 6 month follow-up visit, patients were asked
which nasolabial fold they preferred. Most patients (97%) judged the CaHA fold to
be more satisfactory than the collagen fold (no statistical analyses were reported).
Would recommend treatment to others
Randomised controlled trials
Moers-Carpi et al. (2007) reported that at eight, 12 and 16 months after treatment, a
significantly greater percentage of patients that received CaHA would recommend
treatment than patients who received HA 1, 2 or 3 (p ≤ 0.036 for all) (Table 10).
Table 10. Semi-permanent vs. temporary fillers for ageing – would recommend treatment
Moers –Carpi
et al. 2007
Level II
N
70
33
Intervention
CaHA (Radiesse)
HA 1 (Juvederm 24)
P-value‡
33
HA 2 (Juvederm 24 HV)
P-value‡
69
HA 3 (Perlane)
P-value‡
Would recommend treatment*
8 months after initial
treatment (n = 195†) (%)
12 months after initial
treatment (n = 198†) (%)
16 months after initial
treatment (n = 194†) (%)
95
19
< 0.001
77
0.011
82
0.026
95
13
< 0.001
78
0.013
82
0.026
94
6
< 0.001
74
0.035
81
0.036
CaHA, calcium hydroxylapatite; HA, hyaluronic acid
*
Patients were asked yes/no questions. Percentage of yes answers are tabulated.
†
Compared with CaHA
‡
Details of losses to follow-up not reported
One study centre within Moers-Carpi et al. (2007) administered a separate satisfaction
questionnaire to its patients. A significantly greater percentage of patients in the
CaHA group were extremely satisfied or satisfied with treatment results at eight, 12
and 16 months after treatment than patients who received either HA 1, 2 and 3 (p ≤
0.0015). In addition to this, a significantly greater percentage of patients in the CaHA
group compared with the HA 1, 2 and 3 groups were likely to return for further
treatment with the product they received when asked at eight, 12 and 16 months
after treatment (p < 0.001 for all).
Practitioner satisfaction
Randomised controlled trials
Smith et al. (2007) reported that at the six month follow-up visit, practitioners were
asked which nasolabial fold they preferred. Most (97%) judged the CaHA fold to be
more satisfactory than the collagen fold (no statistical analyses were reported).
Other efficacy outcomes
Randomised controlled trials
Smith et al. (2007) reported that one event of needle clogging occurred during CaHA
treatment.
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Semi-permanent fillers
Two case series studies reported on the use of semi-permanent dermal fillers for
ageing (Jacovello et al. 2006; Sklar & White 2004).
Over-correction
Case series
Sklar & White (2004) reported puffiness of the lower eyelids after injection with
CaHA in one of 64 (2%) patients. It was reported that the authors were unsure
whether this was due to over-correction or lymphoedema. Also, filler was placed too
superficially in one (2%) patient, resulting in a pink-white plaque showing in the tear
trough area.
Patient satisfaction
Case series
Jacovello et al. (2006) conducted a patient satisfaction survey at the end of the 18
month follow-up period after CaHA treatment (Table 11). The majority (≥ 75%) of
responses were in the very good category for the five facial areas treated. However,
the survey tool was not described and no statistical analyses were reported.
Table 11. Semi-permanents filler for ageing - patient satisfaction
Jacovello et
al. 2006
Level IV
N
40
Intervention
CaHA (Radiesse)
Very good
Good
Acceptable
18 month patient satisfaction* (%)
Glab (n=12) NLF (n=24) Lips (n=10) Nose (n=5) Infraoral
(n=4)
75.0
83.3
80.0
100.0
100.0
16.6
8.3
20.0
0.0
0.0
8.3
8.3
0.0
0.0
0.0
MC, mouth corners; NA, not applicable; NLF, nasolabial folds; NR, not reported; NS, not significant,
* Description of patient satisfaction survey not given. Level of satisfaction reported as very good, good, and acceptable.
Safety outcomes for ageing
There was great variation in the level of adverse event reporting. Many adverse
events were reported in the text of the included studies, but were not quantified.
Permanent vs. temporary fillers
One RCT reported safety outcomes for a permanent PMMA filler compared with a
temporary collagen filler (Cohen et al. 2006).
Total adverse events
Randomised controlled trials
Cohen et al. (2006) reported that 21/128 (16%) of PMMA patients and 16/123 (13%)
of collagen patients experienced adverse events. Of the total number of wrinkles
treated, there were 26 (4%) adverse events in the PMMA group and 36 (6%) in the
collagen group. There was no significant difference in the number of adverse events
between the two groups.
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Mortality
Randomised controlled trials
Cohen et al. (2006) reported one death in the collagen group. Although the authors
did not consider the death to be treatment related, details were lacking.
Granuloma and lump formation
Randomised controlled trials
Cohen et al. (2006) reported that one patient in the collagen group experienced
granuloma or enlargement of the implant.
A total of 19 events of lumpiness occurred after the treatments (PMMA, n = 14
events; collagen, n = 5 events). In the PMMA group, it was reported that one lump
was present because PMMA had been used contrary to the protocol for lip
augmentation. One lump was reported to be a seborrheic keratosis, which was
diagnosed after excision (pathology showed no foreign body reaction).
Four to five years after initial treatment, five patients experienced six late adverse
events in the PMMA group. One patient had two severe nodular minimally to noninflammatory reactions in both nasolabial folds. These were treated with steroid
injections. There were four other mild events in four patients: lumpiness of the left
glabellar fold (n = 1), left radial wrinkle (n = 1); left marionette line (n = 1), and the
left nasolabial fold (n = 1). The lump in the left marionette line was excised.
Abscess formation and infections
Randomised controlled trials
Cohen et al. (2006) reported no cases of abscesses or infections in the PMMA group.
In the collagen group, there was one infection, and three instances of abscess
formation. Two (2%) patients underwent removal and/or drainage of abscesses.
One (1%) case of recurring herpes labialis occurred following treatment with PMMA.
Cohen et al. (2006) also reported one event of flu-like symptoms in both study arms.
However, the event in the collagen group was not considered to be treatment related.
Oedema, erythema and ecchymosis
Randomised controlled trials
Cohen et al. (2006) reported combined outcomes for oedema and erythema. In the
PMMA group, there were seven events of persistent oedema or erythema. In the
collagen group, there were 13 events; one of these events was reported to be
unrelated to the treatment.
Other adverse events
Randomised controlled trials
Cohen et al. (2006) reported that after PMMA injections, there were two events of
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rashes or itching lasting more than 48 hours; four increased sensitivity reactions; and
one event of temporary blurred vision. There was one other unspecified local
complication, and one other unspecified systemic complication. The systemic
complication was reported to be unrelated to treatment. Serum immunoglobulin G
levels were elevated in one (1%) patient undergoing PMMA injections after one
month. No cases of sensitisation reactions or visibility of the puncture site were
reported.
In the collagen group, there were six sensitisation reactions; two events where the
puncture site was visible, two events of rashes or itching lasting for more than 48
hours after injection; and one event of increased sensitivity. There was one other
(unspecified) local complication which the primary authors did not feel was related to
the treatment. Serum immunoglobulin G levels were elevated in one (1%) patient at
one, three, and six months after collagen injections. Levels were below normal in six
(5%) patients at one month, three (2%) at three months and one patient (1%) at six
months. It was reported that there was no blurred vision.
Permanent fillers
The four case series studies that examined permanent fillers for ageing reported
various adverse events (Cohen et al. 2007; Fulton et al. 2005; Mladick 1992; Reda-Lari
2008).
Total adverse events
Case series
Cohen et al. (2007) described that 28 adverse events occurred in 21/145 (14%)
patients, and that 20 adverse events in 15/145 (10%) patients were considered
treatment related.
Fulton et al. (2005) stated that 11/608 (2%) patients who underwent lip augmentation
with silicone particles experienced adverse events.
Reda-Lari (2008) noted that 111/1306 (8.5%) patients experienced adverse events
after PAAG treatment.
Mortality
Case series
Cohen et al. (2008) reported one case of death due to cardiac failure. The authors
believed it was unrelated to treatment.
Allergic reactions
Case series
Reda-Lari (2008) described that one patient of 1306 (0.1%) developed a local allergic
reaction eight hours after PAAG treatment for which oral antihistamine therapy was
unsuccessful, and intravenous corticosteroid injections were given three days later. A
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good response was reported.
Granuloma and lump formation
Case series
Cohen et al. (2007) reported 10 cases of lumpiness after PMMA treatment. Of these,
eight were considered mild, one moderate and one severe. There was also a case
where there was mild prominence of the implant. Cohen et al. (2007) also reported
two cases of granuloma or enlargement of the implant. One case presented as an
inflammatory, lumpy area in the lip and the melabial fold six months after the last
PMMA injection. The area was treated with intralesional steroids followed by
intraoral excision. The event was classified as being of moderate intensity. The
patient did not consent to follow-up. The other case presented as a lumpy, inflamed
nodule in each of the nasolabial folds approximately five years after treatment. It was
considered severe in intensity. The affected areas partially responded with
intralesional steroid therapy. No histological examination was conducted in either
patient.
Fulton et al. (2005) stated that 11/608 (2%) patients developed small palpable
granulomas after lip augmentation. In four cases, these were not treated; five were
given intralesional steroids; and two were excised. Pathology of the excised lumps
demonstrated granuloma formation.
Another study noted that one of 40 patients (3%) had a palpable nodule under the
mucosa of the lower lip, which was excised (Mladick 1992).
Reda-Lari (2008) reported that 56/1306 (4%) patients reported lumps after PAAG
treatment. The lumps were felt only on palpation and caused no cosmetic
disfigurement. Patients were advised to massage the affected areas. No further
treatment was provided.
Abscess formation and infections
Case series
Mladick (1992) reported no infections at the treatment sites after injection of liquid
silicone.
Reda-Lari (2008) stated that infections occurred in 3/1306 (0.2%) patients. One
patient developed a severe infection in one cheek after 1.5 ml PAAG was injected
into each cheek. An infection occurred in the other cheek two days later. The patient
was given antibiotics, and underwent surgical removal of the gel. Culture of the
removed material revealed no bacteria. Over the following three months, small
amounts of pus were removed several times. All complications were resolved at 18
months follow-up. Another patient developed an infection one year after treatment
(at the same time, the patient was receiving hormone therapy for ovulation and had
recently had an influenza-like illness). The infection resolved after incision and
drainage under anaesthesia. The infection reccurred six months later. The gel was
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removed under anaesthesia at the patient’s request. Another patient developed
several episodes of minor infections in the malar area that resolved after perioral
antibiotics. The product was removed and the area was irrigated with sterile saline.
No pus was observed. This patient later developed contour deformities which were
corrected by a fat graft procedure two months after the removal of the product.
Oedema, erythema and ecchymosis
Case series
Cohen et al. (2007) described two cases of persistent swelling or redness, one of
which was considered mild and the other severe.
Fulton et al. (2005) reported that the majority of patients developed minor bruising
following lip augmentation procedures with silicone particles, but no data were
provided.
No cases of haematoma or erythema were reported in patients receiving liquid
silicone (Mladick 1992).
Reda-Lari (2008) recorded varying levels of oedema after injections with PAAG, and
that it normally resolved within three to four days. Three cases of intermittent
swelling and oedema were reported by one of 1306 (0.1%) patients, but these events
were not observed by the surgeon. The author suspected that the patient may have
had a subclinical infection because the swelling disappeared after antibiotic treatment.
Pain
Case series
Reda-Lari (2008) noted that patients usually experienced minor pain and discomfort
in the form of pressure or a burning sensation at the injection site, depending on the
amount of PAAG injected. Prolonged pain (persisting more than three months after
treatment) on deep pressure occurred in five of 1306 (0.4%) patients. These
symptoms disappeared within six months after steroidal anti-inflammatory drugs.
Other adverse events
Case series
Cohen et al. (2007) found two mild cases of increased sensitivity, two cases of
sensitisation reactions (one mild and one moderate), and a mild case of occasional
pain when scrubbing the face. Cohen et al. (2007) reported the following adverse
events to be unrelated to treatment: basal cell carcinoma (two cases), a scaly area on
the mid to right upper lip (one case), breast cancer (three cases) and Alzheimer’s
disease (one case).
Mladick (1992) stated that no skin sloughing, irregular contours or leakage through
the injection site was reported.
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Semi-permanent vs. temporary fillers
Two RCTs compared semi-permanent fillers with temporary fillers for ageing
(Moers-Carpi et al. 2007; Smith et al. 2007).
Total adverse events
Randomised controlled trials
Moers-Carpi et al. (2007) did not find any serious adverse events requiring
intervention. No other safety information was reported.
Smith et al. (2007) noted 316 adverse events in the CaHA injected nasolabial folds
and 289 in the collagen injected folds in 117 patients. No serious adverse events were
reported, and all adverse events resolved without sequale.
Allergic reactions
Randomised controlled trials
Smith et al. (2007) stated that no allergic reactions occurred.
Granuloma and lump formation
Randomised controlled trials
Smith et al. (2007) found that one nodule had occurred in one of 117 (1%) patients
on the CaHA side of the face. Three of 117 (3%) patients experienced nodules on
the collagen side of the face. The instances of nodules were not significantly different
between treatments. No granulomas occurred.
Abscess formation and infections
Randomised controlled trials
Smith et al. (2007) reported that no infections occurred.
Oedema, erythema and ecchymosis
Randomised controlled trials
Smith et al. (2007) noted that many patients experienced oedema, erythema and
ecchymosis in the nasolabial folds after dermal filler injections. There were
significantly more events of oedema and ecchymosis in the nasolabial folds that had
been injected with CaHA than in the nasolabial folds that had been injected with
collagen (Table 12).
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Table 12. Semi-permanent vs. temporary fillers - adverse event reporting: oedema (swelling),
erythema (bruising) and eccymosis (bruising)
Smith et al.
2007
Level II
N
117*
117*
Intervention
CaHA (Radiesse)
one side of face
Collagen
(Cosmoplast) other
side of face
P-value
Oedema n (%)
86 (73.5)
Erythema n (%)
82 (70.1)
Ecchymosis n (%)
74 (63.2)
66 (54.6)
88 (75.2)
51 (43.6)
0.009
0.4636
0.0038
*It was stated that 115 and 113 patients were available at the 3 and 6 month follow-ups respectively, but authors used 117 patients to
calculate results.
Pain
Randomised controlled trials
Smith et al. (2007) reported that 34/117 (29%) patients experienced pain in the
nasolabial fold receiving CaHA compared with 27/117 (23%) folds that received
collagen. There was no significant difference between the groups.
Other adverse events
Randomised controlled trials
Smith et al. (2007) stated that 36/117 (31%) patients experienced other adverse
events in the nasolabial fold receiving CaHA compared with 28/117 (44%) folds that
received collagen. It was not reported what these events were. There was no
significant difference between the groups. It was also reported that 22/117 (19%)
patients experienced pruritis (itching) in the nasolabial fold receiving CaHA
compared with 26/117 (2%) folds that received collagen. There was no significant
difference between the groups. No cases of embolisation, erosion, extrusion,
haematoma or necrosis were reported.
Semi-permanent fillers
Two case series studies assessed injection with CaHA (Jacovello et al. 2006; Sklar &
White 2004).
Total adverse events
Case series
Jacovello et al. (2006) noted that were three adverse events (6% of injections) after
CaHA treatment in 40 patients.
Sklar & White (2004) reported that four of 64 (6%) patients experienced adverse
events following treatment. This equated to five adverse events in 101 treatments
(5%).
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Granuloma and lump formation
Case series
One patient in 40 (3%) in Jacovello et al. (2006) developed a lip nodule that was
surgically removed.
Sklar & White (2004) reported that palpable or visible lip nodularity occurred in three
of 64 (5%) patients, which represented 20% of lip patients. The nodules developed
two to four weeks after treatment. All patients were given intralesional
corticosteroids and improved.
Oedema, erythema and ecchymosis
Case series
In Jacovello et al. (2006), two of 40 (5%) patients were reported as having oedema
and haematoma.
Sklar & White (2004) described outcomes for oedema and ecchymosis together.
Results were not quantified, but were categorised as being mild. The oedema and
ecchymosis lasted on average two days for the lips and under eyes. They were judged
negligible for other areas. Patients were permitted to wear make-up over the treated
areas if they wished.
Other adverse events
Case series
Jacovello et al. (2006) stated that there were no systemic reactions, while Sklar &
White (2004) reported that no migration of material occurred.
Efficacy outcomes for HIV-associated lipoatrophy
Permanent vs. semi-permanent vs. temporary fillers
One pseudo-randomised controlled trial (Guaraldi et al. 2005) and two nonrandomised comparative studies (Negredo et al. 2006; Orlando et al. 2007) reported
outcomes of studies investigating permanent, semi-permanent and temporary fillers
for HIV-associated lipoatrophy.
Over-correction
Non-randomised comparative study
Over-correction refers to the injection of too much dermal filling substance into an
area. Over-correction can result in visibility of the substance under the skin, or
lumpiness at the site.
Negredo et al. (2006) reported two events of over-correction in two of 105 (2%)
patients that received PAAG treatment. In both cases, the substance was removed.
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Changes in skin thickness
Pseudo-randomised controlled trial
In a pseudo-randomised controlled trial, Guaraldi et al. (2005) compared PLA,
PAAG or AFT in patients with HIV-associated facial lipoatrophy. At baseline, there
was a significant difference in cheek thickness (mean dermal plus subcutaneous
thickness as measured by ultrasound of the right cheeks) between the three groups,
in favour of the AFT group (p < 0.001) (Table 13). At 24 weeks after the last
treatment session, the change in dermal plus subcutaneous thickness from baseline
for each intervention was equivalent for the three different interventions.
Non-randomised comparative studies
Orlando et al. (2007) administered PLA, PAAG or AFT (with and without PLA) to
patients with HIV-associated facial lipoatrophy. Significant increases in mean skin
thickness measurements using ultrasound were seen in both left and right cheeks for
all interventions 48 weeks after the end of treatment (Table 13).
Table 13. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy
- changes in skin thickness
Guaraldi et
al. 2005
Level III-1
N
Intervention
15
20
24
Orlando et al.
2007
Level III-1
N
PAAG (Aquamid)
PLA (New-Fill)
AFT
P-value
Intervention
130
91
24
54
299
PAAG (Aquamid)
PLA (Sculptra)
AFT + PLA
(Sculptra)
AFT
All patients
Dermal plus subcutaneous thickness* (right cheek), mean mm ± SD
Baseline (week 0)
Week 24†
Change
3.9 ± 2.0
8.4 ± 2.4
2.1 ± 3.0
4.9 ± 2.7
8.8 ± 3.9
3.5 ± 4.0
5.8 ± 2.6
9.7 ± 3.9
3.3 ± 4.1
< 0.001
0.352
0.687
Dermal plus subcutaneous thickness,‡ mean mm ± SD
Baseline
Week 48§
P-value
Baseline
Week 48§ P-value
Right cheek
Left cheek
3.7 ± 1.3
10.0 ± 3.1 < 0.0001
3.8 ± 1.4
10.0 ± 3.2 < 0.0001
4.3 ± 2.0
8.7 ± 2.8
< 0.0001
4.5 ± 2.4
8.9 ± 2.9
< 0.0001
5.1 ± 2.5
9.5 ± 3.3
< 0.0001
5.5 ± 2.3
9.5 ± 3.5
< 0.0001
5.2 ± 2.1
4.3 ± 1.9
9.4 ± 2.6
9.5 ± 3.0
< 0.0001
< 0.0001
5.2 ± 2.1
4.4 ± 2.0
9.8 ± 2.8
9.6 ± 3.1
< 0.0001
< 0.0001
SD, standard deviation
*
Measured by ultrasound/ultrasonography.
†
24 weeks after last treatment session
‡
As measured by ultrasound. Three measurements made and the most reproducible recorded.
§
48 weeks after end of treatment
Observer ratings of appearance
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that an unspecified number of independent reviewers
conducted qualitative pre- and post treatment measurements of standardised picture
comparisons and were unable to determine which interventional method had been
performed. No data were reported.
Non-randomised comparative studies
Negredo et al. (2006) reported the improvement in lipoatrophy score after filler
treatment (Table 14). The degree of HIV-lipoatrophy was classified according to a
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facial lipoatrophy intensity ordinal scale, established by the study team.
In the PAAG arm at baseline, 11/105 (10%) patients had degree one lipoatrophy, 43
(41%) patients had degree two, 41 (39%) patients had degree three, and 10 (10%)
patients had degree four. After injections of PAAG, 98 (97%) patients improved (to
grade zero, one or two), and 19 (19%) patients showed no clinical signs of facial
lipoatrophy. At week 48, no patients had worsened to grade three or four, and 51
(78%) patients were classified as grade zero or one.
In the PLA arm at baseline, five of 25 (20%) patients had degree one lipoatrophy,
nine (36%) patients had degree two, nine (36%) patients had degree three, and two
(8%) patients degree four. After treatment with PLA, most patients were regarded as
having a lesser degree of clinical lipoatrophy. At week 48, one (5%) patient remained
without apparent facial lipoatrophy, and two (10%) relapsed to grade three.
In the AFT arm of the study at baseline, three of eight (38%) patients had degree two
lipoatrophy, and five (62%) patients had degree three. After initial treatment, all
patients improved at least one degree. At week 48, all patients except one (degree two
at baseline) worsened again to their baseline degree of lipoatrophy.
After the evaluation at week 48, the treating physician considered a second round of
injections necessary in 33/93 (35%) patients: seven out of 8 (88%) AFT patients,
17/20 (85%) PLA patients, and 5/65 (8%) PAAG patients.
No statistical analyses were reported.
Table 14. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy
– observer ratings of appearance
Negredo et
al. 2006
Level III-2
N
26║
8
†
‡
§
║
Degree of lipoatrophy*, (% patients)
After 1st round of injections†
Baseline
115§
*
Intervention
PAAG
(Aquamid)
PLA (NewFill)
AFT
P-value
Week 48‡
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
-
10
41
39
10
19
49
28
3
1
22
56
22
-
-
-
20
36
36
8
28
40
28
4
-
5
40
45
10
-
-
-
38
62
-
13
50
38
-
-
13
-
25
62
-
NA
NR
NR
Results measured using facial lipoatrophy intensity ordinal scale (established by the study team): degree 0, no facial lipoatrophy, to degree
4, all areas severely affected. Photographs evaluated by 2 blinded independent observers.
First round of injections consisted of 2 treatment sessions for PAAG group (2 weeks apart), and 3 treatment sessions for PLA group (2
weeks apart).
At the 1 year (ie week 48) follow-up 17/20 (85%) of the PLA group; 5/65 (8%) of the PAAG group, and 7/8 (88%) of the AFT group required
a second round of injections.
10 patients dropped out of follow-up (after the first intervention) and were not included in the analyses. After first intervention, 101 patients
included in analyses (4 lost to follow-up). At week 48, 65 patients included in analyses (30 lost).
1 patient dropped out of follow-up (after the first intervention) and was not included in the analyses. At week 48, 20 patients included in
analyses (5 lost).
Patient satisfaction
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported aesthetic satisfaction as perceived by the patient and
measured on a VAS scale (magnitude not reported). Results indicated no overall
significant difference (week 0 – week 24 for each intervention) between the three
interventional arms (Table 15). It appeared that at week 24, PLA and PAAG were
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significantly better than AFT, but only one p-value was supplied, making it difficult
to determine which product was statistically improved.
Non-randomised comparative studies
Orlando et al. (2007) reported patient aesthetic satisfaction using a VAS scale. At 48
weeks after the last intervention, patients in all groups had significantly better mean
VAS scores than at baseline (Table 15).
Negredo et al. (2006) reported patient satisfaction for the three study arms
collectively (n = 138 for all patients). After the first round of injections 134 (97%)
participants reported a positive impression with results; only four (3%) considered
that the procedure was insufficient (Table 15). A similar degree of approval was
achieved for all the different grades of facial lipoatrophy in the three treatment
groups. After treatment, a total of 120/128 (87%) of patients at week 24 and
116/138 (84%) at week 48 reported being completely satisfied. No statistical analyses
were reported.
Table 15. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy
- patient satisfaction
Guaraldi et
al. 2005
Level III-1
N
Baseline
20
15
24
Orlando et
al. 2007
Level III-2
Negredo et
al. 2006
Level III-2
Intervention
N
PLA (New-Fill)
PAAG (Aquamid)
AFT
P-value‡
Intervention
20 ± 20
25 ± 22
25 ± 16
0.759
Baseline
130
91
24
54
299
N
PAAG (Aquamid)
PLA (Sculptra)
AFT + PLA (Sculptra)
AFT
All patients
Intervention
2.7 ± 2.0
3.3 ± 2.1
1.9 ± 1.9
2.5 ± 2.3
2.9 ± 2.1
149**
PAAG (Aquamid), PLA
(New-Fill) and AFT†
Satisfied
Unsatisfied
Aesthetic facial satisfaction* score (mean ± SD)
Week 24†
Change
83 ± 17
51 ± 32
83 ± 17
57 ± 32
70 ± 22
38 ± 29
0.007
0.057
Aesthetic facial satisfaction§ score (mean ± SD)
Week 48║
P-value
6.5 ± 2.2
< 0.0001
6.2 ± 2.0
< 0.0001
5.0 ± 2.4
0.002
5.9 ± 2.2
< 0.0001
6.2 ± 2.1
< 0.0001
Patient satisfaction¶ n, (%)
st
After 1 round of Week 24
Week 48
treatment
134 (97)
120 (87)
116 (84)
4 (3)
NR
NR
SD, standard deviation
*
Measured on a VAS scale. Magnitude of scale not specified.
†
24 weeks after last treatment session
‡
A p-value of 0.05 used for significant differences between baseline and week 24. Pos hoc comparisons were adjusted according to
Bonferroni’s correction.
§
Patients were asked “How satisfied are you with your facial image?” Response on a VAS (0, poorest satisfaction to 100, best
satisfaction).
║
48 weeks after last treatment session
¶
Measured using a 5-point Likert scale from not at all satisfied to completely satisfied
**
11 patients dropped out of follow-up (after the first intervention) and were not included in the analyses.
†
Results for this section not reported by intervention, and instead reported collectively. When the impact of treatments was compared
on all variables, there were no significant differences among the 3 treatment groups.
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Quality of life
Randomised controlled trials
Guaraldi et al. (2005) reported body image using an Italian translation of the ABCD
questionnaire (reference given was Guaraldi, in press at time of publication of study).
It appeared that there were significant improvements in patient’s perceptions (Table
16). P-values of less than 0.05 were reported, but it was unclear where the differences
were. In the study discussion, the authors stated that the AFT group was less
satisfied with body image at the end of treatment and experienced higher impact of
lipodystrophy in everyday life experiences. No data were reported.
Non-randomised comparative studies
Orlando et al. (2007) reported multiple quality of life outcomes (Table 16). Body
image was measured using the ABCD questionnaire (validated since Guaraldi et al.
2005 was published). Forty eight weeks after the last intervention, there were
significant improvements in body image perception for all treatment groups except
the AFT + PLA group. ABCD questions relating to the negative psychological and
behavioural consequences of lipodystrophy (questions 8a-8v of ABCD) showed a
significant decrease in negative psychological and behavioural consequences in the
PAAG and PLA groups as well as for the overall sample (p < 0.0001 for each
group), but not for the AFT and AFT + PLA groups. It was reported that there was
no statistically significant difference between groups for questions 7 and questions
8a-8v scores. Orlando et al. (2007) also reported depression scores using the BDI.
Forty eight weeks after the last intervention, the BDI revealed a significant
improvement in the depression score for the overall cohort (p < 0.001), the PAAG
group (p = 0.014), and the PLA group (p = 0.001) compared with baseline. There
was no significant difference for the AFT and AFT + PLA groups.
Negredo et al. (2006) assessed quality of life outcomes with the Medical Outcomes
Study-HIV (MOS-HIV) questionnaire for all of the study patients collectively (n =
138) (Table 16). The MOS-HIV scores were transformed on a zero to 100 scale,
where higher scores indicated better health. Only the three domains with lower
scores at baseline were reported. At week 24 after treatment, there were significant
improvements in general health perception (p < 0.001), mental health (p = 0.002)
and energy level (p < 0.001) collectively for the patients included in the study. This
was maintained at week 48: general health perception, p < 0.001; mental health, p =
0.009; and energy level, p = 0.003. When the impact of the treatments was compared
on all psychological variables, there were no significant differences among the three
treatment groups (p-value not reported).
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Table 16. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy
– quality of life outcomes
Guaraldi et
al. 2005
Level III-1
N
Intervention
20
15
24
PLA (New-Fill)
PAAG (Aquamid)
AFT
P-value‡
Intervention
N
20
15
24
Orlando et al.
2007
Level III-2
N
130
91
24
54
299
N
130
91
24
PAAG (Aquamid)
PLA (Sculptra)
AFT + PLA
(Sculptra)
AFT
All patients
Intervention
4.2 ± 0.9
3.7 ± 0.9
0.0017
3.8 ± 1.0
3.1 ± 1.0
< 0.0001
ABCD* q8a-8v In the past 4 weeks the change in my body made me…
(perceptions, social and relational psychological consequences§ (mean ±
SD)
72.6 ± 16.9
78.2 ± 18.4
0.002
70.3 ± 17.5
78.6 ± 15.2
0.001
62.5 ± 16.1
69.2 ± 21.9
NS
54
299
N
PAAG (Aquamid)
PLA (Sculptra)
AFT + PLA
(Sculptra)
AFT
All patients
Intervention
PAAG (Aquamid)
PLA (Sculptra)
AFT + PLA
(Sculptra)
AFT
All patients
Intervention
149**
149**
All groups††
All groups††
Baseline
Week 24
P-value‡‡
10.4 ± 8.7
NS
9.4 ± 7.8
0.001
MOS-HIV Domain¶ (mean ± SD)
General health
Mental health
Energy level
perception
45.2 ± 17.9
68.3 ± 19.1
65.7 ± 14.6
55.7 ±19.2
75.9 ± 17.2
75.8 ± 17.8
< 0.001
0.002
< 0.001
149**
All groups††
Week 48
P-value‡‡
58.2 ± 14.1
< 0.001
54
299
N
130
91
24
Negredo et
al. 2006
Level III-2
PLA (New-Fill)
PAAG (Aquamid)
AFT
P-value‡
Intervention
ABCD* q7 Overall, how satisfied are you with your body look right now?†
(mean ± SD)
Baseline
24 weeks after last
Change
treatment
4.1 ± 1.1
3.0 ± 1.3
-1.1 ± 1.3
3.8 ± 1.1
2.7 ± 1.3
-1.1 ± 1.3
3.9 ± 1.1
3.6 ± 1.0
-0.3 ± 1.1
NS
0.044
0.018
ABCD* q8a-8v In the past 4 weeks the change in my body made me…
(perceptions, social and relational psychological consequences§ (mean ±
SD)
Baseline
24 weeks after last
Change
treatment
64 ± 20
82 ± 15
18 ± 20
63 ± 23
77 ± 23
13 ± 16
63 ± 17
65 ± 21
22 ± 16
0.003
0.016
0.012
Baseline
48 weeks after last
P-value
treatment
ABCD* q7 Overall, how satisfied are you with your body look right now?†
(mean ± SD)
3.7 ± 1.0
2.9 ± 1.1
< 0.0001
3.7 ± 0.9
3.0 ± 0.9
< 0.0001
3.6 ± 1.5
3.2 ± 0.8
NS
68.7 ± 14.7
40.7 ± 16.7
11.8 ± 8.5
10.7 ± 7.4
15.6 ± 10.5
10.0 ± 8.3
11.4 ± 8.3
74.1 ± 15.4
NS
77.2 ± 17.2
< 0.0001
Depression (BDI Scale)║(mean ± SD)
9.6 ± 8.1
0.014
8.0 ± 6.5
0.001
12.7 ± 12.1
NS
75.1 ± 19.7
0.009
72.3 ± 19.6
0.003
Continued over page
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Table 16. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy
– quality of life outcomes continued
HIV; Human Immunodeficiency Virus; MOS-HIV, Medical Outcome Study, MOS-SF 36, Medical Outcome Study Short Form 36-item health
survey; NR, not reported; NS, not significant
*
Body image evaluation performed with an Italian translation of Adult AIDS Clinical Trails Group Assessment of Body Change and Distress
(ABCD) questionnaire.
†
Responses on a 5 point Likert scale (1, best satisfaction to 5, poorest satisfaction)
‡
A p-value of 0.05 used for significant differences between baseline and week 24. Pos hoc comparisons were adjusted according to
Bonferroni’s correction.
§
Measurement scale not reported.
║
Beck Depression Inventory used to assess depression. Self administered. The higher the score the greater the status of depression. Total
possible score ranging from 0 to 63.
¶
Only these 3 aspects were reported. Reported as being the areas with lower scores.
**
11 patients dropped out of follow-up (after the first intervention) and were not included in the analyses.
††
Results for this section not reported by intervention, and instead reported collectively for all groups. When the impact of treatments was
compared on all psychological variables, there were no significant differences among the 3 treatment groups.
‡‡
vs. baseline
Permanent fillers
One case series evaluated the efficacy of PAAG injections for HIV-associated
lipoatrophy (De Santis et al. 2008). Another case series study evaluated the efficacy of
liquid silicone injections for HIV-associated lipoatrophy (Jones et al. 2004).
Over-correction
Case series
Jones et al. (2004) reported no events of over-correction.
Changes in skin thickness
Case series
De Santis et al. (2008) reported that mean cheek thickness measured with
ultrasonography was 4.5 ± 2.5 mm before treatment with PAAG and 8.4 ± 2.7 mm
at the 6-month follow-up (p = 0.028).
Jones et al. (2004) reported that all patients selected for inclusion in their study had
complete correction of their facial lipoatrophy.
Patient satisfaction
Case series
De Santis et al. (2008) reported that patients were asked to objectively quantify
themselves on a score of 1 to 100 with regard to their satisfaction with their
appearance (higher scores represented greater satisfaction). Before treatment, mean
VAS scores (± SD) were 25 ± 20. This increased to 69 ± 17 after PAAG treatment
(p < 0.0001).
Jones et al. (2004) reported that the great majority of patients were exceptionally
satisfied with their treatment. In those patients that had prior treatment with
temporary fillers, silicone treatment was preferred.
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Quality of life outcomes
Case series
De Santis et al. (2008) reported quality of life outcomes for patients who received
PAAG for HIV-associated lipoatrophy (Table 17). The authors reported that results
of question seven of the Assessment of Body Change and Distress (ABCD)
questionnaire indicated that patients had an increase in satisfaction with their
personal body image (p = 0.004). Results of question eight of this questionnaire
showed that there was no significant difference in the impact that lipodystrophy had
on a patient’s relational life after treatment. Using the BDI, there was a significant
decrease in depression scores after patients had been treated with PAAG (p = 0.018).
Table 17. Permanent fillers for HIV-associated lipoatrophy – quality of life outcomes
De Santis
et al. 2008
Level IV
*
†
‡
§
N
Intervention
50
N
PAAG (Aquamid)
Intervention
50
N
50
PAAG (Aquamid)
Intervention
PAAG (Aquamid)
Baseline
At 6 month follow-up
P-value
ABCD* q7 Overall, how satisfied are you with your body look right now?†
(mean ± SD)
3.7 ± 1.1
3.0 ± 1.1
0.004
ABCD* q8a-8v In the past 4 weeks the change in my body made me…
(perceptions, social and relational psychological consequences‡ (mean ±
SD)
63.0 ± 25.6
70.4 ± 30.0
0.219
Depression (BDI Scale§) (mean ± SD)
15.3 ± 9.6
12.1 ± 9.2
0.018
Body image evaluation performed with an Italian translation of Adult AIDS Clinical Trails Group Assessment of Body Change and
Distress (ABCD) questionnaire.
Responses on a 5 point Likert scale (1, best satisfaction to 5, poorest satisfaction)
Measurement scale and magnitude not reported.
Beck Depression Inventory. The higher the score the greater the status of depression.
Semi-permanent fillers
One RCT (Carey et al. 2007) and five case series reported efficacy outcomes for
treatment of HIV-associated lipoatrophy with semi-permanent fillers (Cattelan et al.
2006; Lafaurie et al. 2005; Mest & Humble 2006; Valantin et al. 2003; Silvers et al.
2006).
Changes in skin thickness
Randomised controlled trials
Carey et al. (2007) reported that PLA did not increase facial soft tissue volume after
treatment (Table 18). At week 24, a difference of 10 (95% CI: -7 to 28) cm3 between
the immediate and deferred groups was reported, representing a 0% and -3% change
in facial soft tissue volume respectively. At week 24, 5/50 (16%) of the immediate
group and 5/50 (10%) of the deferred group had a less than 10% increase in facial
soft tissue volume (p = NS). Treatment efficacy assessed by change in facial soft
tissue volume at week 24 did not differ significantly between any subgroup.
The immediate group had a significantly greater mean change in tissue depth at the
maxilla and base of nasal septum levels relative to the deferred group (2.2 [95% CI:
1.6 to 2.9] mm (p < 0.0001) and 1.0 [95% CI: 0.3 to 1.6] mm (p = 0.003)
respectively). There was no difference in facial thickness at the orbit and mandible
(these were untreated areas).
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Analyses to investigate predictors of efficacy yielded inconsistent data. In a
multivariate analysis, significant predictors of a greater increase in facial soft tissue
volume at week 24 were prior AIDS (p = 0.002) and current PI therapy (p < 0.0001).
Predictors of a greater increase in facial thickness at the maxillary level were
Fitzpatrick skin types IV to VI (p = 0.035) and an improvement in limb fat from
baseline to week 24 (p = 0.072). At the base of the nasal septum level, there was a
trend for a greater increase in facial thickness to be associated with a limb fat increase
between baseline and week 24 (p = 0.059).
Case series
Changes in skin thickness after semi-permanent dermal filler treatment for HIVassociated lipoatrophy are shown in Table 18.
Cattelan et al. (2006) reported a significant increase in cutaneous skin thickness of all
patients after completion of treatment (p < 0.001 for left and right side of face). This
improvement remained present at the end of the 12 month follow-up period (p <
0.001 for left and right side of face), although there was a reduction in the total
cutaneous thickness (mean reduction of 0.9 mm [range 0 - 1.8 mm] on the right side
and 1.06 [range 0.2 – 1.9 mm] on the left side) at two and 12 months.
A study by Lafaurie et al. (2005) demonstrated an increase in dermal thickness at the
injection sites in both cheeks using three-dimensional photographs. Among the 49
(52%) patients followed-up, the median increase in dermal thickness was 1.9 mm at
the end of treatment compared with baseline, and was maintained at 2.3 mm at the
last follow-up visit (the last follow-up visit was the last visit in the study, or the visit
at which a new set of injections of PLA was judged necessary, which varied between
patients). Although it was stated that this increase was significant, no statistical data
were reported.
Mest & Humble (2006) reported mean skin thickness increases (using skin callipers)
after PLA treatment and found that compared with baseline skin thickness, patients
at the end of treatment had a mean 65% increase, which increased to 69% at six
months, and was maintained at 73% at the 12 month follow-up period. The increases
in skin thickness were statistically significant at all time points compared with
baseline (p < 0.001).
Valantin et al. (2003) found significant increases in total cutaneous thickness (TCT)
from baseline, as measured by ultrasound evaluation at weeks 6, 26, 48, 72 and 96
after treatment (p < 0.001 for all time points). Valantin et al. (2003) also reported the
number of patients with TCT greater than 10 mm after PLA treatment. At six weeks
(the time of the last treatment), nine of 48 (19%) patients had TCT measurements
greater than 10 mm. At 24 weeks, this increased to 20/49 (41%) patients. At 48
weeks 30/49 (61%) had TCT measurements greater than 10 mm. At 72 and 96 weeks
follow-up, 25/48 (52%) and 18/42 (43%) patients had TCT measurements greater
than 10 mm respectively. No statistical analyses were reported.
Silvers et al. (2006) reported skin thickness measurements as determined by skin
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callipers. It was found that there was a significant increase in skin thickness from
baseline at three, six, and 12 months after CaHA treatment. The statistical
significance of these results was unclear, as both p < 0.0001 and p < 0.05 were
reported in different sections of the study.
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Table 18. Semi-permanent fillers for HIV- associated lipoatrophy - changes in skin thickness
Carey et
al. 2007
Level II
N
Intervention
(cm3),
FSTV*
mean [95%
CI]
50
N
PLA (Sculptra)
Immediate
PLA (Sculptra)
Deferred
Between-group
difference
P-value
Intervention
50
PLA (New-Fill)
6.7
(4.9–7.5)
Lafaurie
et al.
2005
Level IV
N
P-value
Intervention
Mest &
Humble
2006
Level IV
N
NA
NA
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
Maximal increase in dermal thickness from baseline§, median mm (min; max)
End of treatment ║ (n = 49)
Last follow-up¶ (n = 36)
Right cheek
Left cheek
Right cheek
Left cheek
1.9 (0.5; 4.7)
1.9 (0.4; 5.5)
2.4 (0.7; 6.1)
2.2 (0.9; 5.9)
NR**
NR**
NR**
NR**
††
Skin thickness , change from baseline, mean mm (SE)
End of treatment (n = 97)
6 month follow-up (n = 71) 12 month follow-up (n =
75)
3.8 (0.23)
4.0 (0.25)
4.2 (0.25)
Valantin
et al.
2003
Level IV
N
50
Cattelan
et al.
2006
Level IV
Silvers
et al.
2006
Level IV
94
99‡‡
PLA (New-Fill)
P-value
Intervention
PLA (name not
specified)
P-value
Intervention
0 [-14 - 14]
Week 24 change from baseline
Linear measurements†, mean mm [95% CI]
Orbit
Maxilla
Nasal septum
Mandible
(untreated)
(untreated)
0.1 [-0.3 - 0.5]
2.3 [1.7 - 2.8]
1.3 [0.7 - 1.8]
0.5 [-0.2 - 1.2]
-10 [-22 - 1]
10 [-7 - 28]
-0.3 [-0.6 -0.1]
0.1 [-0.3 - 0.4]
0.3 [-0.1 - 0.6]
0.4 [-0.9 - 1.8]
0.3 [-0.2 - 0.9]
2.2 [1.6 - 2.9]
1.0 [0.3 - 1.6]
0.1 [-1.4 - 1.6]
NS
NS
< 0.0001
0.003
NS
Cutaneous skin thickness‡, mean mm (range)
Difference between
Baseline (n = 50)
After 4 or 6
baseline and
baseline and
sessions (n = 50)
month 2 (n = 50)
month 12 (n = 50)
Right
Left
Right
Left
Right
Left
Right
Left
6.6
(4.7–7.4)
10.9
(8.5–
12.3)
< 0.001
Baseline
(n = 50)
50
PLA (New-Fill)
2.9
(2.0–5.5)
P-value
Intervention
NA
N
50
PLA (New-Fill)
N
Intervention
100
CaHA
(Radiesse)
P-value¶¶
11.0
(9.3–
12.6)
4.3
(2.7–6.2)
< 0.001
4.4
(2.7–6.1)
3.4
(2.3–4.9)
3.3
(1.6–5.0)
< 0.001
Changes in total cutaneous thickness‡, mm median (range)
Week 6
Week 24
Week 48
Week 72
Week 96
(n = 48)
(n = 49)
(n = 49)
(n = 48)
(n = 42)
+5.1
(2.2–8.6)
+6.4
(3.1–9.1)
+7.2
(4.2–9.6)
+7.2
(3.5–9.6)
+6.8
(3.9–10.1)
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
Patients with TCT > 10 mm§§, n (%) [range, mm]
Week 6
Week 24
Week 48
Week 72
Week 96
(n = 48)
(n = 49)
(n = 49)
(n = 48)
(n = 42)
9 (19)
20 (41)
30 (61)
25 (52)
18 (43)
[9 – 33mm]
[27 – 56 mm]
[46 – 75 mm]
[37 – 67 mm]
[28 – 59 mm]
Skin thickness║║, mean (mm)
Baseline
3 months
6 months
12 months
Left
Right
Left
Right
Left
Right
Left
Right
4.7
4.9
7.3
8.0
7.1
7.5
6.9
7.0
NA
< 0.0001 or < 0.05
< 0.0001 or < 0.05
< 0.0001 or < 0.05
Continued over page
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Table 18. Semi-permanent fillers for HIV- associated lipoatrophy - changes in skin thickness
continued
Facial soft tissue volume (FSTV) measured by spiral CT scan of the head and 3 dimensional post processing software.
The maximum distance from each landmark to the skin.
‡
Measured by ultrasound/ultrasonography
§
Measured from three dimensional digital photographs. Increase in dermal thickness as compared to baseline photographs taken
before the first injection. Three dimensional photographs were evaluated for the first 50 patients only.
||
Median number of injections was 5 (range 1 – 7) given every 2 weeks.
¶
Median follow-up was 12 months (range 1 – 27 months).
**
Authors stated results were significant in Discussion, but no p-value given.
††
Mean skin thickness is the mean of the left and right side skin thickness measurements. Measured by skin calipers.
‡‡
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the analyses. 1
patient dropped out after third treatment before complete correction.
§§
Primary end point was the proportion of responders with a total cutaneous thickness measurement > 10 mm measured at the
nasogenian fold at week 24 (measured by ultrasonography). Value of 10 mm was chosen arbitrarily as a median range in non-HIV
infected individuals.
║║
As determined by skin calipers.
¶¶
Significance for each subset was reported to be at p < 0.0001 in text, and p < 0.05 in figure.
NA, not applicable; NR, not reported; SD, standard deviation; TCT, total cutaneous thickness
FSTV, facial soft tissue volume
*
†
Observer ratings of appearance
Randomised controlled trials
Carey et al. (2007) assessed lipoatrophy on a scale of zero, none; to three, severe at
baseline, week 12 and week 24. At week 12, practitioners perceived a reduction in
severity in 45/50 (90%) of the immediate group, and 10/50 (20%) of the deferred
patients (p < 0.0001) (Table 19). At week 24, 43/50 (86%) of PLA recipients were
perceived to have improved compared with 10/50 (20%) in the deferred group (p <
0.0001).
Case series
Silvers et al. (2006) reported that all patients were considered improved or better
(defined as a Global Aesthetic Improvement Scale (Narins et al. 2003) rating ≤ 3) at
three, six, and 12 months following treatment (Table 19). At 18 months (one year
from the last treatment), 85/94 (90%) of patients were rated as improved or better,
with no patient rating worse. No statistical analyses were reported.
Table 19. Semi-permanent fillers for HIV- associated lipoatrophy - observer ratings of
appearance
Carey et al.
2007
Level II
N
Intervention
50
PLA (Sculptra)
Immediate
PLA (Sculptra)
Deferred
P-value
Intervention
CaHA (Radiesse)
50
Silvers et al.
2006
Level IV
N
100
3 months (n = 100)
6 months (n = 98)
12 months (n = 98)
18 months (n = 94)
Improvement in severity of lipoatrophy* from baseline, n patients (%)
Week 12
Week 24
45 (90)
43 (86)
10 (20)
< 0.0001
1 (very
much)
26.0
7.1
30.6
9.6
10 (20)
< 0.0001
Global Aesthetic Improvement Scale score (%)
2 (much)
3 (improved)
4 (no
change)
72.0
2.0
0
85.7
7.1
0
53.1
16.3
0
44.7
36.2
9.6
5 (worse)
0
0
0
0
NA, not applicable; NR, not reported
*Assessed on a scale of 0, none; to 3, severe
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Success of dermal filler treatment
Case series
Lafaurie et al. (2005) defined success by the proportion of patients in the study whose
VAS score for success was greater than baseline. Patients lost to follow-up, and
patients that discontinued treatment were considered failures. At the end of
treatment, PLA was considered successful in 77/94 (82%) of patients. At the end of
the last follow-up, PLA was considered to be successful in 69/94 (73%) of patients.
Patients with success were not different from patients with failure in any baseline
characteristic except that their VAS score for success was significantly lower (3 vs. 6,
p < 0.001). Patients with success received a higher median number of injections (5 vs.
4, p = 0.02).
Silvers et al. (2006) defined a successful and clinically meaningful outcome after
CaHA treatment as an improved or better Global Aesthetic Improvement Scale
rating (ie a rating of ≤ 3). At three, six, and 12 months, all patients were considered
improved. At 18 months, 85/94 (91%) patients were considered improved. No
statistical analyses were reported.
Patient satisfaction
Case series
Patient satisfaction outcomes after semi-permanent dermal filler treatment for HIVassociated lipoatrophy are provided in Table 20.
Lafaurie et al. (2005) used a 10 cm VAS scale to investigate patient’s satisfaction with
their facial lipoatrophy. There was an increase in VAS scores according to the
number of injections received, with a plateau obtained after three injections. At the
end of treatment, patients had a higher median VAS score than at baseline (p <
0.0001). This was also the case at the last follow-up assessment (p < 0.0001). The last
follow-up assessment was the last visit in the study, or the visit at which a new set of
injections of PLA was judged necessary. The median duration of treatment (time
between first and last injection) was 2.3 months (range 0.5 – 7 months).
Silvers et al. (2006) reported a greater than 90% satisfaction among patients receiving
CaHA treatment at three, six and 12 months when asked yes/no questions regarding
subjective outcomes of treatment.
Mest & Humble (2006) reported high patient satisfaction after treatment with PLA.
At the end of treatment, all of the patients surveyed had a mean satisfaction rating of
4.6 (on a scale of one, total dissatisfaction to five, total satisfaction). At the six month
follow-up, the 77 surveyed patients reported a mean satisfaction rating of 4.6. At the
12 month follow-up, the 75 patients surveyed reported a mean of 4.8. No statistical
analyses were reported.
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Table 20. Semi-permanent fillers for HIV- associated lipoatrophy - patient satisfaction
Lafaurie et
al. 2005
Level IV
Mest &
Humble 2006
Level IV
N
Intervention
94
PLA (New-Fill)
P-value
Intervention
N
99║
Silvers et al.
2006
Level IV
N
PLA (name not
specified)
Intervention
100
CaHA (Radiesse)
N
Intervention
100
CaHA (Radiesse)
N
Intervention
What is your satisfaction about the aspect of your face, in relation to the
lipoatrophy? VAS score*, median (min; max)†
Baseline (n = 94)
End of treatment (n =
Last follow-up
93)
assessment (n = 87)
3.4 (0; 9.3)
6.8 (1.7; 9.9)
7 (1.8; 9.5)
NA
< 0.0001
< 0.0001
Satisfaction score, mean rating‡
End of treatment§ (n =
6 month follow-up (n =
12 month follow-up (n =
97)
77)
75)
4.6
4.6
4.8
Has the treatment been beneficial to you?¶ (%)
3 months (n = 100)
6 months (n = 98)
12 months (n = 98)
Yes
No
Yes
No
Yes
No
100.0
0.0
100.0
0.0
100.0
0.0
Do you feel more attractive since
treatment?¶
(%)
3 months (n = 100)
6 months (n = 98)
12 months (n = 98)
Yes
No
Yes
No
Yes
No
2.0
98.0
2.0
99.0
1.0
98.0
Is your emotional well being better since treatment?¶ (%)
3 months (n = 100)
6 months (n = 98)
12 months (n = 98)
Yes
No
Yes
No
Yes
No
9.0
95.9
4.1
96.9
3.1
100
CaHA (Radiesse)
91.0
N
Intervention
Do you have more confidence in your appearance since treatment?¶ (%)
100
CaHA (Radiesse)
3 months (n = 100)
6 months (n = 98)
12 months (n = 98)
Yes
No
Yes
No
Yes
No
98.0
2.0
98.0
2.0
99.0
1.0
VAS scale designed for this study. Scale of 0, total dissatisfaction; to 10, total satisfaction.
†
The first assessment of VAS scores was performed before the first injection. VAS scores were assessed before each set of
injections, at the end of the treatment procedure, and at the end of follow-up. There was an increase in VAS scores according to
the number of injections received, with a plateau obtained after 3 injections.
‡
Evaluations on a scale of 1 = dissatisfied to 5 = very satisfied.
§
Patients received between 1 and 6 treatment sessions, as mutually agreed by physician and patient. Sessions were scheduled 3
weeks apart.
║
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the analyses. 1
patient dropped out after third treatment before complete correction.
¶
Questions modeled after the Feidburg Questionnaire on Aesthetic Dermatology and Cosmetic Surgery (Sommer et al. 2003).
NR, not reported
*
Patient-assessed severity of lipoatrophy
Randomised controlled trials
Patients in Carey et al. (2007) assessed their lipoatrophy on a scale of zero, none; to
three, severe, at baseline, week 12 and week 24. At 12 weeks, facial lipoatrophy
severity was perceived as improved in 45/50 (90%) PLA patients compared with
9/50 (18%) in the deferred group (p < 0.0001). At week 24, facial lipoatrophy
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severity was perceived improved in 42/50 (84%) PLA patients and 9/50 (18%)
deferred patients, respectively (p < 0.0001). There was a significant association
between self-assessed change in facial lipoatrophy severity and objectively assessed
change in facial thickness at the maxilla level (p = 0.026).
Case series
Cattelan et al. (2006) reported that at study entry, more than 50% of patients judged
the degree of their facial lipoatrophy as severe, whereas during the follow-up, more
than 50% of patients rated their lipoatrophy as absent or moderate. After finishing
the PLA injections, no patients considered their lipoatrophy as severe, and at month
12 of follow-up, only two patients judged their lipoatrophy as severe. An overall
significant improvement in facial lipoatrophy was observed during the study by all
patients (p < 0.01). The scale used to assess the degree of lipoatrophy was defined by
the use of a severity scoring system based on the sum of the patient’s own
perception, physician examination, and plastic surgeon assessment.
Would recommend treatment to others
Case series
Mest & Humble (2006) reported that of the 75 patients who physically completed the
study, all would recommend the PLA treatment to friends.
Silvers et al. (2006) reported that when asked at the three month follow-up, 99/100
(99%) patients reported that they would recommend CaHA treatment. At the six and
12 month follow-up visits, 97/98 (99%) patients reported that they would
recommend CaHA treatment.
No statistical analyses were reported for either study.
Practitioner satisfaction
Case series
Mest & Humble (2006) reported physician satisfaction at the end of treatment, at the
six month follow-up, and at the 12 month follow-up (for patients that returned for
follow-up). Satisfaction was rated on a scale of one (dissatisfied) to five (very
satisfied). Satisfaction scores were 4.5, 4.7 and 4.8 respectively at these time points.
Quality of life and other psychological outcomes
Randomised controlled trials
Carey et al. (2007) reported quality of life using the Short Form 36-item health survey
(SF-36) (Table 21). At week 12, the mean change from baseline in the score for the
SF-36 in PLA recipients was significantly different from the mean change in the
deferred group (p = 0.026). At week 24, the mean change in scores for Social
Functioning and Mental Health in the immediate group were significantly different
from mean changes in the deferred group (p = 0.031 and p = 0.047, respectively)
(Table 21). Although the mean score for five SF-36 scales increased in the immediate
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group, the mean score for all eight scales decreased in the deferred group.
Additionally, the mean change in the Mental Health Component Summary score
differed significantly in the immediate group relative to the deferred group (p =
0.048), but there was no difference in the Physical Component Summary score or in
any of the scales associated with physical functioning.
Carey et al. (2007) also reported body self-image outcomes as assessed using the
Multidimensional Body-Self Relations Questionnaire – Appearance Scales (MBSRQAS) (Table 21). Results showed that the mean change in appearance evaluation and
body areas satisfaction subscale scores in the immediate group was significantly
different from scores in the deferred group (0.19 and -0.03, p = 0.040 and 0.29 and 0.12, p < 0.0001, respectively) at week 12 and at week 24 (0.15 and -0.15, p = 0.010
and 0.19 and -0.11, p = 0.0004, respectively). No detail of the scoring scale was
reported.
Case series
Quality of life outcomes after semi-permanent dermal filler treatment for HIVassociated facial lipoatrophy are provided in Table 21.
Cattelan et al. (2006) reported that the MOS-HIV questionnaire given to PLA
patients revealed significant differences between baseline and 12 month follow-up
scores for six of the 11 health dimensions (mental health, energy/fatigue, health
distress, cognitive functioning, quality of life, and health transition: p < 0.01 for all).
No significant differences were found in the domains correlated with physical
functioning.
Lafaurie et al. (2005) reported no significant changes from baseline in mental and
physical quality of life scores using the Medical Outcomes Study-HIV (MOS SF-36)
survey at the end of treatment and at the last follow-up visit (p-values not reported).
Mest & Humble (2006) reported the results of an unspecified psychological
questionnaire. Patients verbally reported an increase in confidence and improved
self-image with treatment. It was reported that the vast majority of patients were
happy to be alive and this did not change with treatment. The trend was for patients
to be less sad with treatment and to feel that their facial appearance better reflected
the state of their health after treatment. No statistical analyses were reported.
Valantin et al. (2003) used a VAS to quantify quality of life changes for patients who
had received PLA treatment. Median quality of life results were significantly
improved from baseline at week 24 (p = 0.015), and week 48 (p = 0.021).
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Table 21. Semi-permanent fillers for HIV-associated lipoatrophy - quality of life and other
psychological outcomes
Carey et
al. 2007
Level II
N
100
Intervention
PLA (Sculptra)
N
Intervention
50
Cattelan
et al.
2006
Level IV
N
50
PLA (Sculptra)
immediate
PLA (Sculptra)
deferred
P-value
Intervention
PLA (New-Fill)
Lafaurie
et al.
2005
Level IV
N
Intervention
94
PLA (New-Fill)
P-value
94
PLA (New-Fill)
P-value
Intervention
PLA (name not
specified)
50
Mest &
Humble
2006
Level IV
N
99¶
Dimension
Quality of Life (SF-36v2) questionnaire results*
Difference from baseline at week 24
Immediate (n = 50)
Deferred (n = 50)
P-value
0.5
- 1.2
NS
Physical
functioning
Role physical
- 3.1
- 4.8
NS
Bodily pain
3.0
- 4.0
NS
General Health
- 3.7
- 4.1
NS
Physical health
- 1.2
- 1.3
NS
summary
Vitality
- 0.7
- 6.4
NS
Social functioning 2.0
- 7.0
0.031
Role emotional
0.3
- 4.8
NS
Mental health
3.2
- 3.2
0.047
Mental health
1.0
- 3.0
0.048
summary
Mean change MBSRQ-AS subscale scores†
Appearance
Body areas
Appearance
Body areas
evaluation
satisfaction
evaluation
satisfaction
Week 12
Week 24
0.19
0.29
0.15
0.19
-0.03
-0.12
- 0.15
- 0.11
0.040
< 0.0004
0.010
0.004
Quality of Life (MOS-HIV) questionnaire results‡
Dimension
Difference from baseline and month
P-value
12 follow-up, value (min; max)
Global health
0 (-4; 4.5)
NS
Pain
0.25 (-2.5; 4)
NS
Physical function
-0.25 (-2; 0.5)
NS
Role function
6 (-1; 14)
NS
Social function
-6 (-24.5; 17.5)
NS
Mental health
5 (2; 7)
< 0.01
Energy/fatigue
5 (2; 7)
< 0.01
Health distress
4.5 (1; 7)
< 0.01
Cognitive function
2.5 (0.5; 4)
< 0.01
Quality of life
7 (2; 12.5)
< 0.01
Health transition
16 (12.5; 24.5)
< 0.01
Quality of life (MOS SF-36) score, median (min; max)§
Baseline (n = 89)
End of treatment (n =
Last follow-up
90)
assessment (n = 87)
Mental component summary score
42.9 (17.9; 65.6)
44.8 (17.5; 63.5)
41.6 (17.5; 63.5)
NA
NS
NS
Physical component summary score
53.7 (25.8; 65.6)
52.8 (28.9; 63.5)
51.9 (28.9; 64.5)
NA
NS
NS
Psychological questionnaire║
NR
Continued over page
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Table 21. Semi-permanent fillers for HIV-associated lipoatrophy - quality of life and other
psychological outcomes continued
Valantin
et al.
2003
Level IV
N
Intervention
50
PLA (New-Fill)
P-value
Quality of Life** change from baseline, median (range)
Week 12 (n
Week 24 (n = Week 48 (n
Week 72 (n = Week 96 (n =
= 44)
44)
= 44)
44)
44)
+0.3
+0.8
+0.8
+0.4
+0.4
(–2.9- +10.0) (-3.9 - +10.0) (-2.9 - +10.0) (-3.3 - +10.0) (-3.9 +10.0)
0.165
0.015
0.021
0.209
0.120
Short Form (SF) 36v2 Health Survey from Ware and Sherbourne (1992). Details of scoring not reported.
†
Multidimensional Body-Self Relations Questionnaire – Appearance Scales (MBSRQ-AS). Details of scoring not reported.
‡
Medical Outcome Study Short Form 36-item health survey (MOS SF-36) from Wu et al. 1991. Scored on a 6 point scale: 0, not at
all; to 5, extremely. The scores for each dimension was calculated and transformed linearly to a score from 0 (lowest) to 100
(highest) QoL score. Confidence interval at 95% for differences between baseline and month 12 of follow-up (higher scores mean
a significant positive change).
§
Questionnaire from Wu et al. 1991 and Leplege et al. 2001. The mental and physical component summary scores (min 0, max
100) of the MOS SF-36 were analysed.
||
Description of questionnaire not provided. Patients verbally reported an increase in confidence and improved self-image with
treatment. Statistical correlation was not obtained. It was reported that the vast majority of patients were happy to be alive so this
did not change with treatment. The trend was for patients to be less sad with treatment and to feel that their facial appearance
better reflected the state of their health after treatment.
¶
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the analyses. 1
patient dropped out after third treatment before complete correction.
**
Measured on visual analogue scale. Details of scale not reported.
NR, not reported
NS, not significant
MOS-HIV, Medical Outcome Study, HIV
MOS-SF 36, Medical Outcome Study Short Form 36-item health survey
*
Safety outcomes for HIV-associated lipoatrophy
There was variation between studies in the level of adverse event reporting. Many
adverse events were reported in the text of the included studies, but were not
quantified.
Permanent vs. semi-permanent vs. temporary fillers
One pseudo-randomised controlled trial (Guaraldi et al. 2005) and two nonrandomised comparative studies (Negredo et al. 2006; Orlando et al. 2007) reported
adverse event outcomes after permanent, semi-permanent and temporary fillers for
HIV-associated facial lipoatrophy.
Total adverse events
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that eight of 20 (40%) patients in the PLA group had
adverse events, and that 13/24 (54%) patients in the AFT arm experienced adverse
events.
Non-randomised comparative studies
Negredo et al. (2006) reported that all patients in all groups encountered adverse
events (this included minimal and transient pain at the injection site for two to three
days). This equated to 28 events in the 26 PLA patients, 127 in the 115 PAAG
patients, and eight in the eight AFT patients.
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Mortality
Non-randomised comparative studies
Negredo et al. (2006) reported that one patient in the PLA group died of multifocal
leukoencephalopathy, which was unrelated to the study treatment. The results of this
patient were not included in the analysis of the study. It was not reported at what
stage of study the patient died.
Progression of HIV disease and AIDS-defining illness
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that none of the enrolled patients had any progression
of HIV disease. Mean CD4 cell counts and viral load were not significantly different
from baseline at week 24 (p-value not reported).
Non-randomised comparative studies
Orlando et al. (2007) reported that none of the patients experienced clinical
progression of HIV disease during the study period.
Adherence to antiretroviral treatment
Non-randomised comparative studies
Negredo et al. (2006) reported that there were no significant differences in the levels
of adherence between the three treatment groups during the treatment period (pvalue not reported).
Granuloma and lump formation
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that eight of 20 (40%) patients developed palpable
intradermal papules (< 3 mm) of non-reabsorbed PLA, which were visible when
patients blew their cheeks.
Non-randomised comparative studies
Negredo et al. (2006) reported that two of 25 (8%) patients from the PLA group
presented palpable subcutaneous micronodules in the malar (cheek) area.
Orlando et al. (2007) reported that nonvisible subcutaneous micronodules were
observed during the entire follow-up period in 52/115 (45%) patients who received
PLA.
Abscess formation and infections
Non-randomised comparative studies
Negredo et al. (2006) reported that two of 25 (8%) patients from the PAAG group
developed a superficial cutaneous infection, which was treated with oral antibiotics.
The specific type of bacteria was not identified.
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Orlando et al. (2007) reported that one patient in the PAAG group reported a local
cheek abscess two weeks after the last treatment. It required antibiotic treatment, and
all of the PAAG was removed. There was resolution of the event.
Oedema, ecchymosis and erythema
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that all patients in all treatment groups had minimal
oedema (Table 22). In the AFT arm of the study, nine of 24 (38%) patients had
moderate oedema that lasted up to 48 hours after surgery. No statistical analyses
were reported.
Non-randomised comparative studies
In Negredo et al. (2006) it was reported that all patients in all treatment groups had
minimal oedema (Table 22). It was also reported that ecchymosis were observed in
one (4%) of 25 PLA patients, and 18/105 (17%) PAAG patients. All cases resolved
spontaneously within three to five days. Eccyhmosis did not occur in any of the AFT
patients. No statistical analyses were reported.
Orlando et al. (2007) reported that the most frequent adverse event was ecchymosis,
reported at the injection sites. These events were transient and subsided
spontaneously after 12 to 24 hours.
Table 22. Permanent vs. semi-permanent vs. temporary fillers - adverse event reporting:
oedema (swelling) and eccyhmosis (bruising)
Study
Guaraldi et
al. 2005
Level III-1
N
20
15
24
Negredo et
al. 2006
Level III-2
115†
26‡
8
*
†
‡
§
Intervention
PLA (New-Fill)
PAAG (Aquamid)
AFT
P-value
PAAG (Aquamid)
PLA (New-Fill)
AFT
P-value
Oedema (% patients)
100.0
100.0
100.0*
NR
100.0
100.0
100.0
NR
Ecchymosis (% patients)
NR
NR
NR
NR
17.1§
4.0
0.0
NR
All patients had minimal oedema. 9 patients had moderate oedema that lasted up to 48h after surgery
10 patients dropped out of follow-up (after the first intervention) and were not included in the analyses.
1 patient dropped out of follow-up (after the first intervention) and was not included in the analyses.
7/21 (33%) women in PAAG group developed ecchymosis.
Pain
Pseudo-randomised controlled trial
It was reported by Guaraldi et al. (2005) that mild pain was observed in all patients.
There was no significant difference in the level of discomfort felt by patients in the
PLA group and the PAAG group at time of injection.
Other adverse events
Pseudo-randomised controlled trial
Guaraldi et al. (2005) reported that no serious adverse events occurred in the PLA
and PAAG groups. In the AFT group, four of 24 (17%) patients developed a
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disfiguring fat hypertrophy of the face occurring at the same time of recurrent fat
accumulation in the tissue harvest site (dorso-cervical fat pad in three cases, and in
the abdomen in one case).
Non-randomised comparative studies
Negredo et al. (2006) reported that no serious adverse events occurred in any of the
three study groups.
Orlando et al. (2007) found that no serious adverse events were reported, and no
patients interrupted treatment because of adverse events.
Permanent fillers
One case series study evaluated the safety of PAAG injections for HIV-associated
lipoatrophy (De Santis et al. 2008). Another case series study evaluated the safety of
liquid silicone injections for HIV-associated lipoatrophy (Jones et al. 2004).
Granuloma and lump formation
Case series
De Santis et al. (2008) and Jones et al. (2004) both noted no granulomas. Jones et al.
(2004) also reported no nodules.
Oedema, erythema and ecchymosis
Case series
De Santis et al. (2008) described that two patients of 50 (4%) mentioned a transitory
swelling or redness lasting from 12 to 24 hours after the procedure. Jones et al. (2004)
reported that most patients experienced mild post treatment erythema and oedema,
and occasionally mild tenderness, which in all cases resolved within three days.
Ecchymosis was occasionally noted (particularly in the temporal areas). All cases of
ecchymosis resolved within 14 days.
Pain
Case series
Jones et al. (2004) reported that the majority of patients experienced mild to
moderate discomfort related to multiple needle punctures required for the serial
puncture microdroplet technique, with only 5% or less requiring pre-treatment
analgesia beyond topical EMLA. No treatment was stopped because of patient
discomfort.
Abscess formation and infections
Case series
De Santis et al. (2008) noted no infections. Jones et al. (2004) reported no infections
and ulcerations.
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Other adverse events
Case series
De Santis et al. (2008) found that no significant clinical side effects were detected at
the 12-month follow-up. No colour alteration was reported. Jones et al. (2004)
reported that patients were continued to be followed for dyschromia, embolism, drift
and signs of connective tissue disease, and that none of these cases has occurred.
Semi-permanent fillers
One RCT (Carey et al. 2007) and five case series reported safety outcomes for
treatment of HIV-associated lipoatrophy with semi-permanent fillers (Cattelan et al.
2006; Lafaurie et al. 2005; Mest & Humble 2006; Silvers et al. 2006; Valantin et al.
2003).
Total adverse events
Randomised controlled trials
Carey et al. (2007) reported that 48/50 (96%) PLA patients experienced at least one
procedure/product-related adverse event, but that no treatment was delayed or
terminated for adverse events.
Case series
Cattelan et al. (2006) graded adverse and toxic events according to the AIDS Clinical
Trial Group/World Health Organisation toxicity scales. Adverse events that were
judged by the investigators to be related to treatment occurred in 15/50 (30%)
patients.
Lafaurie et al. (2005) noted that all patients experienced adverse events (including
local oedema at the injection site). There were 191 events in 94 patients.
Mest & Humble (2006) found that 43/98 (44%) patients experienced adverse events.
This equated to 121 adverse events of 479 treatments (25% of treatments). It was
reported narratively that most patients experienced swelling for a few days.
Valantin et al. (2003) described that there were 37 adverse events for 216 sets of
injections (17% of sets of injections). It was reported narratively that minimal and
localised oedema was seen in most patients.
Silvers et al. (2006) reported adverse events in relation to their severity (as determined
by the patient and physician). Of the adverse events, 58% were classed as mild, 39%
as moderate, and 3% as severe. The number of patients in each category was not
reported.
Mortality
Randomised controlled trials
Carey et al. (2007) reported that there were no deaths.
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Case series
Lafaurie et al. (2005) described that one patient died before starting PLA treatment,
and that this patient was not included in the results.
Silvers et al. (2006) reported that three patients died during the study period; two
before the six month follow-up, and one before the 18 month follow-up. It was
reported that these deaths were not related to the CaHA treatment, and the patients
were not included in the results.
Allergic reactions
Case series
One study reported a serious event in one of 94 (1%) patients (Lafaurie et al. 2005).
This patient developed a painful generalised oedema associated with inflammatory
non-infiltrated maculae on wrists, ankles and calves two days after the first injection
of PLA. This was diagnosed as an anaphylactic reaction, and the patient received an
oral non-steroidal anti-inflammatory drug. All signs and symptoms resolved within a
few days. No further injections of PLA were given to this patient.
Silvers et al. (2006) stated that no allergic reactions to CaHA were reported.
Progression of HIV disease and AIDS-defining illness
Randomised controlled trials
Carey et al. (2007) noted that there were no new AIDS-defining events. It was not
reported whether there were any existing AIDS-defining events.
Case series
Cattelan et al. (2006) found that no AIDS defining events were recorded during the
study period. There were no significant differences between CD4 cell counts and
viral load at baseline and month 12 of follow-up. All other reported biological
variables remained unvaried during the study.
Lafaurie et al. (2005) reported that two of 94 (2%) patients discontinued treatment
because of progression of HIV disease after three and five injections respectively.
Valantin et al. (2003) found that no AIDS defining events were recorded during the
study. Viral load and CD4 cell counts remained stable, with 90% of patients
maintaining their plasma HIV ribonucleic acid (RNA) levels < 5000 copies/ml
through 96 weeks.
Adherence to antiretroviral treatment
Randomised controlled trials
Carey et al. (2007) reported that patient-reported ART adherence was not
significantly different between the immediate and delayed groups. Forty eight of 50
(96%) patients of both groups reported a greater than 95% adherence at week 24.
Twenty one antiretroviral drugs were stopped in 15/100 (15%) participants (six
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immediate and nine deferred). Most (62%) changes were within-class substitutions;
60% of these were for regimen simplification. No participant ceased PI therapy or
tNRTI therapy. It was reported that there was one screening protocol violation in the
control arm. The patient had an HIV-1 RNA viral load in excess of 750,000
copies/mm immediately before screening and commenced a new PI-containing
regimen at week six. No participant commenced any prohibited concomitant
medication.
Case series
Cattelan et al. (2006) found that eight of 50 (16%) patients modified their initial
antiretroviral therapy (six patients because of inefficacy and two because of toxic
effects) after a median time from study entry of seven months (range 4 – 9 months).
Valantin et al. (2003) reported that the antiretroviral regimen for three of 50 (6%)
patients was temporarily discontinued and resumed without modification. In 13
(26%) patients, stavudine was switched to other nucleoside reverse transcriptase
inhibitors with a median delay of 9.5 months (range 4.7 – 23 months) from initiation
of injections (in three patients because of lipoatrophy; in four patients because of
inefficacy; in five patients because of other toxicities; and in one patient for personal
reasons), while two patients started stavudine.
Granuloma and lump formation
Randomised controlled trials
Carey et al. (2007) reported nodules as lumps greater than 10 mm and papules as
lumps smaller than 10 mm. Fourteen nodules were reported after 197 (7%)
treatments. The median time to onset was five days, and the median duration was 11
days. Eight papules were reported after 197 (4%) treatments. The median time to
onset was 3.5 days, and the median duration was 10 days. All nodule and papules
were regarded as grade one and two adverse events (having a score between one and
five on VAS). At week 24, there were four palpable and one visible ongoing
subcutaneous noninflammatory nodules and one papule at the injection site in six of
50 (12%) patients. These events were noted at the injection site five to 19 weeks after
the first injection.
Case series
One study noted that non-visible subcutaneous micronodules were not observed
during the entire follow-up period after PLA injections (Cattelan et al. 2006).
It was reported in Lafaurie et al. (2005) that 12/94 (13%) patients developed
subcutaneous non-inflammatory nodules at the injection site of PLA. These
developed two to nine months after the first injection. These small (2 - 4 mm)
nodules were detected by digital palpation and were not symptomatic. No biopsies
were performed and the authors stated that the state of these nodules would require
further follow-up.
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Mest & Humble (2006) described that 13/98 (13%) patients reported 15 events of
palpable lumpiness. Within this group two (2%) patients developed small (< 3 mm)
papules one month after PLA treatment, and 11 (11%) patients developed similar
lumps between three and four months after initial treatment. The majority (seven)
resolved completely over the next six months. The others remained the same size or
slightly smaller for the duration of the study. One patient reported a papule at the 12
month follow-up.
It was reported in Valantin et al. (2003) that 22/50 (44%) patients developed
palpable, non visible subcutaneous micronodules after PLA treatment. In six
patients, these spontaneously resolved at week 96.
Silvers et al. (2006) stated that no granulomas or nodules were reported.
Abscess formation and infections
Case series
Cattelan et al. (2006) reported that one of 50 (2%) patients developed ophthalmic
herpes zoster five days after the fourth injection of PLA. The patient was treated
with a 10-day course of oral acyclovir.
Mest & Humble (2006) and Silvers et al. (2006) reported no infections as a result of
PLA treatment.
Oedema and ecchymosis erythema
Outcomes for oedema, ecchymosis and erythema are shown in Table 23.
Randomised controlled trials
Adverse events in Carey et al. (2007) were recorded using a VAS (higher scores
indicate greater severity). Responses less than 50 mm on the VAS were considered
grade one and two adverse events, and responses 50 to 85 mm were considered
grade three and four adverse events. There were 132 events of oedema after 197
(67%) injections. Of these, 126/132 (95%) were considered grade one and two with
the rest being considered grade three and four. The median duration of all oedema
events was two days. There were 24 events of ecchymosis in 197 (12%) injections.
Twenty were considered grade one and two, and four were considered grade three
and four. The median duration of ecchymosis events was five days. There were 108
events of erythema in 197 (55%) injections. Most (96%) were considered grade one
and two, and had a median duration of two days. The remainder were considered
grade three and four and lasted a median of 6.5 days.
Case series
Cattelan et al. (2006) reported that 15/50 (30 %) patients had grade one oedema,
which resolved spontaneously within 12 - 24 hours. It was also reported that 12/50
(24%) patients developed grade one or two ecchymosis, which resolved
spontaneously within 12 - 24 hours. Cattelan et al. (2006) also reported that eight of
50 (16%) patients developed grade one or two erythema. Erythema was treated with
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topical corticosteroids and resolved within one to two days. Adverse and toxic events
were classified and graded according to the AIDS Clinical Trial Group/ World
Health Organisation toxicity scales.
Lafaurie et al. (2005) reported that all patients had local oedema, which resolved
within two to three days. It was also reported that a small bruising developed a few
minutes after an injection in one of 94 (1%) patients. This healed completely after
several days without any treatment.
Mest & Humble (2006) reported that 17/98 (17%) patients reported 20 cases of
oedema. Bruising was reported to have occurred in 30/99 (30%) patients. The
authors stated that clinically significant bruising occurred in 42/479 (9%) treatment
sessions. The bruising was described as self-limiting, and not bothersome to the
patients. Four cases of black eyes were reported. It was also reported that 5/98 (5%)
patients developed erythema after treatment.
Valantin et al. (2003) did not report values for oedema quantitatively, but stated that
most patients had minimal and localised oedema at the injection site, which resolved
in 24 - 48 hours. It was also reported that 15/50 (30%) patients developed minimal
ecchymosis following injection, which resolved spontaneously within two to three
days.
Silvers et al. (2006) reported that oedema, ecchymosis, and erythema were all
commonly seen at the time of any injection. Results were not quantified.
Table 23. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event reporting:
oedema (swelling) and ecchymosis (bruising) and erythema (redness)
Study
Carey et al. 2007
Level II
Cattelan et al. 2006
Level IV
Lafaurie et al. 2005
(Level IV)
Mest & Humble 2006
Level IV
Valantin et al. 2003
Level IV
Silvers et al. 2006
Level IV
N
50
Intervention
PLA (Sculptra)
Oedema (%)
67*
Ecchymosis (%)
12*
Erythema (%)
55*
50
PLA (New-Fill)
30.0†
24.0†
16†
94
PLA (New-Fill)
100.0
1.1
NR
99‡
17.3
30.6 §
5.0
50
PLA (Name not
specified)
PLA (New-Fill)
NR║
30.0
NR
100
CaHA (Radiesse)
NR¶
NR¶
NR¶
Values represent percentage of total adverse events for group of 197 injections. Adverse events were recorded using a VAS
(higher scores indicated greater severity).
†
Adverse and toxic events classified and graded according to the AIDS Clinical Trial Group/ World Health Organisation toxicity
scales
‡
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the analyses.
1 patient dropped out after third treatment before complete correction.
§
Authors report that clinically significant bruising occurred in 42 of 479 treatment sessions.
║
Value not reported, but minimal and localised oedema at the injection site was seen in most patients.
¶
Oedema, ecchymosis, and erythema are all commonly seen. Results not quantified
NR, not reported
*
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Pain
Randomised controlled trials
Adverse events in Carey et al. (2007) were recorded using a VAS (higher scores
indicate greater severity). Scores between one and five on the VAS were considered
grade one and two adverse events, and responses six to 10 were considered grade
three and four adverse events. In total, pain and discomfort was reported in 156/197
(79%) treatment procedures. Grade one and two pain and discomfort was reported
to occur in 150/197 (76%) treatment procedures. Grade three and four pain and
discomfort was reported in six of 197 (3%) treatment procedures. All reported pain
and discomfort lasted a median of two days.
Case series
Lafaurie et al. (2005) reported that overall, 72/94 (77%) patients felt pain during PLA
treatment. Within this, nearly half (46/94) of the patients classed their pain as slight,
and required no treatment. Just over a quarter (25/94) classed their pain as moderate,
that could require level I analgesics. One patient (1%) classed his/her pain as severe
pain requiring level II/III analgesics. Pain was graded according to Agence Nationale
de Recherche sur le SIDA (ANRS) grading scale: grade one, slight pain requiring no
treatment; grade two, moderate pain that could require level I analgesics; grade three,
moderate to severe pain necessitating level I/II analgesics; grade four, severe pain
requiring level II/III analgesics.
Patients in Mest & Humble (2006) were required to rate pain on a scale of one (no
pain) to five (maximum pain) for the treatment session. An overall mean pain score
of 1.7 was reported. Other more specific pain-related outcomes were also reported.
Eight of 98 (8%) patients reported nine pain events; five patients (5%) reported six
events of soreness; three (3%) patients reported four events of tenderness; and two
(2%) patients reported two events of discomfort. No patient discontinued treatment
because of pain.
Other adverse events
Other adverse events reported in the included studies for semi-permanent dermal
fillers for HIV-associated facial lipoatrophy are listed in Table 24.
Randomised controlled trials
Carey et al. (2007) reported five serious adverse events in four participants: three
events (epidural abscess, surgery to resect renal tumour, and hospitalisation for lower
lobe pneumonia) in two patients in the immediate group, and two events (surgery for
perianal abscess and acute renal retention) in two patients in the deferred group. The
authors reported that none of these events were associated with PLA treatment.
Case series
Cattelan et al. (2006) reported that no serious adverse events occurred.
Lafaurie et al. (2005) reported seven events of malaise caused by vagal hypertonia,
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one event of facial palsy (believed to be unrelated to treatment), and three events of
local bleeding. Cellulitis was reported to not have occurred.
Mest & Humble (2006) reported six events of sinus symptoms, three cold, two
headaches and no lactic acidosis or serious adverse events. It was also reported that
three of 97 (3%) patients who had received PLA had elevated blood glucose levels.
The primary physician did not feel these cases were related to treatment.
Valantin et al. (2003) reported there were no serious adverse events.
Silvers et al. (2006) reported 10 other systemic adverse events including sinus
infection, headache and fever. One patient reported blood in urine that lasted one
day and was mild in nature. It was stated that the authors did not feel any of these
events were related to treatment. The authors reported that no erosions or
haematomas occurred.
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Table 24. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event reporting:
other events
Study
Carey et al.
2007
Level II
N
50
Intervention
PLA (Sculptra) Immediate
50
PLA (Sculptra) Deferred
Cattelan et al.
2006
Level IV
Lafaurie et al.
2005
Level IV
50
PLA (New-Fill)
94
PLA (New-Fill)
Mest & Humble
2006
Level IV
99‡
PLA (Name not specified)
Valantin et al.
2003
Level IV
Silvers et al.
2006
Level IV
50
PLA (New-Fill)
100
CaHA (Radiesse)
*
†
‡
§
║
N other events
epidural abscess, surgery to resect renal tumour,
hospitalisation for lower lobe pneumonia*
5 pruritus (itching)
8 inflammation
4 haematoma
1 surgery for perianal abscess
1 acute renal retention
0 serious adverse events
7 malaise caused by vagal hypertonia
1 facial palsy†
3 local bleeding
0 cellulitis
6 sinus symptoms
3 elevated blood glucose levels
3 cold
2 headache
0 lactic acidosis
0 serious adverse events
0 serious adverse events
1 blood in urine§
10 other systemic adverse events║ including sinus
infection, headache and fever
0 erosion
0 haematomas
It was reported that three events occurred in two patients, but it was unclear which patient had two events. It was
reported that these events not related to treatment.
Appeared 10 days after 3rd injection. Authors believe unrelated to treatment as patient had history of Bell palsy. Patient
continued to have PLA injections.
1 patient had a single treatment and was discontinued (was not HIV positive). This patient’s data not included in the
analyses. 1 patient dropped out after third treatment before complete correction.
Event lasted 1 day and mild in severity. Authors believe unrelated to treatment.
Authors reported that events unlikely to be related to treatment.
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Ongoing and unpublished trials
Searches of the Clinical Trials Database, NHS CRD, NHS HTA, Current Controlled
Trials and the National Research Register identified a number of unpublished
studies. The details for each are provided in Table 25 and Table 26.
Table 25. Ongoing and unpublished studies – Ageing
Study
Study Details
Outcomes
PAAG (Aquamid) vs. HA
(Restylane) for the aesthetic
treatment of nasolabial folds
Design: double-masked, randomised, multi-centre, two-arm
parallel study
Target enrolment: n = 315
Length of follow-up: 12 months
Start date/end date: December 2006/July 2008
Sponsors and collaborators: Contura
Location: USA (ClinicalTrials.gov identifier: NCT00407914)
Safety and efficacy
To evaluate the degree of
correction achievable with PLA
(Sculptra) for nasolabial folds,
mid- and lower facial volume
loss, jaw line laxity and other
signs of facial ageing.
Design: non-randomised, open label, historical control, single
group assignment
Target enrolment: n = 75
Length of follow-up: 6 months
Start date/end date: January 2007/February 2008
Sponsors and Collaborators: Sanofi-Aventis
Location: Canada (ClinicalTrials.gov identifier: NCT00447551)
Safety and efficacy
The volumising effect of PLA
(Sculptra) measured by three
dimensional digital surface
imaging
Design: single centre, non-randomised, open label, active control,
single group assignment
Target enrolment: n = 20
Length of follow-up: 6 months
Start date/end date: June 2007/February 2008
Sponsors and Collaborators: Sanofi-Aventis
Location: UK (ClinicalTrials.gov identifier: NCT00487474)
Safety and efficacy
A randomised study of the safety
and effectiveness of PLA
(DL6049) versus Collagen
(CosmoPlast) in the treatment of
nasolabial fold wrinkles
Design: randomised, single blind, active control, parallel
assignment
Target enrolment: n = 240
Length of follow-up: 13 months
Start date/end date: June 2004/April 2006
Sponsors and Collaborators: Sanofi-Aventis
Location: USA (ClinicalTrials.gov identifier: NCT00444210)
Safety and efficacy
A randomised study of the safety
and effectiveness of PLA
(DL6049) versus Collagen
(CosmoPlast) in the treatment of
nasolabial fold wrinkles (long
term follow-up)
Design: randomised, single blind, active control, parallel
assignment
Target enrolment: n = 240
Length of follow-up: 13 months
Start date/end date: August 2004/January 2007
Sponsors and Collaborators: Sanofi-Aventis
Location: USA (ClinicalTrials.gov identifier: NCT00444353)
Safety and efficacy
CaHA (Radiesse) injection in the
correction of jowl-associated
chin notches
Design: open Label, uncontrolled, single group assignment,
Target enrolment: n = 20
Length of follow-up: 9 months
Start date/end date: July 2007/September 2008
Sponsors and Collaborators: Northwestern University
Location: USA (ClinicalTrials.gov identifier: NCT00510081)
Safety and efficacy
Ageing
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Table 26. Ongoing and unpublished studies – HIV-associated lipoatrophy
Study
Study Details
Outcomes
Polyalkylimide gel(Bio-alcamid)
for HIV-associated facial
lipoatrophy
Design: randomised, open label, active control, parallel
assignment
Target enrolment: n = 36
Length of follow-up: not stated
Start date/end date: December 2004/August 2007
Sponsors and Collaborators: Canadian Immunodeficiency
Research Collaborative, Pur Medical Corporation
Location: Canada (ClinicalTrials.gov identifier: NCT00333684)
Safety, efficacy and
quality of life
To evaluate the safety of PLA
(Sculptra) on the signs of
lipoatrophy of the face in at least
100 evaluable subjects with
human immunodeficiency virus
Design: non-randomised, open label, active control, single group
assignment
Target enrolment: n = 300
Length of follow-up: 5 years
Start date/end date: November 2005/December 2011
Sponsors and Collaborators: Sanofi-Aventis
Location: USA (ClinicalTrials.gov identifier: NCT00360932)
Safety, efficacy,
incidence of
hypertrophic scars
or keloids and
quality of life
Immediate versus deferred
injections of PLA for HIV facial
lipoatrophy
Design: randomised, open label, active control parallel
assignment
Target enrolment: n = 100
Length of follow-up: 96 weeks
Start date/end date: November 2005/December 2007
Sponsors and Collaborators: The National Centre in HIV
Epidemiology and Clinical Research, The University of New South
Wales, Abbott, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck Sharp & Dohme, Hoffmann-La Roche,
AIDS Council of New South Wales.
Location: Australia (ClinicalTrials.gov identifier: NCT00126308)
Safety, efficacy and
quality of life
PLA (New-Fill) vs. PAAG
(Eutrophill) in the treatment of
facial lipoatrophy in HIV-infected
patients
Design: randomised, single blind, active control, parallel
assignment
Target enrolment: n = 140
Length of follow-up: 96 weeks
Start date/end date: October 2006/not stated
Sponsors and Collaborators: French National Agency for
Research on AIDS and Viral Hepatitis, Procitech, Sanofi-Aventis
Location: France (ClinicalTrials.gov identifier: NCT00383734)
Safety, efficacy and
quality of life
HIV-associated facial lipoatrophy
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5. Discussion
Limitations of the evidence
This review, examining the efficacy and safety of semi-permanent and permanent
injectable dermal fillers for ageing and HIV-associated lipoatrophy, was limited by
the quantity and quality of the available evidence. Despite the inclusion of 20 studies,
a number of factors limited the conclusions which could be drawn and prevented
statistical pooling.
A weakness of this systematic review is that studies were selected for inclusion based
on the number of participants. This review may have benefited from the inclusion of
all relevant RCTs and comparative studies irrespective of participant numbers. If
done, this could have increased the number of well-designed studies included in the
review, and may in turn have increased the validity of the overall outcomes.
The number of comparative studies included in this review for both ageing and HIVassociated lipoatrophy was low (three and four studies respectively), resulting in a
small number of studies with comparable interventions. This was confounded by
variability in the units used to report outcomes, making comparisons between the
studies difficult.
The review included studies that had not less than 40 participants. The number of
patients within each study group however, was in some cases considerably lower,
with one study having a study arm of eight patients (Negredo et al. 2006). In this, and
another study (Orlando et al. 2007), the numbers of patients in the groups were
greatly disparate, which could have affected the veracity of the statistical analyses.
Some of the studies were limited by the lack of randomisation, blinding and the use
of unvalidated assessment tools. Many of the studies did not report consecutive
patient enrolment (Carey et al. 2007; Cohen et al.. 2006; Fulton et al. 2005; Jacovello et
al. 2006; Jones et al.. 2004; Lafaurie et al. 2005; Mest & Humble 2006; Mladick 1992;
Moers-Carpi 2007; Reda-Lari 2008; Silvers et al. 2006; Smith et al. 2007; Valantin et al.
2003). In addition to this, some studies were conducted retrospectively (Mladick
1992; Fulton et al. 2005; Reda-Lari 2008). Only two studies reported conducting and
meeting an a priori power calculation (Carey et al. 2007; Valantin et al. 2003) and more
than a third of the studies did not report what statistical analyses, if any, were used
(De Santis et al. 2008; Fulton et al. 2005; Jacovello et al. 2006; Mladick 1992; Reda-Lari
2008; Silvers et al. 2006; Sklar & White 2004).
Some of the studies compared permanent and/or semi-permanent fillers with
temporary interventions, such as collagen, HA and AFT (Cohen et al. 2006; Guaraldi
et al. 2005; Moers-Carpi et al. 2007; Negredo et al. 2006; Orlando et al. 2007; Smith et
al. 2007). These fillers are known to have a temporary aesthetic effect (less than one
year), which may have prevented valid efficacy comparisons between longer lasting
fillers in those studies that compared them (Cohen et al. 2006; Guaraldi et al. 2005;
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Moers-Carpi et al. 2007; Negredo et al. 2006; Smith et al. 2007). The results using
these temporary products appeared to reflect the expectation of diminution of
aesthetic effect over time.
There was great gender disparity between the two study populations, with men
accounting for less than 5% of the patients receiving dermal filler injections for age
related skin changes, while accounting for approximately 70% of the total study
population for HIV-associated lipoatrophy patients. This likely reflects that women
are currently more likely to have dermal filler procedures for age related changes than
men. Carey et al. (2007) suggest that the high proportion of men in their study
reflects the gender distribution of HIV-infection in Australia, which may also hold
true for the other studies which were conducted mainly in the US and European
countries. As a condition of US Food and Drug Administration (FDA) approval,
Dermik Laboratories (Berwyn, Pa, USA) (manufacturer of Sculptra) was requested to
conduct an open-label registry study of 100 patients for five years to evaluate longterm safety (FDA 2004). The study will include at least 30 females and 30 people
with dark skin types. Data from this study have not been published to date, and
therefore whether gender has any influence on the outcomes of dermal filler
treatment remains to be determined. Whether gender has any influence on the
outcomes of dermal filler treatment remains to be determined, and warrants attention
because gender differences in HIV disease progression are becoming larger and
statistically significant in the era of HAART (Jarrin et al. 2008).
The number of treatment sessions and volumes of dermal filler products injected
varied greatly between studies. The number of treatments was pre-determined in
some studies and not in others. In addition to this, some studies allowed follow-up
injections, while others did not. The level of correction was also not uniform
between studies, with some studies aiming to provide for full correction, while others
aimed to merely reduce the stigma associated with the visible effects of HIVassociated lipoatrophy. This highlights a marked lack of uniformity in treatment
methodology between clinicians and centres which may relate directly to the clinical
or perceived outcome.
In general, the HIV-associated lipoatrophy studies appeared to have more
methodological rigor than those for ageing. This may reflect the nature of HIV
infection and the medical and psychological basis for its treatment. It may also reflect
that the effects of the HIV-associated disease process are considered more important
than the need to remove naturally occurring wrinkles.
Efficacy outcomes
For the purposes of this review, semi-permanent fillers were defined as fillers lasting
between one and two years, and permanent fillers were defined as lasting longer than
two years. Less than half of the included studies had follow-up periods longer than
one year, and of these, only four had follow-up periods longer than two years (two
studies reported the same cohort of patients (Cohen et al. 2006 & 2007) and two
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studies were retrospective case series (Fulton et al. 2005; Reda-Lari 2008)). This limits
the conclusions that can be drawn about the long term efficacy of these products.
Many of the studies included in this review were limited by the use of unvalidated
assessment tools. There are currently no consistent and validated tools to measure
outcomes such as skin thickness, success of treatment, or patient satisfaction for
dermal filler interventions. Some studies measured these outcomes subjectively,
which may have introduced bias in favour of a particular treatment if the patient or
assessor was not blinded to treatment allocation.
Ageing
For age related skin changes, nine studies were included, of which three were RCTs
and six were case series. A range of fillers were used for a number of facial areas, and
outcome measures varied. Direct comparisons of improvements between products
was difficult owing to the variations in treatment protocols and outcome
measurements. Only one study (Fulton et al. 2005) determined actual skin thickness
measurements after dermal filler injections, but this was only of the lips of 4% of the
study population. Other efficacy outcomes in the included studies for this
intervention were subjective in nature, but some clear trends were noted.
The results suggest that temporary fillers can provide better or comparable results in
the short-term (within the first month), but that permanent or semi-permanent fillers
are significantly better in the longer term. This is consistent with the mode of action
of these fillers, such as local foreign body response and collagen production, which
occur over the course of months after injection. The two RCTs comparing semipermanent fillers with temporary fillers found that semi-permanent fillers provided
better results in terms of observer ratings of appearance, patient satisfaction and
whether patients would recommend treatment than temporary fillers in most cases
(the notable exception being HA 3, Perlane). When reported, patient and practitioner
satisfaction and success of dermal filler treatment were high.
Only three studies had follow-up periods longer than one year. Cohen et al. (2006 &
2007) had the longest follow-up periods (four to five years and five years
respectively) and reported a continued significant aesthetic improvement from
baseline at these time points, demonstrating that PMMA has a long lasting effect in
this group of patients (there was patient overlap between the two studies). Further
studies are required before the long term aesthetic effects of other fillers are known.
HIV-associated lipoatrophy
For HIV-associated lipoatrophy, 11 studies were included for review, of which one
was an RCT, one a pseudo-RCT, two were non-randomised comparative studies and
seven were case series. Fillers were primarily injected into the cheeks, the area of the
face most visibly affected by antiretroviral induced lipoatrophy. Apart from stopping
antiretroviral treatment, there are no proven therapies for lipoatrophy and therefore
the management of established fat loss can be challenging.
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The evidence from comparative studies that used permanent, semi-permanent and
temporary fillers suggested that skin thickness (Guaraldi et al. 2005; Orlando et al.
2007) or subjective ratings of lipoatrophy (Negredo et al. 2006) were improved after
treatment. There was, however, an inability to conclude which treatment product was
superior in terms of efficacy because one study found no significant difference
between the three interventions six months after treatment (Guaraldi et al. 2005), and
the other study did not compare between products (Orlando et al. 2007). This was
mirrored to patient satisfaction outcomes, with the addition that one study reported
combined outcomes for all treatment groups (Negredo et al. 2006). Quality of life
outcomes appeared favourable after treatment compared with baseline for most, but
not all fillers. The groups with the least likelihood of improvement were AFT
patients (Guaraldi et al. 2005; Orlando et al. 2007) and patients that had combined
AFT and PLA treatment (Orlando et al. 2007) suggesting that these fillers are not as
efficacious as permanent ones. Negredo et al. (2006) also pooled results for the
treatment groups for quality of life outcomes so that it was not possible to
differentiate between the different products. It is important to note that the studies
by Guaraldi et al. (2005), Negredo et al. (2006) and Orlando et al. (2007) were skewed
because treatment allocation occurred first on the basis of body fat, then on the basis
of either product availability or patient choice. In addition to this, the comparison
between AFT and the other filler groups may not have been appropriate because the
patient groups were not identical at baseline. The AFT group had greater body fat
accumulation, which may have affected their response to treatment.
One comparative study compared a semi-permanent filler treatment with deferred
treatment (ie no treatment) (Carey et al. 2007). This study reported no significant
increases in objective measures of tissue volume after treatment (using CT scans and
three dimensional post-processing software), although reporting significant increases
in tissue depth for two of the four facial areas 24 weeks after treatment (using linear
measurements). To explain this, the authors put forward that the study may not have
been adequately powered, that measurement procedures may have been variable and
that PLA may not be as efficacious as initially believed. Observer ratings of
appearance were also determined in this study and indicated that nearly 90% of
patients had significant improvement in their lipoatrophy scores 12 and 24 weeks
after treatment. In the group that did not receive treatment, 20% were also found to
be improved at these time points. The authors suggest that the open-label, unblinded
nature of the study may have caused this bias, which has implications for the
applicability of these results to a wider population.
Evidence from case series of semi-permanent filler treatment found patient and
practitioner satisfaction and the likelihood of recommending treatment to be high,
but statistical analyses were not conducted on much of these data, weakening the
results. Quality of life reporting varied between studies for semi-permanent fillers,
resulting in an inability to draw firm conclusions from the results. The studies found
significant differences for some, but not all quality of life measures. Further
investigation is warranted in this area.
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Safety outcomes
There was great variation in the level of adverse event reporting for both
interventions and it was not possible to accurately compare the total number of
adverse events in each study because of these variations. In general, many adverse
events were transient and mild in nature: the majority of events were associated with
the injection process, such as oedema, ecchymosis and erythema, which usually
resolved within a matter of days.
The studies included were selected on the basis that patients had not undergone
treatment with permanent or semi-permanent dermal fillers within three months
prior to commencement of the study. Five of the nine studies for ageing (Fulton et al.
2005; Jacovello et al. 2006; Mladick 1992; Reda-Lari 2008; Sklar & White 2004) and
one of the 11 studies for HIV-associated lipoatrophy (Silvers et al. 2006) did not
report whether patients had received previous filling or not, and of these, one study
(Sklar & White 2004) reported the use of dermal filler product in areas previously
treated with silicone (it was unclear whether this occurred in a patient included in the
study or not). The long term adverse events of dermal filler products are largely
unknown, so any reported adverse events in studies that did not report previous
filling could potentially be attributed to previous procedures, of from a combination
of procedures. One study (Jones et al. 2004) reported that patients who had received
prior injections with temporary fillers could not begin liquid silicone injections until
three months after their last injection of temporary filling product. The authors of
this study classified PLA as a temporary product that would dissipate within three
months, as opposed to the current study that has classified this filler as semipermanent. This highlights the differences in opinion of classification of longevity of
these products.
Ageing
Evidence from the included studies suggests that the dermal fillers investigated were
generally well tolerated. Lumps were reported in all but one (Moers-Carpi et al. 2007)
of the studies for ageing, with the incidence rate generally being less than five
percent. Cohen et al. (2006 & 2007) reported lumps in patients two to five years after
initial injection, but it was difficult to determine the number of patients affected as
there was overlap between studies and potential attrition bias. These late adverse
events, however, suggest that long term complications may be associated with this, or
potentially any other filler, and that reported complication rates in patients may
increase over time. Liquid injectable silicone is a notable example where this has
occurred in the past, with the debate over the safety of liquid silicone spanning over
half a century (Goulian 1978; Chasan 2007). A review of complications after liquid
silicone injections found that the average time to first complication was eight to 10
years, with a range of six months to 36 years (Chasan 2007). Since first being used in
the 1960s, information regarding liquid silicone treatments has been lost, resulting in
difficulties identifying the exact causes of these complications. It is believed that
many of the complications, such as granulomas (Arin et al. 2005; Austad 2002; Bigata
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et al. 2001) may have been due to high volumes of impure, low-viscosity silicones,
poor injection technique and/or concomitant disease (Chasan 2007).
Lumps were reported in most of the included studies. There is limited knowledge
regarding the exact mechanism of lump formation. Nodules and some other bumps
are not inflammatory, and are generally technique dependent (Lemperle 2003; Mest
& Humble 2006). These lumps can result from excess product being injected into an
area (over-correction), or injecting too superficially (Lemperle 2006). Many lumps are
not bothersome to patients, and are therefore not biopsied (Mest & Humble 2006).
Of the four studies that reported injecting dermal fillers into the lips, all reported
nodules or granulomas at a rate of between two and five percent (Fulton et al. 2005;
Mladick 1992; Jacovello et al. 2006; Sklar & White 2004). The occurrence of lumps is
the reason that some authors do not inject into the lips (PMMA for Cohen et al. 2006
and PLA for Sklar & White 2004). Although steroid injections and excision were the
preferred treatment options for lumps, in many cases the lumps were not treated.
There is a belief that irrespective of treatment given, reactions many continue to
come and go over time (Alcalay et al. 2003) suggesting that further investigations into
these events is warranted.
Granulomas were reported in three studies (Cohen et al. 2006 & 2007; Fulton et al.
2005), with the highest incidence being reported in patients who had received liquid
silicone injections in the lips (2%) (Fulton et al. 2005). Granulomas are a result of a
hyper-inflammatory reaction and occur in areas distant from the injected area. The
reasons for granulomas is unclear, but may be related to the viscosity of products
(Fulton et al. 2005). It has been reported that granulomas react well to intralesional
steroid injections (Lemperle 2006). It is unclear whether this treatment was
successful in resolving the reported granulomas, as not enough detail was provided
regarding individual outcomes, although excision was reported in some cases. It has
been predicted that in the future, increasing numbers of foreign body type
granulomatous reactions will be seen in the oral facial regions of mainly middle-aged
women due to the injection of one or more cosmetic fillers (Parada et al. 2005).
Whether this will be the case will require further follow-up.
Evidence from the included studies suggest that in the short- to medium-term, the
dermal fillers used do not tend to cause serious adverse events, and that there
appeared to be little difference between the fillers in terms of safety.
HIV-associated lipoatrophy
As for ageing, the evidence for dermal filler treatment for HIV-associated
lipoatrophy suggests that the fillers were generally well tolerated. No granulomas
were reported, but lumps were reported in all but one study (Silvers et al. 2006). In
three studies, close to half of the patients experienced lumps (Guaraldi et al. 2005;
Orlando et al. 2007; Valantin et al. 2003). This higher incidence may be attributable to
the greater volume of product required for this group of patients because fat loss
associated with HIV-associated lipoatrophy is generally much higher than the fat loss
as a result of ageing (Negredo et al. 2006; Valantin et al. 2003). In addition to this, the
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reporting of lumps may be influenced by study design (Mest & Humble 2006). In
some studies, investigators specifically searched and palpated for lumps, as opposed
to other studies that relied on patients to report them.
It was reported by one study that although nearly half of the patients experienced
lumps after PLA treatment, patient satisfaction was not altered (Orlando et al. 2007).
It was difficult to determine whether the presence of lumps impacted patient
satisfaction in the other studies that reported high rates of lumps. In Guaraldi et al.
(2005) it appeared that satisfaction was high regardless, while comparisons in
Valantin et al. (2003) were not possible because patient satisfaction was not reported.
For HIV-associated lipoatrophy, PLA featured in eight, and PAAG featured in four
of the 11 studies respectively. Evidence from the included studies suggest that these
dermal fillers do not tend to cause serious adverse events, and that there appears to
be little difference between the fillers in terms of safety. The only exception to this
may be AFT which resulted in four cases of fat graft hypertrophy (Guaraldi et al.
2005). The authors reported that these events may have been related to the dorsocervical harvest site, and that since no longer using this site, no more of these issues
have been reported. In addition to these adverse events, and the temporary nature of
this filler, AFT also has the draw back of requiring anaesthesia.
Other considerations
This review recognises that semi-permanent and permanent dermal fillers are rapidly
evolving and that many long-term follow-up studies are not yet available. Searches
for this review were updated approximately one year after first being conducted and
found an additional seven studies. This resulted in many of the RCTs (three of the
four) included in the review being published within the last year. A search of ongoing
and unpublished trials (Table 25 and Table 26) demonstrates that more studies are
currently underway. This suggests that more efficacy and safety data on dermal filling
products will continue to emerge.
It should be stressed that permanent aesthetic results are rarely possible with dermal
fillers in the studied population, owing to continued tissue volume loss associated
with ageing, and/or the effects of continued fat loss due to specific antiretroviral
therapies. There appeared to be some decline in skin thickness, ratings of lipoatrophy
or patient satisfaction in some HIV-associated lipoatrophy studies during follow-up
(Negredo et al. 2006; Cattelan et al. 2006; Valantin et al. 2003; Silvers et al. 2006). It
was unclear whether these declines were as a result of degradation of the filler
material, or progression of lipoatrophy. Further investigations are required to
determine whether atrophic facial changes around these products will accommodate
their persistence long term.
Long term follow-up of individual dermal fillers is likely to be complicated by
patients undergoing further cosmetic interventions in an effort to maintain
aesthetically pleasing results. More than a third of patients in Cohen et al. (2006), an
unspecified number of patients in Cohen et al. (2007), and approximately 10% of
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patients in Mest & Humble (2006) had undergone further cosmetic procedures
before their respective follow-ups. These additional cosmetic procedures effectively
reduce the number of patients available for follow-up, and confound the ability to
create long term safety and efficacy profiles for individual fillers.
The studies included indicated that nearly all patients had high levels of satisfaction
after dermal filler treatment. The authors of one study reported that patient
satisfaction was related to the number of treatments received (Lafaurie et al. 2005).
The quick and relatively noninvasive nature of these treatments are likely to be a
significant key to their popularity. For all fillers, aesthetic improvement (or the
beginnings thereof) can be seen immediately after the first injection procedure
(particularly for temporary fillers), giving patients instantly visible results without the
need for hospitalisation. For semi-permanent and permanent fillers, augmentation
occurs gradually over time to give a longer lasting effect. Popularity may also be
attributable, in part, to the normalisation and social acceptance of cosmetic surgery
(Brooks 2006).
In the literature, it is not uncommon to find studies concerning patients with dermal
filler complications after treatment by unqualified practitioners, or cases where a
patient is uncertain of the product that was injected (Maas et al. 1997; Mustacchio et
al. 2007; Sidwell et al. 2006). These instances can result in complications being
difficult or impossible to treat (Rohrich et al. 2003). It was acknowledged by many
authors of the included studies that experience, proper indication and skilful injection
technique by the practitioner are important factors for the potential success of filler
materials, particularly to help minimise skin irregularities, lumps and nodule
formation (Cohen et al. 2007; Jacovello et al. 2006; Mest & Humble 2006; Mladick
1992; Sklar & White 2004). The majority of the results in the included studies came
from centres with experienced physicians. Despite this however, over correction
occurred in four studies (Mladick 1992; Reda-Lari 2008; Sklar & White 2004;
Negredo et al. 2006) and superficial placement occurred in one study (Sklar & White
2004). Although over-correction occurred in relatively few patients (0.2 – 8%), this
rate could be much higher when practicing physicians are untrained or unskilled in
proper injection technique. To mitigate this, one study reported that the sponsor of a
product offers product training as a part to becoming an injector of the material
(Cohen et al. 2007). Dermal filler products are continually being refined, improved
and renamed. Publications have emerged regarding the optimisation of reconstitution
of products and injection techniques to minimise adverse events, as well as the
outcomes that individual physicians have had with different products (Lam et al.
2006; Lowe 2008; Narins 2008). Training physicians in the use of particular products
may provide better product placement in the skin and hence reduce technique
dependent complications, especially as products are altered or refined.
Consumers undergoing cosmetic procedures could be at risk when undergoing
cosmetic interventions as the industry is largely self-regulated. This is especially so if
patients are under the care of a poorly qualified clinician looking to make rapid profit
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from these relatively quick procedures. The development of national training
standards or the enforcement of minimum training requirements could go some way
to contributing to consumer safety in Australia and world wide. In addition to this,
industry has an obligation to ensure that the fillers they manufacture are safe for their
intended use, and that they perform as expected. It is therefore both appropriate and
necessary for industry (in conjunction with independent research bodies) to
undertake studies to assist in quantifying the purported clinical benefits of dermal
fillers.
The cost of treatment did not receive widespread attention in the included studies,
but cannot be ignored. Semi-permanent and permanent fillers are attractive to
patients because results are long term and do not require regular repeat injections.
The cost of dermal fillers varies widely, and depends on the amount injected and the
number of syringes injected per session. In the case of HIV-lipoatrophy patients,
large volumes of product were required which could be cost prohibitive for some
patients. When compared with temporary products, semi-permanent and permanent
dermal fillers provide better, longer lasting correction that can be delivered with
fewer injections and less material. Moers-Carpi et al. (2007) put forward the argument
that fewer syringes of CaHA would be required for correction than for HA products,
and suggest that for patients who only wish to buy one syringe of product, that they
would get better immediate and longer lasting effects with a semi-permanent or
permanent filler. Negredo et al. (2006) put forward a similar argument stating that a
smaller proportion of patients who received PAAG required an additional round of
treatment compared with PLA and AFT patients and hence would have a lower
treatment cost.
Future research
From this review, it is evident that there are gaps in the current evidence base which
has limited the conclusions that can be drawn about the safety and efficacy of
permanent and semi-permanent dermal fillers. This is especially apparent for long
term outcomes. It is therefore recommended that further research be done into:
•
Long term efficacy of permanent and semi-permanent dermal fillers
•
Long term safety of permanent and semi-permanent dermal fillers, including the
nature and outcomes of lumps
•
Facial changes around permanent and semi-permanent dermal fillers, and
whether the face can adequately accommodate them in the long term
•
Potential gender differences in response to permanent and semi-permanent
dermal fillers
•
Short and long term quality of life outcomes after permanent and semipermanent dermal filler treatment
•
The development, and/or validation, of standardised assessment tools for use in
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cosmetic intervention studies
•
The development of training standards to aid physicians with injection
techniques and product placement
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6. Conclusions and Recommendations
The aim of this systematic review was to determine the safety and efficacy of
permanent and semi-permanent dermal fillers for age related lines and wrinkles and
for the visible effects of HIV-associated facial lipoatrophy. The small number of
well-designed studies limited the ability to draw firm conclusions. The products
included for review appeared to increase skin thickness as measured by skin callipers,
ultrasound or subjective ratings of appearance, but long term efficacy has not been
established. Patient satisfaction was high in all of the studies, reflecting the desire for
people to feel better about their appearance.
Despite the substantial increase in products available for soft-tissue augmentation,
well-performed clinical studies are scarce, and long-term clinical safety data are
lacking. The results of the review indicate that semi-permanent and permanent fillers
offer a comparable safety profile compared with temporary products in those studies
that compared them, and that aesthetic improvements are maintained over time.
Case series evidence suggests that permanent and semi-permanent dermal fillers
achieve their objective, which is to decrease the visible (objective or subjective)
effects of age related changes or HIV-associated facial lipoatrophy with high patient
satisfaction.
Although the most common adverse events were mild and appeared to be related to
the act of injection, palpable lumps were present in many patients. Biopsy of these
lumps rarely occurred, leaving their exact nature largely unknown. Although
permanent products offer longevity and potentially lower treatment costs, adverse
events, should they occur, may be difficult to manage and of long duration. Long
term studies investigating the safety and efficacy of dermal filling products may be
problematic as patients continue to undergo subsequent cosmetic interventions.
Classification and recommendations
The evidence-base in this review for the use of permanent and semi-permanent
dermal fillers for age-related lines and wrinkles is poor, and for HIV-associated
lipoatrophy is average.
Safety
From the data included in this systematic review, the safety of permanent and semipermanent dermal fillers appear at least as safe as temporary fillers in the short term
in those studies that compared them. Long term safety could not be determined.
Efficacy
The treatment of age related lines and wrinkles of the effects of HIV-associated
lipoatrophy with permanent and semi-permanent dermal fillers is more efficacious
than with temporary fillers in those studies that compared them. Case series evidence
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suggests that permanent and semi-permanent dermal fillers achieve their objective,
which is to decrease the visible (objective or subjective) effects of age related changes
or HIV-associated facial lipoatrophy, with high patient satisfaction.
Clinical and research recommendations
It is recommended that further research be done into:
•
Long term efficacy of permanent and semi-permanent dermal fillers
•
Long term safety of permanent and semi-permanent dermal fillers, including the
nature and outcomes of lumps
•
Facial changes around permanent and semi-permanent dermal fillers, and
whether the face can adequately accommodate them long term
•
Potential gender differences in response to permanent and semi-permanent
dermal fillers
•
Short and long term quality of life outcomes after permanent and semipermanent dermal filler treatment
•
The development, and/or validation, of assessment tools for use in cosmetic
intervention studies
•
The development of training standards to aid physicians with injection
techniques and product placement
Acknowledgments
The authors wish to acknowledge Dr Prema Thavaneswaran for her assistance
during the preparation of this review.
The ASERNIP-S project is funded by the South Australian Department of Health.
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APPENDIX A – EXCLUDED STUDIES
99
Appendix A – Excluded studies
The following articles were excluded from the methodological assessment as outlined
in the methods section of the review.
Excluded Studies
Study
Reason for exclusion
Aivaliotis M, Kontochristopoulos G, Hatziolou E, Aroni K, Zakopoulou N. Successful
colchicine administration in facial granulomas caused by cosmetic implants: report of a
case. Journal of Dermatological Treatment 2007; 18(2): 112-4.
Filler name and composition
unknown
Alam M and Yoo SS. Technique for calcium hydroxylapatite injection for correction of
nasolabial fold depressions. Journal of the American Academy of Dermatology 2007; 56(2):
285-289.
Includes acne scars
Bagal A, Dahiya R, Tsai V, Adamson PA. Clinical experience with polymethylmethacrylate
microspheres (Artecoll) for soft-tissue augmentation: a retrospective review. Archives of
Facial Plastic Surgery 2007; 9(4): 275-80.
Includes previous filling and
other procedures
Bauer U. Poly-L-lactic acid: Six years clinical experience in correction of aesthetic and
pathologic defects of the face. Journal of Plastic Dermatology 2006; 2(1): 5-10.
Study unavailable
Bergeret-Galley CF, Latouche XF, Illouz YG. The value of a new filler material in corrective
and cosmetic surgery: DermaLive and DermaDeep. Aesthetic Plastic Surgery 2001; 25(4):
249-255.
Scars not reported
separately
Breiting V, Aasted A, Jorgensen A, Opitz P, Rosetzsky A. A study on patients treated with
polyacrylamide hydrogel injection for facial corrections. Aesthetic Plastic Surgery 2004; 28
(1): 45-53.
Includes breast
augmentation
Burgess CM and Quiroga RM. Assessment of the safety and efficacy of poly-L-lactic acid for
the treatment of HIV-associated facial lipoatrophy. Journal of the American Academy of
Dermatology 2005; 52(2): 233-239.
Time of previous filling
unknown
Carruthers A, Liebeskind M, Carruthers J, Forster BB. Radiographic and computed
tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial
lipoatrophy and correction of nasolabial folds. Dermatologic Surgery 2008; 34(Supp 1): S78S84.
Not safety or efficacy
Chave H, Ahmed S, Fu B, Webber J, Banwell P, Tiernan E. Salvage of infected dermal
collagen implants with topical negative pressure therapy. Journal of Wound Care 2006;
15(4):156-8.
Not included filler
Christensen L, Breiting V, Vuust J, Hogdall E. Adverse reactions following injection with a
permanent facial filler polyacrylamide hydrogel (Aquamid): Causes and treatment. European
Journal of Plastic Surgery 2006; 28(7); 464-471.
Time of previous filling
unknown
Cox SE. Who is still using expanded polytetrafluoroethylene? Dermatologic Surgery 2005;
31(11 Pt 2): 1613-1615.
Not injectable filler
de Boulle KLVM. Risks of facial fillers. Journal of Plastic Dermatology 2007; 3(1): 37-39.
Study unavailable
de Cassia Novaes WF and Berg A. Experiences with a new nonbiodegradable hydrogel
(Aquamid): a pilot study Aesthetic Plastic Surgery 2003; 27(5): 376-380.
Scars and reconstruction not
reported separately
Desai AM, Browning J, Rosen T. Etanercept therapy for silicone granuloma. Journal of
Drugs in Dermatology: JDD 2006; 5(9): 894-6.
Not face
Ersek RA, Gregory SR, Salisbury AV. Bioplastique at 6 years: clinical outcome studies.
Plastic & Reconstructive Surgery 1997; 100(6): 1570-4.
Scars and ageing not
reported separately
Funk E, Bressler FJ, Brissett AE. Contemporary surgical management of HIV-associated
facial lipoatrophy. Otolaryngology – Head & Neck Surgery 2006; 134(6): 1015-22.
Surgical intervention
Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use of Radiesse in combination
with Restylane for facial augmentation. Archives of Facial Plastic Surgery 2006; 8(2): 92–
97.
Groups not reported
separately
Gurvits GE. Silicone pneumonitis after a cosmetic augmentation procedure. New England
Journal of Medicine 2006; 354(2): 211-2.
Not face
Jansen DA and Graivier MH. Evaluation of a calcium hydroxylapatite-based implant
(Radiesse) for facial soft-tissue augmentation. Plastic & Reconstructive Surgery 2006;
118(3S): 22S-30S.
Areas not reported
separately
Kalantar-Hormozi A, Mozafari N, Rasti M. Adverse effects after use of polyacrylamide gel as
a facial soft tissue filler. Aesthetic Surgery Journal 2008; 28(2): 139-142.
No efficacy outcomes
reported
Kanchwala SK, Holloway L, Bucky LP. Reliable soft tissue augmentation: a clinical
comparison of injectable soft-tissue fillers for facial-volume augmentation. Annals of Plastic
Surgery 2005; 55(1): 30-35.
Pre-op botulinum toxin in
glabella
Lahiri A and Waters R. Experience with Bio-Alcamid, a new soft tissue endoprosthesis.
Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS 2007: 60(6): 663-667.
Anatomical regions not
reported separately
Lemperle GF, Gauthier-Hazan NF, Lemperle M. PMMA-Microspheres (Artecoll) for longlasting correction of wrinkles: refinements and statistical results. Aesthetic Plastic Surgery
1998; 22(5): 356-365.
Scars and facial palsy not
reported separately
Mustacchio V, Cabibi D, Minervini MI, Barresi E. Amato S. A diagnostic trap for the
dermatopathologist: granulomatous reactions from cutaneous microimplants for cosmetic
purposes. Journal of Cutaneous Pathology. 2007; 34(3): 281-3.
Filler name and composition
unknown
Protopapa C, Sito G, Caporale D, et al. Bio-AlcamidTM in drug-induced lipodystrophy.
Journal of Cosmetic and Laser Therapy 2003; 5(3-4): 226 – 230.
Face and buttocks not
reported separately
Piacquadio D, Smith S, Anderson R. A comparison of commercially available
polymethylmethacrylate-based soft tissue fillers. Dermatologic Surgery 2008; 34 (Suppl 1):
S48-S52.
Product not injected into face
Nelson L and Stewart KJ. Experience in the treatment of HIV-associated lipodystrophy.
Journal of Plastic & Reconstructive Aesthetic Surgery 2008; 61(4): 366-371.
Previous filling
Roy D, Sadick N, Mangat D. Clinical trial of a novel filler material for soft tissue
augmentation of the face containing synthetic calcium hydroxylapatite microspheres.
Dermatologic Surgery 2006; 32(9): 1134-1139.
Previous filling
Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety and efficacy of calcium
hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas of the face.
Dermatologic Surgery 2007; 33(Supp 2): S122-S126.
Acne scars not reported
separately
Sherris, DF and Larrabee WF Jr. Expanded polytetrafluoroethylene augmentation of the
lower face. Laryngoscope 1996; 106(5 Pt 1): 658-663.
Not injectable filler
Sidwell RU, McL Johnson N, Francis N, Bunker CB. Cutaneous sarcoidal granulomas
developing after Artecoll facial cosmetic filler in a patient with newly diagnosed systemic
sarcoidosis. Clinical & Experimental Dermatology 2006; 31(2): 208-11. [erratum appears in
Clinical & Experimental Dermatology 2006;31(2):208].
Filler composition and name
uncertain
Simons G, Mazaleyrat P, Masurel T. Utilisation of injectable microimplants in aesthetic facial
surgery. Aesthetic Plastic Surgery 1992; 16(1): 77-82.
Scars not reported
separately
Tzikas TL. Evaluation of the Radiance FN soft tissue filler for facial soft tissue
augmentation. Archives of Facial Plastic Surgery 2004; 6(4): 234-239.
Acne not reported separately
Tzikas TL. A 52-month summary of results using calcium hydroxylapatite for facial soft
tissue augmentation. Dermatologic Surgery 2008; 34(1): S9-S15.
Acne not reported separately
von Buelow S and Pallua N. Efficacy and safety of polyacrylamide hydrogel for facial softtissue augmentation in a 2-year follow-up: a prospective multicentre study for evaluation of
safety and aesthetic results in 101 patients. Plastic & Reconstructive Surgery 2006; 118
(3S): 85S-91S.
Scarring and acne not
reported separately
von Buelow S, von Heimburg D, Pallua N. Efficacy and safety of polyacrylamide hydrogel
for facial soft-tissue augmentation. Plastic & Reconstructive Surgery 2005; 116(4): 11371146.
Includes deformities
APPENDIX B – STUDY PROFILE TABLES
Appendix B – Study profile tables
Appendix B.1 Study profile tables – facial augmentation for ageing
Polymethylmethacrylate (PMMA) (Artecoll) vs. Collagen (Zyderm II/Zyplast)
Author
Cohen et al. (2006)
Thaler & Ubogy (2005)
Cohen & Holmes (2004)
Location
Division of Plastic
Surgery, University of
California
USA
US Food and Drug
Administration trial
sponsored by Artes
Medical. In Thaler and
Ubogy (2005) it was
reported that both
authors had a financial
interest in Artes Medical
Intervention
Objective: safety and efficacy of PMMA vs collagen.
Prior to treatment, blood sample for anti-bovine collagen serum
IgG was taken and collagen allergy testing done.
Anaesthesia
EMLA cream (2.5% lidocaine and 2.5% prilocaine). Local
anaesthesia for upper lip. In Thaler and Ubogy (2005) EMLA or
nerve blocks implementing 1% lidocaine with epinephrine
sometimes used.
Treatment
Areas treated: glabella, nasolabial folds, radial upper lip lines
and/or mouth corners.
Patients permitted to return for as many as 2 re-treatments over a
maximum period of one month, with no limits on the volume of
PMMA or collagen injected. In Thaler and Ubogy (2005), all
patients injected 3 times.
Standardised photographs taken at baseline, 1, 3 and 6 months
and if PMMA administered, 12 months post treatment.
Study Design
Randomised controlled trial
Prospective clinical trial at 8 centres
Level of evidence: II
Patient allocation: not stated
Method of randomisation:
(Thaler and Ubogy - off-site computer).
Rating conducted in randomised
manner.
Blinding: injecting physicians not
masked, but patients and evaluators
were. Three raters independently
evaluated each standardised
photograph.
Method of allocation concealment: not
stated
Power calculation: not stated
Injection technique
PMMA injected deep dermally with 27g needle using multiple
tunnelling technique (into the reticular dermis just above the
junction between the dermis and the subcutaneous fat). If
blanching occurred, injection stopped and needle placed deeper.
Implant then massaged with finger nail and slight pressure
applied to any detected lump.
Collagen injected intradermally with 30g needle in glabella.
Zyplast in all other areas.
Post-treatment
Area massaged with finger tip and slight pressure applied to any
detected lump. Patients advised to minimise mimetic activity for 1
to 2 days after treatment.
104
Patients unmasked at 6 months after last treatment session.
At end of 6mths, PMMA offered to collagen group (106 people
(91%) took this up).
Intention-to-treat analysis: not stated
Follow-up: 1, 3, 6 and 12 months.
•
PMMA patients recalled 4 to 5
years after PMMA injections.
Inducement of $100 offered.
Lost to follow-up:
•
6 months: 18/251 (7.1%)
•
12 months: 17/128 (13.3%)
•
4 to 5 years: 59/128 (46.1%)
Study period: not stated. Only data
collected prior to 9 September 2005
presented.
Study population
Sample size: n = 251
•
PMMA: 128
•
Collagen: 123
Mean age (years):
•
PMMA: 53.2 (range 28 - 82), SD 10.3
•
Collagen: 51.2 (range 29 – 78), SD 11.3
Gender (M/F):
•
PMMA: 11/117
•
Collagen: 11/112
Patient co-morbidities: not stated
Outcome measures and validity:
Physician and patient classed a wrinkle fully corrected if
a fold that previously had a wrinkle did not have one after
treatment.
•
Safety assessed by measuring all adverse events
and by measuring IgG levels at 1 month visit (and
subsequent visits if elevated)
•
Efficacy measured by 3 masked observers using
Facial Fold Assessment Scale (validated by
Lemperle et al. 2001) on photographs
•
Investigator assessment of success was recorded
at 1, 3 and 6 months using the following scale: 1,
completely successful; 2, very successful; 3,
moderately successful; 4, somewhat successful; 5,
not at all successful.
•
Subject assessment of satisfaction was recorded at
1, 3 and 6 month intervals using the following scale:
1, very satisfied; 2, satisfied; 3, somewhat satisfied;
4, dissatisfied; 5, very dissatisfied.
•
Subject satisfaction was assessed using a
questionnaire (not validated).
Efficacy dependent variables expressed as the
improvement of Facial Fold Assessment from baseline,
averaged across 2 facial sides in the case of bilateral
Inclusion/Exclusion Criteria
Inclusion:
•
18 years or older
•
Realistic expectations of benefits
•
Provide informed consent
•
Presenting for treatment in at least
one of the four injection sites
•
Willing and able to comply with
follow-up requirements
Exclusion:
•
Pregnancy
•
Treatment with any wrinkle
augmentation material within 6
months of the trial
•
Anticipation of cosmetic surgery
before completing the study
•
Chemotherapy or corticosteroid
treatment within 3 months of
beginning study
•
Anticoagulant therapy
•
Autoimmune disorder or history
thereof
•
Atrophic skin disease
•
Extremely thin and/or flaccid skin
•
Known susceptibility to keloids
•
Known lidocaine sensitivity
•
History of dietary beef allergy or
under going desensitisation
•
Known allergy to collagen
•
Severe allergies (history of
anaphylaxis)
•
Cellulites or infection at prior
implant site
•
Serum immunoglobulin G levels
outside normal range
•
Positive skin test to collagen or two
equivocal tests
Statistical analysis:
treatment.
Tests for treatment group differences in
A single overall improvement score was also computed
number of treatments and quantity of
for each subject and was calculated by averaging the
product were made using independent t- improvement across facial areas.
tests. Nonparametric tests were used for
rating variables. Groups were compared
with Mann-Whitney U tests for
improvements in observer-rated and
investigator-rated Facial Fold
Assessment Scale scores and for
investigator success ratings and subject
satisfaction ratings. Within group tests
for improvements in the PMMA
treatment group were made using
Wilcoxon matched pairs signed rank
data to accommodate the 12-month
observations. Rater reliability for
observer Facial Fold Assessment Scale
ratings was evaluated using intraclass
correlation.
Lemperle G, Holmes RE, Cohen SR, Lemperle SM. A classification of facial wrinkles. Plastic & Reconstructive Surgery 2001; 108(6): 1735-1750.
Products:
Artecoll, Artes Medical, Inc, San Diego, California, USA.
Zyderm II/Zyplast, Inamed Corporation, Santa Barbara, Calif,
USA
105
Appendix B.1 Study profile tables – facial augmentation for ageing
Polymethylmethacrylate (PMMA) (Artecoll)
Author
Cohen et al. (2007)
Intervention
Objective: safety and efficacy of PMMA at 5 years.
Location
Division of Plastic
Surgery, University of
California
Study protocol as per Cohen et al. (2006).
USA
Study sponsored by
Artes Medical
Study Design
Case series
Prospective follow-up study at 8 centres
Level of evidence: IV
At the end of the 2006 study, of the 116 collagen patients who
completed the 6 month follow-up evaluation, 106 (91%) were
treated with PMMA. All subjects participated in a follow-up visit to
measure safety and efficacy of PMMA.
Blinding: Reviewers blind. Three raters
independently evaluated each
standardised photograph.
Product: Artecoll, Artes Medical, Inc, San Diego, California, USA.
Lost to follow-up:
•
89/234 (38.0%)
Study period: not stated
Statistical analysis: efficacy data
analysed for normal distribution by the
Kolmogorov-Smirnov test. Paired t-tests
employed unless distributions deviated
significantly from normality, in which
case Wilcoxon matched-pairs signedrank tests used.
Study population
Sample size:
•
For efficacy n = 142 (3 patients excluded)
o PMMA: 82
o PMMA cross over: 60
•
For safety n = 145 (number of patients from
each arm of pervious study not reported)
Efficacy measurements conducted only on NLF.
Mean follow-up from original study (years):
5.36 (range 4.53 – 6.32 years)
Mean age (years): 52.4
Gender (M/F): 15/127 (3 patients excluded from efficacy
but included for safety: gender unknown)
Patient co-morbidities: not stated
Outcome measures and validity:
•
Efficacy measured by 3 masked observers
using Facial Fold Assessment Scale
(validated by Lemperle et al. 2001) on
photographs from baseline and between 6
months and 5 years
•
Investigator assessment of success on scale
of 1, completely successful; 2, very
successful; 3, moderately successful; 4,
somewhat successful; 5, not at all successful.
•
Subject assessment of satisfaction on scale of
1, very satisfied; 2, satisfied; 3, somewhat
satisfied; 4, dissatisfied; 5, very dissatisfied.
•
Adverse events
•
Other cosmetic interventions
Lemperle G, Holmes RE, Cohen SR, Lemperle SM. A classification of facial wrinkles. Plastic & Reconstructive Surgery 2001; 108(6): 1735-1750.
Inclusion/Exclusion Criteria
Inclusion:
•
as per Cohen et al. (2006)
Exclusion:
•
as per Cohen et al. (2006)
106
Appendix B.1 Study profile tables – facial augmentation for ageing
Silicone Particles (Bioplastique)
Author
Mladick 1992
Location
Virginia Beach, Virginia
USA
Intervention
Objective: to report experience with Bioplastique.
Article not written in traditional scientific style (ie ‘should’ and
‘may’ used through out).
Injections should be made subdermally. Area to be injected
marked prior to treatment.
Product supplied in 1 and 0.5 ml syringes mounted on a special
injection gun that allows application of material to the pretunneled area.
Anaesthesia
Local anaesthesia with epinephrine is injected directly into the
site to be treated to decrease potential of bleeding.
No over-correction necessary.
Injection technique
The amount of material to be injected should be pre-planned.
Pre-tunneling technique used with a trocar (except for lips). A
point of entry slightly remote of defect area is preferred. Injection
should be done as needle withdrawn. Best results may be
achieved by cross-tunneling technique. For lips, each half of the
upper and lower lip is done using an injection site on the opposite
half of the lip.
Release injection pressure before withdrawing the needle. Pinch
the track, then immediately irritate the skin opening to remove
any extraneous material.
Apply ice compresses for the first 24 hours to decrease swelling
and bruising. Administer prophylactic antibiotics for 2 days
following treatment. Tape splinting of the area is optional.
Product: Bioplastique, Bioplasty, Inc, St Paul, MN, USA.
Study Design
Case series
Retrospective
Level of evidence: IV
Study population
Sample size: n = 40
Inclusion/Exclusion Criteria
Inclusion: not stated
Mean age (years): not stated
Exclusion: not stated
Gender (M/F): not stated
Patient allocation: not stated
Patient co-morbidities: not stated
Follow-up (years): not stated
Lost to follow-up: not stated
Study period: not stated
Operator details: not stated
Statistical analysis: not stated
Outcome measures and validity: Results evaluated by
patient and surgeon and values averaged using 5-point
scale. 5, excellent; 4, very good; 3, good; 2, acceptable;
1, poor.
107
Appendix B.1 Study profile tables – facial augmentation for ageing (lips only)
Liquid Silicone (Silikon)
Author
Fulton et al. (2005)
Intervention
Objective: to demonstrate safety and efficacy of lip augmentation
with liquid silicone.
Study Design
Case series
Retrospective
Location
Vivant Skin Care, Inc,
Miami, Florida
Patients told not to take any salicylates, ibuprofens, or vitamin E
for 2 weeks before therapy. Patients with type III lips asked to
consider additional therapies for lip augmentation.
Patients told to return in 1 month for follow-up and possible
reinjection.
Level of evidence: IV
Anaesthesia
Intraoral regional nerve blocks of the infraorbital and mental
nerves using 2% lidocaine with epinephrine (1:200000) buffered
with sodium bicarbonate. If patient sensitive to epinephrine, the
2% lidocaine diluted with plain 1% lidocaine (50:50). Approx
0.5ml of anaesthetic is injected through the gingival lining directly
above both incisor teeth on the upper jaw bilaterally and below
both incisor teeth on the lower jaw bilaterally using a half-inch 30gauge needle. A small amount of additional injection of 0.25ml is
placed adjacent to the frenulum of the upper lip to complete the
process.
Lost to follow-up: not stated
USA
Authors reported no
significant interest with
commercial supporters.
Injection technique
0.25 – 0.5ml liquid silicone injected through 27-gauge needle into
vermillion border in a micro-droplet fashion. The shaft of the
needle is inserted into the vermillion border, and the product is
injected as the needle is withdrawn.
In selected patients, additional injections given into the lateral
orbicularius oris muscle to attempt lip eversion.
Finger compression of the angular artery and direct compression
with cotton gauze are immediately applied to reduce bruising.
Following hemostasis, the area is compressed with ice for 3 – 4
minutes to reduce swelling. Patients warned not to eat or drink
hot tea or coffee until the anaesthesia has worn off. The desired
augmentation is attained with a series if treatments at monthly
intervals.
Lip thickness measured using a micrometer. Measurements
taken in both quadrants of the upper lip.
108
Two millimeter punch biopsies were obtained from the vermillion
border of the upper lip in 5 patients 8 – 12 weeks following
augmentation.
Product: Silikon, Acon Labs, Fort Worth, TX, USA.
Study population
Sample size: n = 608
Inclusion/Exclusion Criteria
Inclusion: not stated
Average age: 38
Exclusion: not stated
Gender (M/F): 18/590
Patient allocation: not stated
Patient co-morbidities: not stated
Follow-up: 3 years
Study period: the last 3 years
Operator details: not stated
Statistical analysis: not stated
Outcome measures and validity:
Results were documented with millimeter measurements
of the lips using a micrometer. Lip thickness
measurements in both quadrants of the upper lip. The
results were averaged and chartered. Results were also
documented with digital photography.
Appendix B.1 Study profile tables – facial augmentation for ageing
Polyacrylamide hydrogel (PAAG) (product name not specified)
Author
Reda-Lari (2008)
Location
Private practice, AlSulaibikhat,
Kuwait
Author has no financial
interest in and receive
no compensation from
manufacturers of
products mentioned in
article
Intervention
Objective: malar augmentation with PAAG.
Pre and post operative photos taken of all patients.
Malar area defined by the middle of the line drawn from upper
auricular notch to the alar base or the point where the vertical line
from the lateral orbital wall crosses the line.
Anaesthesia
1% lidocaine 0.2ml administered at injection site. Nerve block
anaesthesia of the inferior orbital nerve through an intraoral
approach was used during the first 2 years that procedure
performed. Local anaesthesia now used in selected cases. Nerve
block still used at beginning of treatment to relax and ease
patient and surgeon.
Prophylactic broad spectrum antibiotics routinely given after
procedure.
Injection technique
Single entry point technique. 16 – 18 gauge needles for injection
into deep cutaneous tissue layer or even closer to the bone
(sometimes a more superficial plane chosen for correction of
linear cheek depressions). Gel ‘pooling’ method used in all cases.
All gel is injected at one point, forming a pool of gel in the tissue.
Manual massaging after injection to distribute gel evenly and to
prevent irregularities. If more gel required, another pool deposited
in an adjacent area for better distribution of gel.
Post-treatment
Patients advised to massage the treated area lightly to soften and
smooth the edge, as well as to minimise the sensation of
pressure.
Prophylactic broad spectrum antibiotics routinely given after
procedure.
Follow-up scheduled for 5 days, 2 weeks, and 3, 6 and 12
months after treatment.
Product: PAAG (product name not specified)
Study Design
Case series
Retrospective
Level of evidence: IV
Study population
Sample size: n = 1306
Inclusion/Exclusion Criteria
Inclusion: not stated
Average age: 18 – 55 (80% between 25 – 40 years)
Exclusion:
•
Pregnancy
•
Connective tissue disorders
•
Skin disorders affecting the face
•
Insulin-dependent diabetes
mellitus
•
Compromised immune functions
•
Acute inflammatory diseases
including acne
•
Known substance abuse
•
Mental disorder
•
Relative complications were
unstable personality and
unrealistic expectations
Gender (M/F): 11/1295
Follow-up: 3 months – 6 years
Patient co-morbidities: not stated
Lost to follow-up: not stated
Study period: not stated
Operator details: same surgeon treated
all patients in same facility
Statistical analysis: not stated
Outcome measures and validity:
Photographs taken before and after treatment.
Patients asked to evaluate their results.
Validation not stated.
109
Appendix B.1 Study profile tables – facial augmentation for ageing
CaHA vs. Hyaluronic acid (HA) (Juvederm 24/24HV and Perlane)
Author
Moers-Carpi et al.
(2007)
Location
Private clinic, Hautok
Germany
BioForm Medical Inc
provided support and
funding for study.
Moers-Carpi has
received compensation
for presentations about
Radiesse to medical
community. Howell is a
professional medical
writer employed by
BioForm.
Intervention
Objective: Immediate efficacy, duration of correction, patient
satisfaction and likelihood to return after CaHA or HA treatment
of NLFs.
All patients had photographs taken of entire lower face below
eyes to determine Global Aesthetic Improvement Scale rating.
Anaesthesia
Performed at the discretion of treating physician (eg local nerve
block and ice).
Treatment
Same injection technique used on both NLF. Volume at discretion
of treating physician. Physicians advised to inject enough
material to create optimal augmentation.
All patients were intended to receive an initial treatment and a
touch-up at 4 months. Patients then returned at 4, 8 and 12
months after second injection for evaluation of NLF, with no
further touch-up offered until the end of the study.
Injection technique
27 gauge needle into mid to deep dermis. Injection technique not
reported.
Post-treatment
Not reported
Products:
•
CaHA (Radiesse, BioForm Medical Inc, San Mateo, CA,
USA)
•
HA 1 (Juvederm 24, Allergan)
•
HA 2 (Juvederm 24 HV)
•
HA 3 (Perlane, Medicis)
Study Design
Randomised controlled trial
Prospective, multicentre
Level of evidence: II
Method of randomisation: treatment
assignment done at the time of injection
Method of allocation concealment: not
stated
Blinding: each centre had a consistent
blinded evaluator throughout the study
Intention-to-treat analysis: not stated
Power calculation: not stated
Follow-up: 12 months
Lost to follow-up: not clearly reported
•
4 months n = 10
•
8 months n = 7
•
12 months n = 11
Reasons and treatment groups not
reported
Study period: September 2005 –
January 2006
110
Statistical analysis:
For patient satisfaction, Fisher exact test
used to test proportions of CaHA
patients compared to control treatments
responding positively to satisfactionrelated question. For Global Aesthetic
Improvement Scale analysis, Fisher
exact binomial test used to test the
proportion of CaHA patients compared
to the proportion of the control
treatments showing improvements on
the Global Aesthetic Improvement
Scale. Patients for whom there was no
Study population
Sample size: n = 205
•
CaHA n = 70
•
HA 1 (Juvederm 24) n = 33
•
HA 2 (Juvederm 24 HV) n = 33
•
HA 3 (Perlane) n = 69
Mean age (years): 52 (range 27 – 80 years)
Gender (M/F): 20/185
Patient co-morbidities: not stated
Outcome measures and validity:
•
Global Aesthetic Improvement Scale (Narins et al.
2003) determined by comparing patient’s live
appearance to baseline photograph
•
Wrinkle Severity Rating Scale score (validated by
Day et al. 2004) determined by evaluating patient’s
live appearance
•
Patient satisfaction assessment (not described)
•
Survey questionnaire (only patients enrolled at lead
investigator’s site n = 120) (not described)
Inclusion/Exclusion Criteria
Inclusion:
•
Both NLF with a rating of 3 or 4 on
Wrinkle Severity Rating Scale as
judged by blinded evaluator
•
18 years or older
•
No other facial procedures
affecting the NLFs
•
To present for study visits for the
study period
Exclusion:
•
Known bleeding disorder
•
History of keloid formation or
hypertrophic scarring
•
Chronic or recurrent infection or
inflammation
•
Severe allergies manifested by
history of anaphylaxis
•
Pregnancy, lactation or unreliable
contraception
•
Platelets, anticoagulants,
thrombolytics, Vitamin E or
antiinflammatories from 1 week
before to 1 month after treatment
•
Systematic corticosteroids or
anabolic steroids
•
History of chronic or recurrent
infection or inflammation
•
Fat grafts, silicone, polymers or
hydrogels or any other surgery of
tissue augmentation other than
collagen or HA in either NLF within
6 months before enrollment
•
Severe allergies manifested by a
history of prophylaxis
•
Any condition contraindicated in
the product labeling or prescription
treatments within 4 weeks before
study or intention to receive
products during the study.
difference between the products were
excluded from Global Aesthetic
Improvement Scale analysis. Significant
if two-sided p-value ≤ 0.05.
Narins R, Brandt, F, Leydon J et al. A randomised, double blind, multicentre comparison of the efficacy and tolerability of Restylane vs. Zyplast for the correction of nasolabial folds. Dermatologic Surgery 2003; 29: 588.
Day DJ, Littler CM, Swift RW, Gottlieb S. The Wrinkle Severity Rating Scale: a validation study. American Journal of Clinical Dermatology 2004; 5: 49-52.
111
Appendix B.1 Study profile tables – facial augmentation for ageing
CaHA (Radiesse) vs. Collagen (Cosmoplast)
Author
Smith et al. (2007)
Location
Therapeutics Clinical
Research and USCD
Division of
Dermatology, San
Diego, California,
USA
Filler, supplies and
equipment for
photographic
documentation provided
by BioForm Medical.
Investigators were paid
an honorarium to
conduct study. Drs
Busso and Bass have
received compensation
for presentations about
Radiesse to medical
community.
Intervention
Objective: compare safety and efficacy of CaHA to collagen with
bilateral injections
Study Design
Randomised controlled trial
Multicentre, prospective
Standardised photographs of NLF taken.
Level of evidence: II
Anaesthesia
Topical anaesthetic cream, local infiltration, intraorbital
anaesthetic block or combination of these at the discretion of
investigator. Care was taken to apply anaesthesia symmetrically
Method of randomisation: computer
generated randomisation codes
Treatment
CaHA: 27 gauge needle into dermal/subcutaneous junction.
Collagen: 30 or 31 gauge needle mid to deep dermis.
Each side treated until investigator thought optimal result was
achieved.
Injection technique
For both, linear threading was used. Over correction not
permitted.
After initial injection, patients were seen 2 weeks later. Patients
could receive an additional 2 touch up injections 2 weeks apart at
discretion of treating physician.
Patients were seen 1, 3 and 6 months after final injections.
Post-treatment
Treatment areas were massaged as needed to ensure deposition
of product. Ice or cool compresses could be applied to the NLF
before and/or after injections but were applied equally to both
sides.
Study population
Sample size: n = 117
Mean age (years): 54.7 (31 – 76)
87.2 Caucasian, 9.4% Hispanic, 1.7% black, 1.7% other
Gender (M/F): 12/105
Patient co-morbidities: not stated
Method of allocation concealment: not
stated
Blinding: independent panel of 3 blind
experts viewed photographs in
randomised order. Patients had eyes
covered during injections.
Intention-to-treat analysis: not stated
Power calculation: not stated
Outcome measures and validity:
•
NLF severity determined by Facial Fold
Assessment Scale (Lemperle et al. 2001 validated)
•
Global Aesthetic Improvement Score (Narins et al.
2003) assigned to each follow-up NLF photograph
after comparison with baseline images.
•
A subset of patients evaluated using Global
Aesthetic Improvement Score at 6 months using
patients not photographs to confirm blinded
evaluator analysis (not blinded).
Inclusion/Exclusion Criteria
Inclusion:
•
Symmetric, moderate to deep NLF
(Grade 3 – 4)
•
No confounding therapies in last 6
months or during the study
(injectable fillers, chemical peeling,
laser resurfacing)
Exclusion: not stated
Follow-up: 6 months
Lost to follow-up: n = 4, reported that no
further data available on these patients
Study period: not stated
Statistical analysis:
Safety and efficacy outcomes using
McNemar’s paired comparison test in a
predetermined population. Intraobserver
Products:
and interobserver agreement assessed
CaHA (Radiesse, San Mateo, CA, USA)
using weighted kappa. Confirmatory
Collagen (Cosmoplast, Allergan, Irvine, CA, USA)
analysis performed Similar results found
for each evaluator as reported for the
median scores of the 3 evaluators. Pvalue of ≤ 0.025.
Lemperle G, Holmes RE, Cohen SR, Lemperle SM. A classification of facial wrinkles. Plastic & Reconstructive Surgery 2001; 108(6): 1735-1750.
Narins R, Brandt, F, Leydon J et al. A randomised, double blind, multicentre comparison of the efficacy and tolerability of Restylane vs. Zyplast for the correction of nasolabial folds. Dermatologic Surgery 2003; 29: 588.
112
Appendix B.1 Study profile tables – facial augmentation for ageing
Calcium Hydroxylapatite (CaHA) (Radiesse)
Author
Jacovello et al. (2006)
Intervention
Objective: to examine patient satisfaction and longevity of CaHA
as a facial filler to improve aesthetic appearance.
Location
University of Buenos
Aires.
Pretreatment photographs taken. Post treatment photographs
obtained soon after injection and at the conclusion of the 18
month follow-up period.
Argentina
Financial support from
BioForm Medical Inc
received for preparation
of article. No author had
any financial interest in
BioForm Medical
Anaesthesia
Depending on anatomical area, regional or nerve block
anaesthesia (2% lidocaine) was injected avoiding infiltration near
the region to be corrected.
Injection technique
Each region treated only once.
Either a 25- or 27-gauge needle. Into deep dermis. Injected in the
created track during slow withdrawal of the needle.
•
Glabella: 27 gauge 0.5 inch long needle longitudinally into
deep dermis. Injected into created tunnel by simultaneously
slowly withdrawing syringe and pressing material out of
syringe into dermis.
•
Nasolabial folds: 25-gauge, 1-inch long needle into entire
fold longitudinally. Procedure involved only 1 puncture,
starting at the inferior end and terminating at the corner of
the mouth. 2 or 3 bands of CaHA implanted in parallel rows,
depending on the depth of the nasolabial fold.
•
Lip augmentation: 25-gauge, 1-inch long needle. 4
tunneling puncture wounds made during procedure. 1 layer
injections of ≤ 0.5ml per site injected while withdrawing the
needle.
•
Nose: injected in a previously created space with a 27gauge needle with a back-and-forth multidirectional
technique. Puncture site distal to corrected regions.
•
Infraorbital region: 25-gauge, 1-inch long needle used to
approach area from the cheek. Puncture site distal to
injected region: a crisscross (2 direction) technique used to
spread product. Both infraoral regions treated.
Product: Radiesse, BioForm Medical, Inc, San Mateo, California,
USA.
Study Design
Case series
Study population
Sample size: n = 40
Inclusion/Exclusion Criteria
Inclusion: not stated
Patient recruitment and allocation: not
stated
Age (years): between 25 - 60
All Argentinean
Level of evidence: IV
Gender (M/F): 5/35
Follow-up: 18 months
Patient co-morbidities: not stated
Exclusion:
•
Acute or chronic local infection
•
Existing keloidal scarring
•
Systemic collagen diseases
•
Bleeding disorders
•
Clearly unrealistic expectations
Lost to follow-up: not stated
Outcome measures and validity:
Patient satisfaction survey (not validated)
Study period: December 2002 – June
2004
Statistical analysis: none
113
Appendix B.1 Study profile tables – facial augmentation for ageing
Calcium Hydroxylapatite (CaHA) (Radiance FN)
Author
Sklar & White (2004)
Intervention
Objective: to demonstrate safety and effectiveness of CaHA as
an aesthetic soft tissue filler.
Location
Centre for Aesthetic
Dermatology,
Woodbury, New York
and Dermatologic
Surgery, Metropolitan
Hospital, New York.
Injection technique not written in traditional style – ie use of the
words ‘should’ and ‘may’.
USA
Authors reported no
significant interest with
commercial supporters.
Can be injected subcutaneously or intramuscularly (not
intradermally as it results in granulomas).
Material comes in a sterile prepackaged 1ml syringe with 27guage 1.25 inch needle that does not require refrigeration. Small
amounts can be saved and corrections made after a couple of
weeks.
Anaesthesia
A nerve block is preferred for the nasolabial folds and lips. Tiny
bleb of lidocaine used to prepare injection site – kept away from
treatment site to prevent distortion and intradermal injection.
Injection technique
Needle advanced at 45o angle through dermis to subcutaneous
space and then is advanced parallel to the skin to the distal point
to be injected. Injection is performed in a retrograde manner as
the needle is slowly withdrawn through the subcutaneous space.
Injection should be at a constant rate on withdrawal. Multiple
passes can be made at an area. Injection of the lips is either
intramuscularly or deep glandular in the lip mucosa.
Authors routinely massage all treated areas after treatment.
In most areas (nasolabial folds, infraoral folds, cheeks) superficial
subcutaneous placement gives better correction. In the tear
trough area too superficial placement will cause lumpiness and
the white colour of the material may show through the skin.
Product: Radiance FN, BioForm Inc.
Study Design
Case series
Consecutive patients from 2 centres.
Retrospective
Level of evidence: IV
Follow-up: 6 months
Lost to follow-up: not stated
Study period: not stated
Operator details: not stated
Statistical analysis: not stated
Study population
Sample size: n = 64
•
101 treatments
Mean age (years): not stated
Gender (M/F): not stated
Patient co-morbidities: not stated
Outcome measures and validity: not stated
Inclusion/Exclusion Criteria
Inclusion: not stated
Exclusion: not stated
114
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Autologous Fat Transfer vs. Polylactic Acid (New-Fill) vs. Polyacylamide Hydrogel (Aquamid)
Author
Guaraldi et al. (2005)
Intervention
Objective: to compare AFT with PLA and PAAG fillers for HIVassociated facial lipoatrophy.
Location
Department of
Infectious and Tropical
Diseases, University of
Modena and Reggio
Emilia Italy & San
Rafaele Hospital, Milan.
Lipoatrophy defined as thinning of the cheeks and deepening of
the nasolabial folds:
•
Moderate: easily noted by patient and physician
•
Severe: obvious to casual observer
Italy
Pre-lipoatrophy photos compared with current appearance.
Anaesthesia
No lidocaine given before injections.
Injection technique
•
AFT: performed according to Coleman’s technique. Amount
determined from photos. Amount injected determined by
surgeon and patient. Cheeks massaged to distribute filler.
•
PLA: Suspension reconstituted from powder (0.15 g powder
+ 4 ml water and suspended for 24 hrs). Max 4 ml given in
each cheek. Given every 4 wks into deep dermis around
atrophied area in cheek. 26g needle.
•
PAAG: Supplied in 1ml syringe with 27g needle. Injected
into subcutaneous space every 4 weeks. Volume
augmentation to amount injected 1:1.
At the end of each set of injections, cheeks massaged for better
distribution of product.
Product:
•
New-Fill, Biotech Industries, SA, Luxembourg.
•
Aquamid, Contura Industries, Denmark.
Study Design
Randomised controlled trial
Consecutive patients to clinic.
Prospective
Level of evidence: II
Method of randomisation: if enough
residual subcutaneous fat, patient had
AFT. Other patients blindly assigned
PLA or PAAG.
Blinding: not stated
Method of allocation concealment: not
stated
Intention-to-treat analysis: not stated
Power calculation: not stated
Follow-up: 6 months
Lost to follow-up: not stated
Study period: 24 wks
Operator details:
PLA and PAAG injected by different
teams (ie one team did PAAG, the other
PLA for technique reasons).
Ultrasound and measurements
performed by same operator.
Study population
Sample size: n = 59
•
AFT: n = 24
•
PLA: n = 20
•
PAAG: n = 15
Patient co-morbidities: HIV infection
Mean age:
•
AFT: 43 ± 6
•
PLA: 44 ± 8
•
PAAG: 45 ± 8
Gender (M/F): 41/18
•
AFT: 15/9
•
PLA: 14/6
•
PAAG: 12/3
Outcome measures and validity:
Primary endpoint
•
Measurement of Bichat’s fat pad region (dermal
plus subcutaneous thickness). Ultrasound (linear
array transducer 7.5 MHz frequency probe)
measurements on both cheeks made perpendicular
to skin surface at nasolabial fold, corner of mouth,
zygotic arch and centrally between these points in
buccal fat pad area. Three measurements taken
and most reproducible measurement recorded. Not
validated.
Secondary endpoint
•
Body image evaluation via Adult AIDS Clinical
Trails Group Assessment of Body Change and
Distress (ABCD) (not yet validated when this paper
published, but later published as Guaraldi et al.
2006).
•
Facial aesthetic satisfaction measured via Visual
Analogue Scale.
Inclusion/Exclusion Criteria
Inclusion:
•
Documented HIV infection
•
Lipoatrophy diagnosis with facial
wasting.
•
Over 18 years
•
Treatment with highly active
antiretroviral therapy (HAART) for
at least 6 months.
Exclusion:
•
Severe immuno-suppression (<
100 CD4+ cells/uL
•
Haemorrhagic disease
•
Thrombocytopaenia (< 50,000/uL)
•
Surgeon’s opinions of no benefit
•
Unwillingness for 6mth follow-up
•
Previous procedures for treatment
of HIV-associated with lipoatrophy
115
Statistical analysis: performed by
ANOVA test (α = 0.05) which was used
to compare baseline results with week
24 and between the 3 study arms. Post
hoc comparisons were adjusted
according to Bonferroni’s correction. ttests were performed to analyse intergroup differences.
Guaraldi et al. Quality of life and body image in the assessment of psychological impact of lipodystrophy: validation of the Italian version of assessment of body change and distress questionnaire. Quality of Life Research
2006; 15(1): 173 – 178.
Appendix B.1 Study profile tables – facial augmentation for HIV-associated lipoatrophy
AFT ± PLA (Sculptra), PLA (Sculptra) and PAAG (Aquamid)
Author
Orlando et al. (2007)
Location
Infectious Disease
Clinic, University of
Modena and Reggio
Emilia, Modena
Italy
Intervention
Objective: to assess long-term psychometric outcomes of
treatment of HIV-related facial lipoatrophy
Study Design
Non-randomised comparative
Consecutive, observational, prospective
Objective outcomes and facial surgical techniques and
interventions described in Guaraldi et al. (2005) and Guaraldi et
al. (2006) as follows:
Level of evidence: III-2
Pre-lipoatrophy photos compared with current appearance.
Lost to follow-up: not stated
Anaesthesia
No lidocaine given before injections.
Study period: November 2005 – July
2006
Injection technique
•
AFT: performed according to Coleman’s technique. Amount
determined from photos. Amount injected determined by
surgeon and patient. Cheeks massaged to distribute filler.
•
PLA: Suspension reconstituted from powder (0.15 g powder
+ 4 ml water and suspended for 24 hrs). Max 4 ml given in
each cheek. Given every 4 wks into deep dermis around
atrophied area in cheek. 26g needle.
•
PAAG: Supplied in 1ml syringe with 27g needle. Injected
into subcutaneous space every 4 weeks. Volume
augmentation to amount injected 1:1.
Operator details: Ultrasound by same
single radiologist
Follow-up: 48 weeks
Statistical analysis: Comparison of
variables done using the paired samples
t-test for continuous variables and the χ2
test for categorical variables. Analysis of
variance (ANOVA) used to analyse
differences of variables among groups.
A p-value of < 0.05 considered
statistically significant.
Study population
Sample size: n = 299
If enough residual abdominal subcutaneous fat
•
AFT n = 54
•
AFT + PLA n = 24
If not enough subcutaneous fat, patients could choose
•
PLA n = 91
•
PAAG n = 130
Mean age (years): 46 ± 7
•
AFT 45 ± 6
•
AFT + PLA 47 ± 8
•
PLA 46 ± 7
•
PAAG 14 ± 7
Gender (M/F): 212/87
•
AFT 27/27
•
AFT + PLA 14/10
•
PLA 60/31
•
PAAG 111/19
Patient co-morbidities: HIV infection
Inclusion/Exclusion Criteria
Inclusion:
•
18 years of age
•
Documented HIV infection
•
On stable highly active
antiretroviral therapy for at least 6
months
•
Physician and patient’s
concordance about lipodystrophy
diagnosis with moderate-to-severe
facial wasting
Exclusion:
•
Concomitant active dermatologic
disease of the face HSV-1, HZV
recurrence, acne rosacea)
•
Increased bleeding risk (limited to
the lipofilling technique) defined by
a platelet count < 50,000 /ul and/or
international normalised ratio > 2
•
Surgeon’s opinions of no aesthetic
benefit from intervention
•
Unwillingness to be followed up for
12 months
•
Previous procedures for treatment
of HIV-associated facial
lipoatrophy
Outcome measures and validity:
Subjective outcome measures:
•
Face aesthetic satisfaction (VAS)
•
Body image perception by Assessment of Body
Change and Distress questionnaire (ABCD)
(validated Guaraldi et al. 2006),
Products:
•
Depression by the Beck Depression Inventory.
PLA (Sculptra, Aventis Pharmaceutical, Collegeville, PA, USA)
Objective
outcome measure:
PAAG (Aquamid, Contura, Soeberg, Denmark)
•
Cheek thickness evaluated by ultrasound probe
perpendicular to the skin surface at the nasolabial
fold, the corner of the mouth, the zygomatic arch,
and centrally between these points in the buccal fat
pad area.
Guaraldi G, Orlando G, De Fazio D, De Lorenzi I, Rottino A, De Santis G, Pedone A, Spaggiari A, Baccarani A, Borghi V, Esposito R. Comparison of three different interventions for the correction of HIV-associated facial
lipoatrophy: a prospective study. Antiviral Therapy 2005; 10(6): 753-759.
Guaraldi G, Orlando G, Squillace N, et al. Multidisciplinary approach to the treatment of metabolic and morphologic alterations of HIV-related lipodystrophy. HIV Clinical Trials 2006; 7: 97-106.
Guaraldi G, Orlando G, Murri R, et al. Quality of life and body image in the assessment of psychological impact of lipodystrophy: validation of the Italian version of assessment of body change and distress questionnaire.
Quality of Life Research 2006; 15(1): 173–178.
At the end of each set of injections, cheeks massaged for better
distribution of product.
116
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Autologous Fat Transfer, Polylactic Acid (New-Fill) and Polyacylamide Hydrogel (Aquamid)
Author
Negredo et al. (2006)
Location
HIV Unit, Fundaco de la
Lluita contra la Sida,
Germans Trias i Pujol
University Hospital,
Universitat Autonoma
de Barcelona,
Barcelona
Spain
Intervention
Objective: to determine the benefit for treatments for facial
lipoatrophy in relation to the stigma associated with facial
lipoatrophy.
Patients received injections into the perimalar area and
nasolabial folds.
AFT – for people with fat accumulations in abdomen, hump or
breast areas.
PLA or PAAG gel for others. Selection of product depended on
availability (product donated) and technical feasibility.
PLA - intradermal
PAAG – subcutaneous
Standardised photographs taken at each visit (baseline, 7 days
after each injection session, and every 12 weeks there after).
Anaesthesia
Both administered in ambulatory regimen by retrotracing using
bilateral intra-buccal truncal anaesthesia at the level of the
infraorbital nerve.
Each vial of PLA also included 3ml of distilled water and 2ml of
lidiocaine 2%
Quantity of substance depended on severity of lipoatrophy and
surgeon.
Massage of treated area conducted to redistribute product.
A 2nd treatment given 2 weeks after 1st session. A 3rd session
given 4 weeks after 1st session for patients in the PLA group who
needed it (according the plastic surgeon). This was referred to as
the first round of treatment.
Patients evaluated after a 1 year follow-up to consider a second
round of treatment.
Dual-energy x-ray absorptiometry (DEXA) scans performed
during the screening visit and at weeks 24 and 48, to measure
body fat variations throughout the follow-up period.
Product:
•
PLA, New-Fill, Biotech Industries SA, Luxembourg.
•
PAAG, Aquamid, Contura International SA, Copenhagen,
Denmark.
Study Design
Non-randomised comparative
Prospective study, consecutive patients
Level of evidence: III-2
Blinding: photographs evaluated by 2
independent blinded assessors not
involved in the study.
Follow-up: 12 months
Lost to follow-up: n = 11
•
PLA: n = 1
•
PAAG: n = 10 (1 died from
leukoencephalopathy)
Other reasons not stated.
Lost patients not included in analysis.
Study period: September 2002 –
September 2004
Operator details: not stated
117
Statistical analysis:
Changes in facial lipoatrophy intensity
scores between baseline and week 48
calculated. Changes in patient
satisfaction, quality of life etc and the
tolerance and safety of techniques
calculated from baseline to week 48.
An exploratory statistical analysis
carried out according to a ‘complete
population’ analysis. Differences among
groups evaluated by χ2 test or Fischer’s
exact test for qualitative variables, and
the Student’s t test for quantitative
variables following a normal distribution,
or by the Mann-Whitney and Wilcoxon
rank sum test for those who failed the
normality test. The corresponding 95%
confidence intervals were calculated for
the differences between groups. A
significant level of α = 0.05 was used.
Study population
Sample size: n = 149
•
AFT: n = 8
•
PLA: n = 26
•
PAAG: n = 115
Mean age (years):
•
AFT: 39 ± 6
•
PLA: 45 ± 5
•
PAAG: 43 ± 9
Gender (M/F):
•
AFT: 8/0
•
PLA: 25/0
•
PAAG: 8/97
Patient co-morbidities: HIV infection
Outcome measures and validity:
•
Lipoatrophy classified by authors as follows. Facial
lipoatrophy intensity ordinal scale: degree 0, no
facial lipoatrophy, to degree 4, all areas severely
affected.
•
Patient limitation measured on a 100 mm visual
analogue scale, with higher scores indicating a
greater negative impact.
•
Patient satisfaction after treatment measured on 5
point Likert scale.
•
Quality of life assessed with Medical Outcomes
Study – HIV (MOS-HIV) questionnaire
•
Adherence to antiretroviral therapy self-reported by
patients. Adherence defined as the consumption of
at least 95% of the prescribed medication.
Inclusion/Exclusion Criteria
Inclusion:
•
HIV infected patients presenting
with antiretroviral-associated facial
lipoatrophy for more than 6 months
•
1 year minimum duration of
antiretroviral treatment
•
CD4 cell count > 100 cells/mm3.
Exclusion:
•
Previous facial cosmetic facial
intervention
Appendix B.1 Study profile tables – facial augmentation for HIV-associated lipoatrophy
PAAG (Aquamid)
Author
De Santis et al. (2008)
Location
Department of Plastic
and Reconstructive
Surgery, University of
Modena and Reggio
Emilia, Modena
Italy
The authors reported no
financial interests in the
products, devices, or
drugs mentioned in the
article.
Intervention
Objective: evaluate the safety and efficacy of PAAG over 12
months in HIV infected patients
Study Design
Case series
Consecutive patients
Patients presented pre-lipoatrophy photographs and a
comparison of the current facial appearance with the photograph
was done.
Level of evidence: IV
Patients injected with limited volumes of not more than 1 ml at
multiple sites of a hemiface in such a volume as was required to
reconstruct the facial morphology with maximum aesthetic gains.
Injection technique
Material injected below dermis, in the deeper subcutaneous
plane.
Post-treatment
The use of ice packs immediately after the procedure helps
reduce local tissue reactions.
Product: PAAG (Aquamid, Contura SA, Montreux, Switzerland).
Follow-up: 12 months
Lost to follow-up: none at 12 months, 19
at 24 months
Study period: not stated
Operator details: not stated
Statistical analysis: not stated
Study population
Sample size: n = 50
•
61.3% isolated facial lipoatrophy
•
39.7% other lipodystrophy symptoms
Mean age (years): 44.5
Gender (M/F): 39/11
Patient co-morbidities: HIV infection
Outcome measures and validity:
•
Standardised ultrasonography
•
Psychological tests
o visual analogue scale
o Beck Depression Inventory
o Assessment of Body Change and
Distress questionnaire
No details regarding any these outcome measures
reported
Inclusion/Exclusion Criteria
Inclusion:
•
Documented HIV type 1 infection
•
Facial lipoatrophy
•
Age older than 18 years
•
Highly active antiretroviral therapy
for at least 6 months
•
CD4 cell count greater than 100
cells/µl
•
Platelet count greater than 50,000
cells/µl,
•
Willingness to participate in followup for at least 12 months.
Exclusion:
•
Severe immunosuppression
•
Previous permanent fillers at the
same site
•
Previous resorbable fillers at the
site less than 6 months before
screening
•
Pregnancy or lactation.
118
Appendix B.1 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Liquid silicone (Silikon 1000 or VitreSil 1000))
Author
Jones et al. (2004)
Location
Division of
Dermatology, David
Geffen School of
Medicine, University of
California, Los Angeles
USA
The authors reported
that Dr Jones has
served as a speaker for
RJ Development
(developer of Silskin).
Dr Azen was paid by
the company that
provided silicone oil. RJ
Development provided
VitreSil 1000 to Dr
Carruthers and paid Dr
Azen.
Intervention
Objective: to evaluate safety and efficacy of highly purified 1000cSt silicone oil injected by microdroplet serial puncture technique
for treatment of HIV-associated lipoatrophy.
Study Design
Case series:
Multicentre sub sample (not
consecutive)
Injection technique
At each session, patient photographed. Microdroplets (0.01ml)
injected at 2 – 4 mm intervals as described by Orentreich (2000).
Overlapping generally avoided.
Level of evidence: IV
Post-treatment
Finger pressure applied when necessary to areas of pinpoint
bleeding to reduce bruising. Patients instructed to avoid contact
with sports or activities that would predispose treated area to
trauma.
Product:
•
Silikon 1000 (Alcon Laboratories, Ft Worth, TX, USA
•
VitreSil 1000 (Richard James Inc, Peabody, MA, USA
Follow-up: NR (time from first to last
injection given according to lipoatrophy
score, but no specific length of follow
up)
Lost to follow-up: NR
Study period: NR
Operator details: NR
Statistical analysis: p-value for time
lipoatrophy score compared with time
from first to last injection obtained using
ANOVA across groups.
James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatologic Surgery 2002; 28: 979-986.
Orentreich DS. Liquid injectable silicone: techniques for soft tissue augmentation. Clinical Plastic Surgery 2000; 27: 595-612.
Study population
Sample size: n = 77
Age (years):
•
30 – 39 n = 12
•
40 – 49 n = 46
•
50 – 59 n = 17
•
60 + n = 2
Gender (M/F): 76/1
Patient co-morbidities: HIV infection
Outcome measures and validity:
•
Lipoatrophy severity measured using Carruthers
lipoatrophy severity scale (0, no lipoatrophy to 4,
very severe lipoatrophy) (James et al. 2002).
•
Patients had ‘complete correction’ when 1 month or
more after their final injection, their facial contour
had returned to a level that the physician and
patient believed was close to the patients’
prelipoatrophy appearance. Photograph taken.
•
Independent rater rated pre and post photographs
using Carruthers lipoatrophy severity rating scale.
•
Adverse events defined as post-treatment pain,
erythema, or oedema lasting for longer than 3 days
or ecchymosis lasting longer than 2 weeks.
Inclusion/Exclusion Criteria
Inclusion:
•
Patients with stable, well-controlled
HIV
•
No opportunistic infections
•
No history of treatment with
permanent fillers (silicone oil,
ePTFE, other permanent implants)
•
No history of facial surgery to
correct lipoatrophy
Exclusion:
•
As above
119
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
PLA (Sculptra)
Author
Carey et al. (2007)
Location
National Centre in HIV
Epidemiology and
Clinical Research,
University of NSW,
Sydney
Australia
Study supported by
Abbot, Myers Squibb,
GlaxoSmithKline,
Gilead, Merck Sharpe &
Dohme, Roche
Products, AIDS Council
of NSW Department of
Health.
Product supplied by
Sanofi-Aventis.
Intervention
Objective: to determine safety and efficacy of immediate vs.
delayed injections of PLA
Study Design
Randomised controlled trial
Prospective, multicentre, open label
Anaesthesia
PLA reconstituted to 5 ml after an infraorbital nerve block (1 ml of
lignocaine 2% with adrenaline).
Level of evidence: II
Treatment
Aliquots of 0.1 to 0.3 ml were deposited deep into the
subcutaneous tissue in a predefined buccal area below the orbital
margin.
Four open label PLA treatments (1 vial [150 mg] per cheek) every
2 weeks with a minimum 14 day interval between treatments
•
Immediate: bilateral PLA at weeks 0, 2, 4 and 6
•
Deferred: same as immediate, but delayed by 24 weeks (ie
no treatment)
CT, DEXA measured at screening and week 24.
Severity of lipoatrophy assessed at screening, week 12 and 24
QoL measured 1 week before treatment, week 12 and 24.
Injection technique
Not stated
Post-treatment
After injection, areas firmly massaged to promote even
distribution. Participants instructed to repeat massage procedure
3 times daily for at least 3 days after each treatment.
120
Statistical analysis:
Continuous endpoints were investigated using analysis of
variance or nonparametric equivalents and binary endpoints
assessed by χ2 tests or logistic regression. All significance tests
were 2-sided and not adjusted for multiple comparisons.
Differences in outcome between the treatment arms were
assessed with tests of interaction between treatment and strata.
Univariate linear regression and multivariate linear regression
were used to determine predictors of efficacy in PLA recipients,
as assessed by change in facial volume at week 24, and
predictors of safety, as determined by PLA cessation for toxicity
or grade 3 or 4 adverse events. Post hoc analysis was performed
to assess additional predictors of efficacy assessed by change in
facial linear measurements at the maxilla and base of nasal
septum levels at week 24. The final predictive model was
Method of randomisation: randomisation
using minimisation performed by single
statistician at NCHECR and was
stratified by age, facial lipoatrophy
severity, current PI use, current tNRTI
use, and surgeon
Method of allocation concealment: not
stated
Blinding: not blind
Intention-to-treat analysis: Data for 100
participants (50 immediate and 50
deferred) were available for the
intention-to-treat-analysis, Primary
efficacy analyses adopted a last-valuecarried-forward approach for participants
lost to follow-up.
Power calculation:
50 subjects chosen per arm, to give
80% power to detect a difference in the
proportion with a clinically relevant
improvement in cheek volume to 10% in
the placebo arm versus 35% in the
treatment arm.
Follow-up: 96 weeks
Lost to follow-up: none (1 patient
withdrew after randomisation but before
treatment. Not included)
Study period: December 2005 – January
2006
Operator details: All baseline CT scans,
Study population
Sample size: n = 100
•
immediate 50
•
deferred 50
Mean age (years) ± SD):
•
immediate 49.8 ± 8
•
deferred 47 ± 8
Gender (M/F): 92/8
•
immediate 46/4
•
deferred 46/4
Patient co-morbidities: HIV infection
Outcome measures and validity:
•
Lipoatrophy assessed and scored by physical
examination and patient report. Patient and
physician assessment made using validated facial
lipodystrophy scale (Carr and Law 2003; HIV
Lipodystrophy Case Definition Study Group, 2003)
(0, normal to 3, severe) with accompanying
descriptions and facial diagrams.
•
At screening and week 24, spiral CT of the head
was performed to quantify total facial tissue
volume. Volumetric assessment was performed
using 3-dimensional (3-D) postprocessing software.
•
Body composition measured by dual-energy x-ray
absorptiometry (DEXA).
•
Subjective measures of lipodystrophy severity were
recorded independently by clinicians and patients
on a scale of 0, none; 1, mild; 2, moderate; 3,
severe) (Carr et al. 2003; HIV Lipodystrophy Case
Definition Study Group, 1999).
•
Quality of life self-reported using Short Form (SF)36v2 Health Survey (Ware and Sherbourne, 1992).
•
The Multidimensional Body-Self Relations
Questionnaire-Appearance Scales (MBSRQ-AS)
(Cash 2000).
•
Antiretroviral adherence was assessed using a
standardized self-report form (Mannheimer et al.
2005). Participants recorded whether they took
“all,” “most,” “about half,” “very few,” or “none” of
Inclusion/Exclusion Criteria
Inclusion:
•
Documented HIV-1 infection
•
18 years or over
•
Had received combination
antiretroviral therapy
•
Moderate to severe facial
lipoatrophy with lipodystrophy at 1
or more sites
•
Current ART unchanged for 12
weeks
•
For patients not on ART, no
intention to recommence before
week 24
•
Women had a negative test result
and using contraception
Exclusion:
•
Active AIDS-defining illness
•
HIV wasting syndrome
•
Active herpes labialis
•
Any facial skin disorder
•
Any coagulopathy
•
Previous treatment for facial
lipoatrophy
•
Anabolic steroids (except
testosterone replacement for
hypogonadism), oral
glucocorticosteroids at greater
than replacement dose (7.5 mg of
prednisolone daily or equivalent)
•
Anticoagulant therapies
•
Growth hormone or other agents to
increase appetite or improve
weight
determined using forward-stepwise regression. Variables with a
univariate p-value ≤ 0.1 were assessed in multivariate analysis.
linear measurements, and soft tissue
their pills during the preceding 7 days.
volumes quality reviewed at a single
radiology site to ensure adherence to
Product: PLA (Sculptra, Dermik Laboratories, Berwyn, PA, USA). protocol.
Carr A, Law M, for the HIV Lipodystrophy Case Definition Study Group. An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score. Journal of Acquired Immune Deficiency Syndrome
2003; 33: 571-576.
Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 2093-2099.
Cash TF. Users' Manual for the Multidimensional Body-Self Relations Questionnaire. Norfolk, VA: Old Dominion University; 2000.
HIV Lipodystrophy Case Definition Study Group. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 2003; 361: 726-735.
Mannheimer SB, Matts J, Telzak E, et al, for Terry Beirn Community Programs for Clinical Research on AIDS. Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence. AIDS Care 2005; 17:
10-22.
Ware JE Jr, Sherbourne CD. The MOS-36 Item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection. Medical Care 1992; 30: 473-483.
NCHECR, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia; PI, protease inhibitor; tNRTI, thymidine analogue reverse transcriptase inhibitor.
121
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Polylactic Acid (New-Fill)
Author
Cattelan et al. (2006)
Intervention
Objective: to determine safety and efficacy and tolerability of PLA
for HIV-associated lipoatrophy patients.
Location
Department of
Infectious Diseases,
Unit of Radiology,
Departments of Plastic
Surgery and
Dermatology and
Infectious Diseases,
General Hospital and
University of Padua,
Padua
Italy
Reported that there
were no financial
disclosures and that
funding was
independent of the
study device.
Study Design
Case series
Consecutive patients at 1 centre.
Prospective
Study population
Sample size: n = 50
Medical history and laboratory tests preformed. CD4 cell count
and HIV-RNA plasma levels obtained initially and then every 3
months during follow-up.
Level of evidence: IV
Gender (M/F): 42/8
Follow-up (years): 12 months
Patient co-morbidities: HIV infection
4 sets of PLA injections were given at baseline and on days 0,
30, 45 and 60 of the study.
2 more sets of injections on days 75 and 90 allowed if necessary.
Lost to follow-up: not stated
Outcome measures and validity:
•
Degree of lipoatrophy defined subjectively using a
severity scoring system based on the sum of the
patient’s perception, physical examination, and
plastic surgeon assessment. Clinicians looked at
photographs of patients before CART initiation and
at screening. Score of 1 (no facial lipoatrophy) to 3
(severe) assigned. Maximum score was 9. Patients
with a score of 6 or more were eligible for the study.
Not validated.
•
Adverse and toxic events classified and graded
according to the AIDS Clinical Trial Group/ World
Health Organisation toxicity scales.
•
Two questionnaires completed at enrolment and
during study.
1. To assess self-perception of lipoatrophy and
degree of improvement with treatment. Not
validated. Administered at enrollment, month
2, and at 12 month follow-up.
2. Medical Outcomes Study (MOS)-HIV (Wu et
al. 1991). Administered at enrolment and 12
month follow-up.
Anaesthesia
No prophylactic antibiotics or local anaesthesia was administered
preoperatively.
Injection technique
1 vial 125mg was added to 3 – 4 ml of sterile water.
The reconstituted suspension was injected by multiple parallel or
crisscross passes into the deep dermis of the affected area. In
total 3 – 4 ml was injected into each side.
In case of thinner skin layers, a greater dilution was used, using
more (up to 6 – 8 ml) sterile water.
After injections, area massaged to distribute material
homogenously. Ice cubes applied with a topical antibiotic for at
least 20 minutes.
Patients advised to massage areas twice a day for 10 minutes
each day for at least 10 days.
Study period: 15 January 2002 – 30
June 2002
Operator details: same nurse and plastic
surgeon staff member for entire study.
Radiologic evaluation performed by
same radiologist during study.
Median age (range): 41 (35 – 69)
Inclusion/Exclusion Criteria
Inclusion:
•
Documented HIV infection
•
18 years or older
•
Stable plasma HIV-RNA load <
1000 copies/ml in the preceding 6
months
•
CART therapy, including either a
protease inhibitor or a nonnucleoside reverse transcriptase
inhibitor, for at least 24 months
•
CD4 cell count > 100/uL
•
Moderate or severe lipoatrophy
Exclusion:
•
Presence of an AIDS-defining
illness
•
Systematic therapy for malignancy
and therapy with immune
modulators or systemic anabolic
corticosteroids
•
Alcohol or other drug use
•
Prior facial implants
Statistical analysis:
Descriptive statistics were performed for
all variables. For ultrasonic data, a 99%
CI computed at 3 time points of
observation (baseline, after injections,
and after 12 months); an nonparametric
Wilcoxon rank sum test for paired data
was also performed to test the
significance of the observed changes.
For questionnaire data, the difference
between scores at baseline and the
Ultrasonographic evaluation performed at baseline, after the 4
other set points was considered. 95% CI
sets of injections (at month 2) and at the end of follow-up (at 12
intervals applied to judge the
months).
significance in the QoL change for each
MOS dimension.
Product: New-Fill; Biotech Industry SA, Luxembourg, Europe.
Wu AW, Rubin HR, Mathews WC et al. A health status questionnaire using 30 items from the Medical Outcome Study: preliminary validation in persons with early HIV infection. Medical Care 1991; 29: 786-798.
122
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Polylactic Acid (New-Fill)
Author
Lafaurie et al. (2005)
Intervention
Objective: to assess safety and efficacy of PLA in patients with
facial lipoatrophy.
Location
Service des Maladies et
Tropicales, Department
de Bioplastique et
Informatique et
Medicales, and
Pharmacie Centrale,
Hopital Saint-Louis,
Paris
Screening visit 1 month before first injection.
Lipoatrophy classed into 3 categories (adapted from James et al.
2002): mild, moderate and severe.
Support by a psychologist was offered throughout the treatment
and follow-up.
France
Product used in study
provided by
manufacturer
Injection technique
Injections into median-deep layer of dermis according to
manufacturer’s instructions.
PLA reconstituted according to manufacturer’s instructions: 0.15g
of PLA reconstituted with 3ml of sterile water.
Anaesthesia
PLA mixed with 1ml of adrenaline-free lidocaine.
PLA mixture divided into 4 syringes of 1ml and injected using 26
gauge 1/2 needles. At each session, patients received several
injections in each cheek. Ice applied after for 10 minutes to
reduce risk of haematoma and oedema. Prolonged massage
performed to homogenise distribution of product and to prevent
dermal nodules.
Injection in both cheeks at each visit every 2 weeks. Injections
into temples done if necessary. Number of injections given was at
discretion of patient and dermatologist.
At end of treatment procedure, patients assessed by same
dermatologist on a monthly basis. New injections of PLA were
allowed during follow-up but could not to be performed in the first
3 months following the last injection. Patients’ follow-up was
censored at the time of reinjection.
Safety assessed at each visit. Severity of adverse events graded
according to the Agence Nationale de Recherche sur le SIDA
(ANRS) grading scale. Pain related to injections graded on a
scale of 1 (slight pain) to 4 (severe pain requiring level II/III
analgesics).
Study Design
Case series
Prospective, open-label, single-arm
study
Study population
Sample size: n = 94
Level of evidence: IV
Gender (M/F): 88/6
Patient allocation: not stated
Patient co-morbidities: HIV infection
Follow-up: median follow-up from time of
first injection was 12 month (1 – 27
months)
Outcome measures and validity:
•
Primary efficacy endpoint was the patient’s
subjective self-perception of improvement of facial
lipoatrophy as assessed by a visual analogue scale
(VAS). This was specifically designed for this study.
Patients were asked “What is your satisfaction
about the aspect of your face, in relation to the
lipoatrophy?” VAS scores assessed before each
set of injections, at the end of treatment, and at the
end of follow-up. Not validated.
•
Success rate defined as the proportion of patients
with an increased VAS score as compared with
baseline, at the end of the treatment procedure,
and at the end of follow-up. The last follow-up visit
was the last visit in the study or the visit at which a
new set of PLA injection was judged necessary.
•
Secondary endpoints included quality of life (QoL)
questionnaires (Medical Outcome Study Short
Form 36-item health survey MOS SF-36 (Wu et al.
1991; Leplege et al. 2001)), digital photographs and
3 dimensional photographs. The mental and
physical component summary scores (MCS and
PCS, respectively) of the MOS SF-36 were
analysed.
•
Three dimensional photographs were evaluated for
the first 50 treated patients.
•
Digital photographs of all patients were
independently assessed by 2 assessors.
•
Patients were assessed at baseline, at the end of
the treatment procedure, and at the end of followup.
Lost to follow-up: 7 (4 lost; 2
discontinued treatment due to HIV
progression; 1 discontinued due to
anaphylactic reaction after first injection)
Study period: September 2001 –
December 2002
Operator details: same dermatologist did
all injections
Median age (years), (min; max): 44 (30;64)
Inclusion/Exclusion Criteria
Inclusion:
Main criteria included:
•
Adult with HIV infection
•
Facial lipoatrophy
•
No current opportunistic infection
•
Sustained control of HIV infection
with a CD4 cell count ≥ 200/mm3
•
Stable antiretroviral therapy for at
least 3 months
Exclusion:
•
Abnormal coagulation tests
•
Concomitant therapy with nonsteroidal anti inflammatory drugs
or acetyl salicylic acid
•
Skin disease of the face
•
Pregnancy or breast feeding
•
Major or unstable concomitant
illness
•
History of surgical or cosmetic
intervention for facial lipoatrophy
123
Statistical analysis:
Data presented as median (min; max)
for quantitative variables and frequency
(percent) for factors. Analysis of end
points was performed by comparing
values measured at baseline, at the end
of therapy, and at the last follow-up visit
using paired Wilcoxon tests. Association
between patients’ baseline,
characteristics and treatment failure was
tested using Fisher exact tests of
Wilcoxon tests. Assessment of
agreement between the 2 observers
performed using Kappa statistics.
Cumulative incidence of reinjections
Product: New-Fill, Dermik Laboratories, Berwyn, PA, a division of during follow-up was estimated using
Kaplan-Meier product-limit method.
Aventis, Stasbourg, France.
James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatologic Surgery 2002; 28: 979-986.
Leplege A, Ecosse E, Pouchot J et al. Questionnaire MOS SF-36: Manuel de L’Utilisateur et Guide d’interpretation des Scores. Edited by Editions Scientifiques Techniques et Medicales (ESTEM). Paris, France: 2001.
Wu AW, Rubin HR, Mathews WC et al. A health status questionnaire using 30 items from the Medical Outcome Study: preliminary validation in persons with early HIV infection. Medical Care 1991; 29: 786-798.
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Polylactic Acid (product name not provided)
Author
Mest & Humble (2006)
Location
Blue Pacific Medical
Group, El Segundo,
California
USA
Authors are consultants
for manufacturer.
Authors have no
financial interest in the
manufacture of the
material.
Intervention
Objective: to evaluate improvement in facial wasting after
injections of PLA and to assess the long-term safety and
durability of product.
Deep dermal/subdermal injections into targeted treatment areas
using 1 – 6ml PLA reconstituted with 3ml sterile water for
injection per vial (50mg of PLA per ml) per session.
Volume injected was subjective and individualised based on
investigators’ previous experience.
No more than 6ml of reconstituted PLA (2 vials) were used at any
one treatment session.
Treatment sessions scheduled 3 weeks apart with an allowed
variability of 10 days.
Digital photographs and caliper skin thickness were measured
before each treatment session.
Laboratory studies performed at 3 month intervals during the
active phase and at 6 and 12 months after the final treatment
session.
Study questionnaires were completed at the end of treatment and
at 6 and 12 months after completion of treatment.
Patients contacted by phone 48 – 72 hours after each treatment
to monitor any adverse events. Treatment sessions stopped in
the case of local skin reaction, infection, patient intolerance, or
significant and unexplained change in laboratory values, and on
the request of the patient. Photographs taken in the event of an
adverse reaction.
Study Design
Case series
Open-label, single site
Level of evidence: IV
Patient recruitment and allocation: not
stated
Follow-up: 12 months
Lost to follow-up: n = 2 (1 patient not
HIV-positive; 1 patient unsatisfied with
speed of correction)
Study period: 23 July 2002 – 24 August
2003
Operator details: all treatments
performed by 1 or the 2 study authors.
Each physician responsible for
measuring results of own patients.
Statistical analysis:
p < 0.05 was used for determination of
statistical significance. Significance of
mean skin thickness changes calculated
using a paired t-test on change from
baseline to time point of interest.
Product: Product name not reported.
James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatologic Surgery 2002; 29: 979-86.
Study population
Sample size: n = 98
Mean age (years): 45 (32 – 65 years)
Gender (M/F): 97/2
Patient co-morbidities: HIV infection
Outcome measures and validity:
•
Facial lipoatrophy graded according to James et al.
(2002).
•
Initial examination that included baseline buccal
skin thickness as determined by skin calipers at
standard points bilaterally (at the intersection of the
vertical axis of the lateral canthus of the eye and
the horizontal axis of the nares). Not validated.
•
Laboratory evaluation (serum chemistry, liver
function tests, serum bicarbonate, venous lactate,
PT/PTT, and CBC with differential).
•
Psychological well-being questionnaire and study
questionnaire.
Inclusion/Exclusion Criteria
Inclusion:
•
18 years or older
•
lipoatrophy of the cheek/temple of
a degree bothersome to patient (ie
clinically significant)
•
Willing to actively participate in
study
•
HIV positive
Exclusion:
•
Facial injections of any substance
in the last 3 months
•
Active infection of the face
•
Active Kaposi’s sarcoma involving
treatment area
•
Active treatment with interferon or
systemic corticosteroids
•
Pregnancy or breast feeding
•
Non-compliance based on history
or previous experience
•
Signs or systems of lactic acidosis,
known preexisting renal disease,
and poorly controlled diabetes
mellitus.
124
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Polylactic Acid (New-Fill)
Author
Valantin et al. (2003)
Location
Departement des
Maladies Infectieuses et
Tropicales, Hopital
Pitie-Salpetriere,
INSERM 0214
Universite Pierre et
Marie CURIE, Paris
France
Intervention
Objective: evaluate the efficacy, safety and durability of PLA in
the correction of facial lipoatrophy in HIV-infected patients over
96 weeks.
PLA administered as a set of injections given every 2 weeks: at
day 0 and at weeks 2, 4 and 6.
Injections into and around the deep dermis of the atrophied area
in each cheek.
Before injection, PLA reconstituted from 0.15g sterile dry powder
(1 vial PLA) with 3 – 4 ml of water for injections BP.
Anaesthesia
1ml of lidocaine was injected locally.
Study Design
Case series
Open-label, single-arm, pilot study
Level of evidence: IV
Patient recruitment and allocation: not
stated
Power calculation: The sample size was
chosen to allow a 90% power to
determine the percentage of responders
with a precision of 20%, assuming a
response rate of 80% with a type 1 error
of 0.05.
Follow-up: 96 weeks
Volume injected dependent on severity of skin depression.
At each visit, a maximum of 4ml was injected into each cheek.
At the end of the injections, cheeks were thoroughly massaged to
ensure better distribution of product.
Patients evaluated by clinical examination, facial ultrasonography
and photographs at screening and at weeks 6, 24, 48, 72 and 96.
Quality of Life (QoL) measured by visual analogue scale and
collected at screening, week 12, 24, 48, 72 and 96.
Following the ultrasound evaluation at week 6, a 5th set of
injections could be given if the total cutaneous thickness (TCT)
was < 8 mm. Injections were discontinued if any severe or
moderate reaction developed after injection.
Ultrasonographic and colour Doppler evaluation to quantify the
dermal, epidermal and fat thickness were performed using a
digital multi-frequencies 7.5 – 13 MHz transducer and a 7 MHz
colour Doppler. Measurements performed in the nasgenian area
located below the malar bone, ahead of the masseter. The
temporal region was limited by the zygomatic apophysis and the
orbital arcade. The change in TCT between the skin and the
epidermis was measured by the study radiologist and local
reactions at the injection site were noted.
Lost to follow-up:
Table. Patients lost to follow-up for
ultrasound evaluations
Week of study
6
24
48
72
96
N patients lost
2
1
1
2
8
Reasons for losses not stated
Study population
Sample size: n = 50
Age, median years (range): 45.9 (33.1 – 58.0)
Gender (M/F): 49/1
Patient co-morbidities: HIV-infection
Outcome measures and validity:
•
Severe lipoatrophy defined as thickness of fat
tissue in the nasogenian area less than 2 mm as
measured by ultrasonography. Not validated.
•
Quality of Life (QoL) measured by visual analogue
scale. Not validated.
•
Primary end point was the proportion of
responders, defined as patients with TCT > 10
mm*, measured at the nasogenian fold, at week 24.
Not validated. For each patient, the TCT
measurements were summarised by the mean of
two values, one minimal and one maximal for each
cheek.
•
Secondary endpoints included the change in TCT
and QoL from baseline at weeks 6, 12, 24, 48, 72
and 96; the proportion of responders at weeks 6,
24, 48, 72 and 96; and the patient tolerability.
•
Median and ranges were reported for TCT and QoL
changes over time.
Study period: June 2000 – Feb 2001
Operator details: all injections performed
by same dermatologist. Ultrasonographic and colour Doppler evaluation
performed by same radiologist.
125
Statistical analysis:
Paired Wilcoxon tests used in analysis
of change from baseline for TCT and
QoL. The % of responders was
calculated together with exact 95% CI.
Descriptive statistics given for CD4 cell
Product: New-Fill, Biotech Industries, SA, Luxembourg.
counts, HIV viral load, and antiretroviral
treatment at each time point.
*In the absence of standard values for facial thickness measured by ultrasonography, this value was chosen arbitrarily as a median range in a few non-HIV infected individuals.
Inclusion/Exclusion Criteria
Inclusion:
•
Over 18 years of age
•
Have severe lipoatrophy (thickness
of fat tissue in the nasogenian area
less than 2mm as measured by
ultrasonography).
•
Antiretroviral therapy for more than
3 years
•
Stable plasma HIV-RNA levels <
5000 copies/ml in the last 3
months
Exclusion:
•
Facial skin disease
•
Facial implant in the last 6 months
•
Current interferon or cytokine
therapy
Appendix B.2 Study profile tables – facial augmentation for HIV-associated lipoatrophy
Calcium Hydroxylapatite (Radiesse)
Author
Silvers et al. (2006)
Intervention
Objective: to assess safety and effectiveness of CaHA in patients
with facial lipoatrophy secondary to HIV.
Study Design
Case series
Prospective, open-label trial at 3 sites
Location
Chelsea Eye and
Cosmetic Surgery
Associates, and St
Vincent’s Catholic
Medical Centre, New
York and San
Francisco, California.
Photographs taken at baseline and all follow-up visits.
All patients had baseline and subsequent facial skin thickness
measurements taken. Skin thickness measured using calipers at
bilateral fixed points located at the intersection of the vertical axis
through the lateral canthus of the eye and the horizontal axis of
the nares.
Level of evidence: IV
USA
Treatment restricted to the cheek area, usually the submalar
region.
An initial injection was performed followed by touch-up injections
at 1 month, 6 months and at 18 months from initial injection as
deemed appropriate by investigators.
The decision to perform 2 initial injections (at baseline and 1
month) and touch-up injections at 6 and 18 months made at
discretion of treating physician.
Aneasthesia
Performed at the discretion of the treating physician. If desired,
ice applied after injection by treating physician to aid reduction of
erythema and oedema.
Study population
Sample size: n = 100
Gender (M/F): 94/6
Mean age: 48.2 years
Patient allocation: not stated
Patient co-morbidities: HIV infection
Intention-to-treat analysis: defined as all
patients who received treatment as
planned
Follow-up: 1, 3, 6, 12 and 18 months
Lost to follow-up: none. 3 patients died
during study period (deaths unrelated to
study); 3 patients withdrew from study
for reasons unrelated to study.
Study period: not stated
Statistical analysis: not stated
Operator details: all injections performed
by investigators. People taking
photographs were trained to ensure
consistency.
Outcome measures and validity:
•
Primary effectiveness endpoint: to evaluate
correction of facial lipoatrophy at 3 months by
comparing changes from baseline to Global
Aesthetic Improvement Scale (Narins et al. 2003)
with confirmation using standardised photography.
From a 3 month clinical perspective, a minimal
standard of effectiveness was achieved if 20% of
patients had improvement (Global Aesthetic
Improvement Scale score ≤ 3, with 1 being the
most favourable and 5 being the worst). A clinically
meaningful standard of effectiveness was achieved
if 50% showed improvement.
•
Secondary endpoints: to evaluate correction of
facial lipoatrophy at 6 months (as above), and to
evaluate correction after 3 and 6 months by
comparing changes in skin thickness
measurements. 12 and 18 month data also
included. From a 6 month perspective, a 10%
improvement was regarded as minimal and a 25%
improvement was regarded as clinically meaningful.
•
Safety endpoint: to report the incidence, severity,
and duration of all local and systemic adverse
events through 12 months (18 month safety data
not available at time of publication).
Inclusion/Exclusion Criteria
Inclusion: based in part on the Facial
Lipoatrophy Severity Scale (James et al.
2002). Included, but not restricted to:
•
18 years of age or older
•
HIV positive
•
CD4 count ≤ 250/mm3
•
Viral load ≥ 5000 copies/ml
•
Highly active antiretroviral
therapy regimen of at least 3
years
•
HIV lipoatrophy of grade 2, 3,
or 4 on the Facial
Lipoatrophy Severity Scale
Exclusion: not stated
Injection technique
All injections performed by investigators
25-gauge, 1.5-inch needle, linear threading (depositing filler in a
single strand) into subdermis
As many strands of CaHA were injected as deemed necessary.
Injections restricted to cheek area, usually the submalar region.
The lipoatrophy was treated until the treating physician judged it
to be corrected. Evaluations performed by, or under direction of
the investigator at each site.
Overcorrection not permitted.
Product: Radiesse, BioForm Medical, San Mateo, California,
USA.
James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatologic Surgery 2002; 29: 979-86.
Narins R, Brandt, F, Leydon J et al. A randomised, double blind, multicentre comparison of the efficacy and tolerability of Restylane vs. Zyplast for the correction of nasolabial folds. Dermatologic Surgery 2003; 29: 588.
Sommer B, Zschoke I, Bergeld D, et al. Satisfaction of patients after treatment with botulinum toxin for dynamic facial lines. Dermatologic Surgery 2003; 29: 456.
126
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APPENDIX C – TREATMENT DATA
127
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Appendix C – Treatment data
N
Appendix C.1 Injection technique - ageing
Product
Description and/or
Gauge
reconstitution of
product
AGEING
Cohen et al. 2006 (Level II) & Cohen et al. 2007 (Level IV)
128
PMMA (Artecoll*)
NR
27 (In Cohen et al.
Injection location
Anaesthesia
Injection technique
Post injection
Intradermal
Before injection EMLA cream
(2.5% lidocaine and 2.5%
prilocaine). For upper lip EMLA
or nerve blocks implementing 1%
lidocaine with epinephrine used
at investigator’s discretion.
NR
Multiple tunnelling technique and injecting
with constant pressure while withdrawing
the needle.
Area massaged with finger tip and slight
pressure applied to any detected lump.
Patients advised to minimise mimetic
activity for 1 to 2 days after treatment.
Zyderm II intradermally in glabella; Zyplast
in all other areas. Injection technique in
accordance with Klein 1998.
Implant was palpated and slight
pressure applied to smooth out any
irregularities.
2006, a 26-gauge
needle used).
123
Collagen (Zyderm II/
Zyplast)
Mladick 1992 (Level IV)
40
Silicone particles
(Bioplastique)
Fulton et al. 2005 (Level IV)
608
Liquid silicone
(Silikon)
NR
30
Intradermal
Supplied in 1 and 0.5 ml
syringes mounted on an
injection gun that allows
application of material to
pre-tunneled area.
NR
Subdermis
Epinephrine injected directly into
the site to be treated to decrease
potential of bleeding.
Pre-tunneling technique used with a trocar
(except for lips). A point of entry remote of
defect area preferred. Injection done as
needle withdrawn. Best results achieved by
cross-tunneling technique. For lips, each
half of upper and lower lip done using
injection site on opposite half of the lip.
Ice compresses applied for first 24 hours
to decrease swelling and bruising.
Prophylactic antibiotics administered for
2 days after treatment. Tape splinting of
area optional.
NR
27
NR
Intraoral regional nerve blocks of
the infraorbital and mental
nerves using 2% lidocaine with
epinephrine buffered with sodium
bicarbonate. If patient sensitive
to epinephrine, the 2% lidocaine
diluted with plain 1% lidocaine.
Injected into vermillion border in microdroplet fashion. Shaft of needle is inserted
and product is injected as needle
withdrawn. In selected patients, additional
injections given into lateral orbicularius oris
muscle to attempt lip eversion.
Finger compression of angular artery
and direct compression with cotton
gauze immediately applied to reduce
bruising. Following haemostasis, the
area is compressed with ice for 3 – 4
minutes to reduce swelling. Patients
warned not to eat or drink hot tea or
coffee until the anaesthesia has worn
off.
Klein AW. Injectable bovine collagen. In: Klein AW (Ed). Tissue Augmentation in Clinical Practice. New York: Marcel Dekker; 1998. p 125 – 144.
128
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Appendix C.1 Injection technique – ageing continued
Product
Description and/or
Gauge
reconstitution of
product
Reda-Lari 2008 (Level IV)
1306
PAAG (name not
NR
16 – 18
specified)
N
Moers-Carpi et al. 2007 (Level II)
70
CaHA (Radiesse)
33
HA 1 (Juvederm 24)
NR
33
HA 2 (Juvederm
24HV)
69
HA 3 (Perlane)
Smith et al. 2007 (Level II)
117
CaHA (Radiesse)
one half of face
117
Collagen
(Cosmoplast) other
half
NR
Injection location
Anaesthesia
Injection technique
Post injection
Into deep
cutaneous tissue
layer or even
closer to the bone
(sometimes a
more superficial
plane chosen for
correction of linear
cheek
depressions).
1% lidocaine 0.2ml administered
at injection site. Nerve block
anaesthesia of the inferior orbital
nerve through an intraoral
approach was used during the
first 2 years that procedure
performed. Local anaesthesia
now used in selected cases.
Nerve block still used at
beginning of treatment to relax
and ease patient and surgeon.
Single entry point technique. Gel ‘pooling’
method used in all cases. All gel is injected
at one point, forming a pool of gel in the
tissue.
Manual massaging after injection to
distribute gel evenly and to prevent
irregularities. If more gel required,
another pool deposited in an adjacent
area for better distribution of gel.
Patients advised to massage the treated
area lightly to soften and smooth the
edge, as well as to minimise the
sensation of pressure.
Prophylactic broad spectrum antibiotics
routinely given after procedure.
27
Mid – deep dermis
27
Dermal/
subcutaneous
junction
Mid – deep dermis
30 or 31
At the discretion of treating
physician (eg local nerve block
and ice).
Topical anaesthetic cream, local
infiltration, intraorbital
anaesthetic block or combination
of these at the discretion of
investigator. Care was taken to
apply anaesthesia symmetrically
Same injection technique used on both
NLF. Volume at discretion of treating
physician. Physicians advised to inject
enough material to create optimal
augmentation.
NR
For both, linear threading was used. Over
correction not permitted.
Treatment areas massaged as needed
to ensure deposition of product. Ice or
cool compresses could be applied to the
NLF before and/or after injections but
were applied equally to both sides.
129
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Appendix C.1 Injection technique – ageing continued
Product
Description and/or
Gauge
reconstitution of
product
Jacovello et al. 2006 (Level IV)
40
CaHA (Radiesse)
NR
25 – 27
depending on
treatment site
N
Sklar & White 2004 (Level IV)
64
CaHA (Radiance
FN)
Supplied in pre-sterilised
1 ml package. Does not
require refrigeration.
Small amounts saved and
corrections made after a
couple of weeks.
27
Injection location
Anaesthesia
Injection technique
Post injection
Deep dermis
Depending on anatomical area,
regional or nerve block
anaesthesia (2% lidocaine)
injected, avoiding infiltration near
the region to be corrected.
Material injected in created track during
slow withdrawal of needle.
Glabella - needle inserted longitudinally
injected on withdrawing
Nasolabial folds - needle inserted into entire
fold longitudinally. One puncture, starting at
inferior end and ending at corner of mouth.
Bands of material implanted in parallel rows,
depending on depth of nasolabial fold.
Lips - four tunneling puncture wounds.
Nose - back-and-forth multidirectional
technique. Puncture site distal to corrected
regions.
Infraorbital region (tear trough) - area
approached from cheek. Puncture site distal
to injected region. Two direction crisscross
technique to spread product.
NR
Subcutaneous
space
Lips: intramuscular or deep
glandular in lip
mucosa.
Nerve block preferred for
nasolabial folds and lips. Tiny
bleb of lidocaine used to prepare
injection site – kept away from
treatment site to prevent
distortion and intradermal
injection.
Needle advanced at 45o. Injection
performed in a retrograde manner as needle
is withdrawn through subcutaneous space.
Inject at a constant rate on withdrawal.
Multiple passes can be made at an area.
All treated areas routinely massaged
after treatment.
130
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Appendix C.2 Injection technique – HIV associated lipoatrophy
Product
Description and/or
Gauge
Injection location
reconstitution of
product
HIV-ASSOCIATED LIPOATROPHY
Guaraldi et al. 2005 (Level III -1)
15
PAAG (Aquamid)
Supplied in disposable 1
27
Subcutaneous
ml syringe.
N
20
PLA (New-Fill)
24
AFT
Reconstituted from
powder (0.15 g powder +
4 ml water and
suspended for 24 hrs).
Fat harvested from
patient, purified and
injected into patient’s
face.
Injection technique
Post injection
No lidocaine injected locally
before injections.
NR
After each set of injections, cheeks
massaged for better distribution of
product.
After each set of injections, cheeks
massaged for better distribution of
product.
26
Deep dermis
No lidocaine injected locally
before injections.
NR
18
NR
Local or general anaesthesia or
deep sedation.
Performed according to Coleman’s
technique (Coleman 1997; Coleman 2001;
Carraway and Mellow 1990). Fat harvested
from groin, abdomen of dorso-cervical
region and purified. Cannula and positive
pressure used to implant fat.
Orlando et al. 2007 (Level III-2)
130
PAAG (Aquamid)
91
PLA (Sculptra)
24
AFT+PLA (Sculptra)
54
AFT
Negredo et al. 2006 (Level III-2)
115§
PAAG (Aquamid)
NR
NR
Subcutaneous
26‡
PLA (New-Fill)
NR
Intradermal
8
AFT
NR
Subcutaneous
Each vial of PLA also
included 3 ml of distilled
water and 2 ml of
lidocaine 2%.
Fat harvested from
patient.
Anaesthesia
For 8 – 12 hours post operatively, cold
compress or ice packs are applied
continuously on the infiltrated sites.
In accordance with Guaraldi et al. 2005
Bilateral intra-buccal truncal
anaesthesia at the level of the
infraorbital nerve.
Bilateral intra-buccal truncal
anaesthesia at the level of the
infraorbital nerve.
Administered in ambulatory regimen by
retrotracing.
Massage of treated area conducted to
redistribute product.
Administered in ambulatory regimen by
retrotracing.
Massage of treated area conducted to
redistribute product.
Performed under general
anaesthesia.
Surgeon extracted fat from abdomen, breast
or hump through liposuction by tunnelling.
The processed fat was subsequently
infiltrated into the atrophied facial areas.
NR
Carraway JH and Mellow CG. Syringe aspiration and fat concentration. A simple technique for autologous fat injections. Annals of Plastic Surgery 1990; 24: 293 – 296.
Coleman SR. Facial recontouring with lipostructure. Clinics in Plastic Surgery 1997; 28: 347 – 367
Coleman SR. Structural fat grafts. The ideal filler? Clinics in Plastic Surgery 2001; 28: 111 – 119.
131
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Appendix C.2 Injection technique - HIV associated lipoatrophy continued
Product
Description and/or
Gauge
Injection location
reconstitution of
product
De Santis et al. 2008 (Level IV)
50
PAAG (Aquamid)
NR
NR
Below dermis in
deeper
subcutaneous
plane
Carey et al. 2007 (Level II)
50
PLA (Sculptra)
1 vial of 150 mg
NR
Deep into
reconstituted to 5 ml after
subcutaneous
an infraorbital nerve block
tissue
N
Jones et al. 2004 (Level IV)
77
Liquid silicone
(Silikon 1000/
VitreSil 1000)
Cattelan et al. 2006 (Level IV)
50
PLA (New-Fill)
Lafaurie et al. 2005 (Level IV)
94
PLA (New-Fill)
Anaesthesia
Injection technique
Post injection
NR
NR
The use of ice packs immediately after
the procedure helps reduce local tissue
reactions.
1 ml of lignocaine 2% with
adrenaline.
NR
Areas firmly massaged to promote even
distribution. Participants instructed to
repeat massage procedure 3 times daily
for at least 3 days after each treatment.
NR
30
Subdermal plane
or deeper (5mm
depth below skin
surface or deeper)
Nerve blocks avoided. Topical
anaesthetic with EMLA or topical
benzocaine under plastic wrap
occlusion for 30 – 45 minutes
before injection. If patients had
excessive pain, pretreated with
analgesic (paracetamol plus
codeine and/or alprazolam) a
half hour before next treatment
along with EMLA.
Microdroplets (0.01ml) injected at 2 – 4 mm
intervals as described by Orentreich (2000).
Overlapping generally avoided.
Finger pressure applied when necessary
to areas of pinpoint bleeding to reduce
bruising. Patients instructed to avoid
contact with sports or activities that
would predispose treated area to
trauma.
1 vial of 125 mg PLA
added to 3 – 4 ml of
sterile water.
NR
Deep dermis
No local anaesthesia used.
Multiple parallel or crisscross passes (in
case of thinner skin layers, a greater dilution
was used).
Area massaged to distribute material
homogenously. Ice cubes applied with a
topical antibiotic for at least 20 minutes.
Patients advised to massage areas
twice a day for 10 minutes each day for
at least 10 days.
Reconstituted according
to manufacturer’s
instructions: 150 m g of
PLA reconstituted with
3ml of sterile water.
26
Deep dermis
PLA mixed with 1ml of
adrenaline-free lidocaine.
NR
After injections ice applied for 10
minutes to reduce risk of haematoma
and oedema. Prolonged massage
performed to homogenise distribution of
product and to prevent dermal nodules.
132
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Appendix D.2 Injection technique - HIV associated lipoatrophy continued
N
Product
Description and/or
Gauge
Injection location
reconstitution of
product
Mest & Humble 2006 (Level IV)
99||
PLA¶(name not
Reconstituted with 3ml
NR
Deep dermis/
specified)
sterile water for injection
subdermis
per vial (50 mg of PLA
per ml)
Valantin et al. 2006 (Level IV)
50
PLA (New-Fill)
Reconstituted from 150
NR
Deep dermis
mg sterile dry powder (1
vial) with 3 – 4 ml of
water for injections BP.
Silvers et al. 2006 (Level IV)
100
CaHA (Radiesse)
NR
25
Subdermis
Anaesthesia
Injection technique
Post injection
NR
NR
NR
1ml of lidocaine injected locally.
NR
Cheeks were thoroughly massaged to
ensure better distribution of product.
Performed at discretion of
treating physician.
Linear threading - depositing filler in a single
strand
If desired, ice applied after injection by
treating physician to aid reduction of
erythema and oedema.
133
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N
Appendix C.3 Facial areas addressed for ageing
Intervention
Glabella
NLF*
AGEING
Cohen et al. 2006 (Level II)
128
PMMA (Artecoll)
123
Collagen (Zyderm II/Zyplast)
P-value
Cohen et al. (2007) (Level IV)
145
PMMA (Artecoll‡)
Mladick 1992 (Level IV)
40
Silicone particles (Bioplastique)
Fulton et al. 2005 (Level IV)
608
Liquid silicone (Silikon)
Reda-Lari 2008 (Level IV)
1306 PAAG (name not specified)
Moers-Carpi et al. 2007 (Level II)
70
CaHA (Radiesse)
33
HA 1 (Juvederm 24)
33
HA 2 (Juvederm 24HV)
69
HA 3 (Perlane)
Smith et al. 2007 (Level II)
117
CaHA (Radiesse) one side of
face
117
Collagen (Cosmoplast) other
side
Jacovello et al. 2006 (Level IV)
40
CaHA (Radiesse)
Sklar & White 2004 (Level IV)
64
CaHA (Radiance FN)
Lips
Lip lines
Mouth
corners
Number of patients treated*
Cheek†
Chin
Tear
trough
Nose
Other
facial
area
Hands
Total
81
86
NS
108
104
NS
-
69
59
NS
86
87
NS
-
-
-
-
-
-
344
336
NA
-
145
-
-
-
-
-
-
-
-
-
145*
4
6
18
-
6
8
7
-
3
3
1
55
-
-
608
-
-
-
-
-
-
-
-
608
-
-
-
-
-
1306
-
-
-
-
-
1306
-
70
33
33
69
-
-
-
-
-
-
-
-
-
70
33
33
69
-
117
-
-
-
-
-
-
-
-
-
117
-
117
-
-
-
-
-
-
-
-
-
117
12
24
10
-
-
-
-
4
5
-
-
55
-
52
15
1
11
5
2
15
-
-
-
101
Mouth corners (infraoral region); tear trough (infraorbital region); chin includes mental crease and labiomental crease.
NR, not reported: studies stated that injections had been given in a particular region, but did not provide specific data.
*
Many patients had treatment of multiple facial areas.
†
NLF includes melolabial folds. Includes zygomal and buccal areas.
‡
145 patients included for safety; 142 for efficacy. Only NLF used for efficacy. This is a follow-up study of Cohen et al. (2006), so initial PMMA patients are the same.
134
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N
Appendix C.3 Facial areas addressed for HIV-assocaited lipoatrophy
Intervention
Glabella
NLF*
Lips
Lip lines
HIV-ASSOCIATED LIPOATROPHY
Guaraldi et al. 2005 (Level II)
15
PAAG (Aquamid)
20
PLA (New-Fill)
24
AFT
P-value
Negredo et al. 2006 (Level III-2)
115
PAAG (Aquamid)
26
PLA (New-Fill)
8
AFT
P-value
Orlando et al. 2007 (Level III-2)
130
PAAG (Aquamid)
91
PLA (Sculptra)
24
AFT + PLA (Sculptra)
54
AFT
P-value
Carey et al. 2007 (Level II)
50
PLA (Sculptra)
Cattelan et al. 2006 (Level IV)
50
PLA (New-Fill)
Lafaurie et al. 2005 (Level IV)
94
PLA (New-Fill)
Mest & Humble 2006 (Level IV)
99
PLA (name not specified)
Valantin et al. 2003 (Level IV)
50
PLA (New-Fill)
Silvers et al. 2006 (Level IV)
100
CaHA (Radiesse)
Mouth
corners
Number of patients treated*
Cheek†
Chin
Tear
trough
Nose
Other
facial
area
Hands
Total
-
-
-
-
-
20
24
25
NR
-
-
-
-
-
20
24
25
NA
-
NR
NR
NR
NR
-
-
-
NR
NR
NR
NR
-
-
-
-
-
NR
NR
NR
NA
-
-
-
-
-
130
91
24
54
NR
-
-
-
-
-
130
91
24
54
NA
-
-
-
-
-
50
-
-
-
-
-
50
-
-
-
-
-
50
-
-
-
-
-
50
-
-
-
-
-
94
-
-
-
39
-
133
-
-
-
-
-
NR
-
-
-
NR
-
NR
-
-
-
-
-
50
-
-
-
-
-
50
-
-
-
-
-
100
-
-
-
-
-
100
Mouth corners (infraoral region); tear trough (infraorbital region); chin includes mental crease and labiomental crease.
NR, not reported: studies stated that injections had been given in a particular region, but did not provide specific data.
*
Many patients had treatment of multiple facial areas.
†
NLF includes melolabial folds. Includes zygomal and buccal areas.
135
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Appendix C.4 Volume of product injected for ageing
PERMANENT VS. TEMPORARY FILLERS
Cohen et al. 2006 (Level II)
N
Intervention
Volume, ml (mean)
Glabella
NLF
Upper lip
Mouth corners
128
PMMA (Artecoll*)
n = 81
n = 108
n = 69
n = 86
0.25
0.75
0.3
0.4
123
Collagen (Zyderm
n = 86
n = 104
n = 59
n = 87
II/Zyplast)
0.50
1.4
0.6
0.8
P-value
< 0.001
< 0.001
< 0.001
< 0.001
PERMANENT FILLERS
Cohen et al. 2007 (Level IV)
145
PMMA (Artecoll*)
As for Cohen et al. (2006) for original PMMA group. Volume for cross over group not reported.
Mladick 1992 (Level IV)
40
Silcone particles
NR
(Bioplastique)
Fulton et al. 2006 (Level IV)
608
Liquid silicone
Approximately 0.25 ml for upper lip and approximately 0.25 ml for lower lip
(Silikon)
Reda-Lari 2008 (Level IV)
1306 PAAG (name not
Average 2 – 3 ml per site (range 1.5 – 5 ml)
specified)
SEMI-PERMANENT VS TEMPORARY FILLERS
Moers-Carpi et al. 2007 (Level II)
Initial volume(ml)
Volume at 4 months
Total (ml)
P-value compared to
(n = 205)
(ml)
CaHA (total)
70
CaHA (Radiesse)
1.3
1.1 (n =60)
2.21
33
HA1 (Juvederm 24)
2.2
2.7 (n = 31)
4.78
< 0.001
33
HA 2 (Juvederm
1.7
1.2 (n = 33)
2.94
0.0034
24HV)
69
HA 3 (Perlane)
1.6
1.4 (n = 65)
2.89
< 0.001
Smith et al. 2007 (Level II)
Mean volume to reach optimum correction in NLF, ml (min: max)
117
CaHA (Radiesse) one 2.4 (0.8: 4.7)
side of face
117
Collagen
1.2 (0.3: 2.7)
(Cosmoplast) other
side of face
P-value
0.0001
SEMI-PERMANENT FILLERS
Jacovello et al. 2006 (Level IV)
N
Intervention
Mean volume per patient†, ml
Glabella n = 12
NLF n = 24
Lips n = 10
Nose n = 5
Infraorbital n = 4
40
CaHA (Radiesse)
0.5
0.5 – 1.0
0.5 – 1.0
0.5 – 1.0
1.0 – 2.0
(each side)
(each lip)
Sklar & White 2004 (Level IV)
N
Intervention
Average volume injected per site, ml (range)
NLF
Tear
Lips
Mouth
Above up Cheeks
Chin
n = 52
trough
n = 15
n = 11
lip n = 1
n=2
Zygoma Buccal
n = 15
n=4
n=1
0.35
0.67
0.29
0.2 (0.2)
0.6 (0.3–
2.0 (2.0)
0.15
64
CaHA (Radiance FN) 0.91
*
†
(0.4 – 2.0)
(0.3 – 0.7)
(0.2 –1.4)
(0.1 – 0.5)
1.2)
In Cohen & Holmes (2004), product referred to as Artecoll. In Cohen et al. (2006), product referred to as Arte-Fill.
Mean overall volume per patient was 0.75 ml.
(0.1 - 0.2)
136
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Appendix C.4 Volume of product injected for HIV-associated lipoatrophy
PERMANENT VS. SEMI-PERMANENT VS. TEMPORARY FILLERS
Guaraldi et al. 2005 (Level II)
N
Intervention
Volume per cheek at each treatment session, ml
15
PAAG (Aquamid)
1
20
PLA (New-Fill)
Max of 4
24
AFT
NR
Negredo et al. 2006 (Level III-2)
N
Intervention
Mean cumulative volume after first round of injections, ml (range)
115
PAAG (Aquamid)
5.5 (4 – 18)
26
PLA (New-Fill)
6 (3 – 13)
8
AFT
NR
Orlando et al. 2007 (Level III-2)
N
Intervention
Volume per cheek at each treatment session, ml
130
PAAG (Aquamid)
1
91
PLA (Sculptra)
Max of 4
24
AFT + PLA (Sculptra) NR
54
AFT
NR
PERMANENT FILLERS
Jones et al. 2004 (Level IV)
N
Intervention
Mean total volume injected per patient (ml)
77
Liquid silicone (Silikon 8.4*
1000/ VitreSil 1000)
SEMI-PERMANENT FILLERS
Carey et al. 2007 (Level II)
Vials per cheek per treatment session
50
PLA (Sculptra)
1 (5 ml)
Cattelan et al. 2006 (Level IV)
N
Intervention
Total vials per patient† by lipoatrophy score
6 (n = 7)
7 (n = 13)
8 (n = 14)
50
PLA (New-Fill)
8
8
8‡
Lafaurie et al. 2005 (Level IV)
N
Intervention
Median volume injected per treatment session, ml (range)
Right cheek
Left cheek
94
PLA (New-Fill)
2.5 (1.0 – 3.5)
2.4 (1.0 – 3.8)
Mest & Humble 2006 (Level IV)
N
Intervention
Median volume injected at each session, ml
99║
PLA¶ (name not
6
specified)
Valantin et al. 2003 (Level IV)
N
Intervention
Volume injected into each cheek at each visit, ml
50
PLA (New-Fill)
Max of 4
Silvers et al. 2003 (Level IV)
N
Intervention
Volume injected, ml (mean ± SD)
Baseline n = 100
1 month n = 85
6 months n = 89
100
CaHA (Radiesse)
4.8 ± 1.9
1.8 ± 1.1
2.4 ± 1.5
9 (n = 16)
12§
Total
8.4 ± 3.6
NSF, nasolabial folds; NR, not reported; SD, standard deviation.
*
15 (19%) patients received less than 5ml in total; 39 (51%) received 5 to 10 ml; 14 (18%) received 10 to 15 ml; 7 (9%) received 15 to 20
ml; 2 (3%) received more than 20ml.
†
There were 2 vials used per session for each set of patients.
‡
In 5 patients, the PLA was reconstituted with 6 ml of sterile water.
§
In 2 patients, the PLA was reconstituted with 8 ml sterile water.
║
10 patients dropped out of follow-up (after the first intervention). Data for these patients not included in the analyses.
¶
1 patient dropped out of follow-up (after the first intervention). Data for this patient not included in the analyses
137
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