Paediatric HIV
衛生署 疾病管制局
中區傳染病防治醫療網
王任賢 指揮官
Objectives
•
•
•
•
At the end of this presentation participants
should be able to:
Understand the pathogenesis of HIV in infants
and children
Recognise common presenting features of
paediatric HIV
Understand the strategies for management of
HIV-affected infants and children
Appreciate the application of paediatric
HIV/AIDS management in the Jamaican context
Philosophy
• Life-cycle / developmental approach to
issues of diagnosis and treatment
• Public-health approach to management
– Prevention of HIV
– Prevention of acute illnesses / opportunistic
infections
– Preservation of immune function
– Improving quality of life
– Palliative care issues
Historical perspective
• Paediatric HIV first recognised in 1986 in Jamaica
• ‘Pioneers’ who initiated individual ‘pockets’ of paediatric HIV care
• 2002: Development of Pediatric Infectious Diseases Clinics in
Greater Kingston region coordinated by Prof CDC Christie & the
implementation of the Kingston Pediatric & Perinatal Program
Overall Aim: Reduce MTCT
Improve survival & QOL of infected children and
adolescents
• 2003: Program received a major boost in therapeutic and laboratory
support through Clinton HIV/AIDS Initiative and Global Fund
• 2003-present: Established clinics in St. Ann’s Bay, Cornwall
Regional, Mandeville, and MayPen Hospitals through outreach and
preceptorship training
JAMAICA
Pediatric AIDS Cases & Deaths (1982 - 2004)
90
Cases
Deaths
Number of Cases
80
70
60
50
40
30
20
10
0
86
87
88
89
90
91
92
93
94
95
96
97
98
99 2000 2001 2002 2003 2004
Cases
1
1
4
10
7
9
12
12
30
27
49
44
55
70
83
66
81
67
61
Deaths
1
0
1
7
6
7
7
5
23
21
17
25
35
36
34
27
45
29
34
Source: Ministry of Health, Jamaica
Historical perspective
Dramatic fall in incidence of
new cases of paediatric
infections in US
Paediatric ARV History
•1988 – monotherapy with
AZT
•1994 – dual therapy
•1998 – triple therapy with
HAART
Key differences from infected
adults
• Perinatal transmission
• Effect of virus on immature immune
system
• Virologic response
• CD4+ response – reliance on CD4% to
determine severity of immunologic
deterioration
• Clinical presentation
• Diagnostic challenge in < 18 months
Possible routes of
transmission
In-utero
At Birth
During breastfeeding
Other modes of transmission
• Sexual – abuse, exploitation,
experimentation, consensual
• Transfusion (rare in Ja)
• Intravenous drug use (rare in Ja)
Natural history of paediatric
HIV
Newborns: most studies – generally well at birth
Virologic response: increases rapidly in initial 2-3
months then slowly declines to virologic set-point
after several months to years
Immunologic response: brisk and variable T cell
proliferation; hence cannot rely on absolute
CD4+ as marker of immune deficiency; CD4+
percent <15% indicative of severe immune
deficiency
Virologic set-point: state of in-vivo equilibrium between viral production
and elimination
Virologic response
Time (years)
Child
Adult
Infection
Natural history of paediatric
HIV
Pattern of Clinical Progression
Asymptomatic
Mild to
Moderate
Severe
Natural history of paediatric
HIV
Patterns of Progression
Rapid
Intermediate
Slow
20 %
70 %
10 %
Rapid Progressors
•
•
•
•
•
•
•
PCP
FTT
CNS invovlement
Chronic GE
Recurrent infections
CMV infection
Persistent candidiasis
Progression to AIDS
Early onset – perinatal infections in infants < 12
months
Commonest manifestations:
•
•
•
•
recurrent pneumonia
recurrent diarrhoea
growth failure
neurological abnormalities
Slow Progressors
• Generally well until late childhood
• Some completely asymptomatic
• Few---progress to AIDS
• Main problems : pneumonia / Lymphocytic
interstitial pneumonitis (LIP), stunting
Clinical manifestations
Generalised, persistent
lymphadenopathy
Dermatitis
Mucocutaneous Candidiasis
Recurrent lower respiratory
tract infections
• Bacterial pneumonia
• Community acquired
infections
• Need to always
consider tuberculosis
• Increased occurrence
of LRTI associated
with LIP
Pneumocystis jiroveci
pneumonia (PCP)
Lymphocytic Interstitial
Pneumonitis
Chronic lung disease
Wasting / FTT / Malnutrition
Hepatosplenomegaly
Neurodevelopmental
abnormalities
•
•
•
•
Developmental delay
Developmental regression
Spasticity, hyperreflexia
Impaired cognitive
function
• CT scan brain: generalized
cortical atrophy with
ventricular enlargement and
calcified basal ganglia (arrow)
• (Ref. D. Carli C et al, Ann
Neurol 34(2): 198-205, 1993.)
Clinical manifestations
• Recurrent or
persistent upper
respiratory tract
infection, sinusitus or
otitis media
• Parotitis
• Recurrent diarrhoea
• Bacterial sepsis
• Organ-specific
dysfunction
CDC. 1994 Revised
classification
system for human
immunodeficiency
virus infection in
children less than
13 years of age.
MMWR, 1994. 43 (No.
RR-12): p. 1-10
Reducing the impact of HIV
on children
AIM
Increase survival
&
Improve quality of life
Give a child a chance
Early Intervention is the key
Framework for a comprehensive approach to
manage HIV in infants children
Prevent HIV
in women
Prevent
unintended
pregnancy in
HIV + women
Prevent
MTCT
Provide accessible treatment, care and support
for HIV-infected women,
their infants and families
Key aspects of management
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•
•
•
•
•
•
•
Prevention of HIV infection
Early diagnosis
Early detection – high index of suspicion
Prevention (& timely treatment) of common
childhood illnesses
Prevention and early treatment of opportunistic
infections
HAART – preserve / restore immune system
Palliative care
Multidisciplinary management approach
Management of HIV-exposed
infant
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•
•
•
•
•
•
•
•
•
ARV prophylaxis (pre- and post-exposure)
Breastfeeding alternatives
Follow-up and monitoring
PCP prophylaxis – Cotrimoxazole
Diagnosis of HIV infection
Immunizations – National EPI recommendations
Nutrition
Growth & development
Clinical evaluation for stigmata of HIV infection
Challenges – follow-up, adherence to
prophylaxis, stigma of non-breastfeeding
Diagnosis of HIV infection in
exposed infant
• Serial qualitative DNA PCR is currently the
accepted standard for early diagnosis
• DNA-PCR [2 consecutive readings]
– 1-2 months
– 3-6 months
• Antibodies (Elisa)
– 12 months in non-breastfed infant
• Others – RNA PCR, p24, viral culture
• Passive transfer of maternal Ig G leads to
detectable antibody in uninfected children for up
to 18 months
• Antibody tests e.g.ELISA not diagnostic until 18
months unless negative
Lancet 2004; 364: 1865-71
Diagnosis of HIV infection in
child
HIV Elisa with confirmatory Western blot
[> 18 months of age]
Classification of paediatric
HIV/AIDS
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•
•
•
CDC Clinical Category
N – asymptomatic
A – mildly symptomatic
B – moderately symptomatic
C – severely symptomatic – AIDS
defining conditions
CDC 1994 Revised classification system for human immunodeficiency virus infection in
children less than 13 years of age. MMWR, 1994. 43 (No. RR-12): p. 1-10
Classification of paediatric
HIV/AIDS
CDC Immune Category
CD4%, and age-specific CD4 count
• 1 –  25% [none/mild suppression]
• 2 – 15 – 24% [moderate suppression]
• 3 – < 15% [severe suppression]
Classification of paediatric
HIV/AIDS
WHO Staging System
• Clinical Stage 1 (asymptomatic)
• Clinical Stage 11 (mild to moderate)
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–
–
–
–
Chronic diarrhoea
Candidiasis
FTT
Persistent fever
Recurrent severe bacterial infections
• Clinical Stage 111(severely symptomatic)
–
–
–
–
–
AIDS defining conditions
Severe FTT
Progressive encephalopathy
Malignancy
Recurrent sepsis
Comprehensive management
of HIV-infected child
• Multidisciplinary management approach
• Prevention (& timely treatment) of
common childhood illnesses
– Regular ambulatory care
– Growth & development monitoring
– Immunizations – National EPI guidelines;
influenza, pneumococcal
• Nutrition & food safety
Comprehensive management
of HIV-infected child
• Prevention and early treatment of
opportunistic infections
– Cotrimoxazole
– Fluconazole
– Azithromycin
– Aciclovir
– Isoniazid
– IVIG
• Palliative care
Antiretroviral Therapy
Preserve and restore
immune system
Who, when, what, how???
• Several guidelines: Caribbean, Jamaican,
WHO, DHHS…………..
• Bottom-line issues for consideration
–Feasible
–Accessible
–Affordable
–Safe
–Sustainable
–Practical
Practical guidelines
• Any HIV-infected infant or child with AIDS
defining condition or severe
immunosuppression (CD4 < 15%)
• All HIV-infected infants < 12 months of age,
regardless of clinical, immunologic or
virologic parameters
• All others – discuss and consider
treatment according to guidelines
Practical considerations
• Limited range of paediatric formulations in
Jamaica
• Initiation of therapy & adherence in
children is caregiver – dependent
• Treatment options are limited
• Aim for practical, simplified regimes
Effectiveness of
interventions in treating
Paediatric HIV/AIDS
The Jamaican Experience
Collaborators
• Kingston Pediatric & Perinatal HIV/AIDS
Program (KPAIDS) Team
• University of the West Indies; University Hospital
of the West Indies
• Jamaica Ministry of Health – Bustamante
Hospital for Children, Comprehensive Health
Centre, Spanish Town Hospital, National AIDS
Program
• Elizabeth Glaser Pediatric AIDS Foundation
(EGPAF), Pfizer Foundation
Aim
To characterize the effectiveness of
interventions in a cohort of HIV-infected
children and adolescents attending
Paediatric Infectious Diseases Clinics in
Greater Kingston, Jamaica
Objectives
• Describe the demographic and clinical &
immunological profile of the cohort
• Determine enrollment pattern and uptake
of Antiretroviral therapy (ART)
• Characterize outcomes related to
hospitalisations, bacterial and
opportunistic infections, growth, morbidity
and mortality
Methods
• Longitudinal observational cohort study
• Paediatric Infectious Diseases Clinics at
UHWI, BHC, CHC & STH
• HIV-infected infants and children
consecutively enrolled in KPAIDS Program
• Period: 1 Sept. 2002 to 31 Aug. 2005
• HIV status confirmed by HIV DNA pcr,
Elisa/WB where appropriate
Methods
• Training of healthcare personnel
• Development of unified protocols for clinical
management
• Primarily ambulatory surveillance; also inpatient consultations, case management
• Data tracking and audit – morbidity, mortality,
hospitalisations, laboratory markers
(haematology, biochemistry, cultures,
immunology, flow cytometry, viral load)
• Dbase management; analysis-Excel, Access,
SPSS, EpiInfo where indicated
Comprehensive Interventions
• Integrated
multidisciplinary
approach to ambulatory
treatment & care
• Increased access to care
• Inpatient consultations
• Immunisation*, nutrition,
growth/development
surveillance
• MOH Jamaica
guidelines*
• Prophylaxis:
Opportunistic Infections
[bactrim, fluconazole,
azithromycin, isoniazid,
clotrimazole];
beclomethasone/
salbutamol MDI
• ARV counselling,
treatment, adherence and
AE monitoring
• High index of suspicion
for TB
Results
Enrollment Profile
Total Enrolled
196
Transfer
Deaths
7
13
Migration Overseas
Lost to Follow-up
2
12
‘Actively’ Enrolled
~ 162
Enrollment Pattern
45
Yearly Enrollment (%)
40
35
30
25
20
15
10
5
0
B ef or e P r Program
ogr am
Before
YYear
ear 1
1
YYear
ear 2
2
YYear
ear 3
3
Characteristics of Cohort
Gender
Age
Female
107 (54.6%)
Male
89 (45.4%)
At
Enrollment
Median 5.0 yr; Range <1 to 19.0 yr;
IQR 2.2-8.1yr
Current
Age
Median 6.0 yr; Range <1 to 20 yr;
IQR 4.0-10.0 yr
Mode of transmission
MTCT
88.8%
Sexual
7.1%
Transfusion
1.5%
Unknown
2.5%
Clinic Site Population
UHWI
51.5%
BHC
32.6%
CHC
9.2%
STH
6.6%
Guardian Status
Family Care
151 (77%)
Institution Care
45 (23%)
Clinical & Immunological
Profile
CDC Category Profile
90
80
70
60
50
40
30
20
10
Last Visit
0
CDC
N – asymptomatic
A – mild
B – moderate
C - severe
Last V i si t
N
N
E nr ol l ment
Enrollment
A
A
B
B
C
C
Median CD4+ percentage by
year
70.0
60.0
CD4+
50.0
CD4 percent
40.0
30.0
20.0
10.0
0.0
0.0
1995
Year
2001
2002
2003
2004
2005
ANOVA
F 1.015; p=0.318
ARV Uptake
ARV Uptake
Cumulative proportion on ARV (%)
100
90
80
70
60
50
40
30
20
10
0
Before Program
Before
Program
Year
1
Year
1
Year
2
Year
2
Year 3 3
Year
ARV Uptake
Ever on ARV
Ever on ARV
yesYes
noNo
38%
62%
ARV Uptake
Regime 1
Zidovudine
Lamivudine
Nevirapine
120
85%
100
80
60
40
20
6%
2%
1%
6%
0
AZT/3TC/ABC
AZT/3TC/D4T
AZT/3TC/EFV
AZT/3TC/IND
AZT/3TC/NVP
ARV Uptake
• ARV-experienced group:
– Regime 2 – 10.7%
– Regime 3 – 5 %
– Regime 4 – 0.8 %
• Reasons for regime change: toxicity/AE
(13), clinical failure (8), ‘financial’
limitations (3), optimisation (2)
• ~ 80% (ARV-naïve) currently on initial
regime
Adherence levels for children on ART
Percentage of respondents (%)
120
100
13
25.9
80
60
40
100
87
74.1
20
0
Overall
Family Care
Adherent
Residential
care
Non-adherent
Factors affecting
adherence
Factors significantly
associated with nonadherence:
1. Older age of child
(r=0.428,p=0.001)
2. Missing clinic
appointments (r=0.340,
p=0.018)
3. Nausea (p=0.003)
Adherence to ART
• Adherence to pediatric ART 87%
• Adherence correlated with immunereconstitution, measured by CD4 counts/percent
• Adherence in institutions better because of
directly observed therapy (DOT)
• Main reasons for non-adherence in children on
ART are caregiver-related
• Knowledge about ART excellent except
development of resistance
• Predictors of non-adherence: Older age of child,
missing appointments, nausea
Growth Outcome
• Weight, height, BMI values standardized
to z scores (CDC 2000 growth chart)
• Baseline, 6, 12, 24 months since initiation
of antiretroviral therapy
Weight for Age
Weight for Age Z- Score
[Median]
24 mos
12 mos
6 mos
Baseline
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Weight for Height
Weight for Height Z- Score
[Median]
24 mos
12 mos
6 mos
Baseline
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
BMI for Age
BMI for Age Z- Score
[Median]
24 mos
12 mos
6 mos
Baseline
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
Height for Age
Height for Age Z- Score
[Median]
24 mos
12 mos
6 mos
Baseline
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Hospitalisation Profile
Median 1.0 (Range 0 to 20) hospital
admissions
IQR 0 – 3 admissions
Incidence Density
Event
Incidence (per 100 patient months of follow-up)
No ARV
On ARV
Hospitalizations
11.02
5.93
Pneumonia
4.71
2.49
Presumed PCP
0.58
0.05
Culture-positive sepsis
1.29
0.33
Tuberculosis
0.67
0.14
Toxoplasmosis CNS
0.13
0
CMV retinitis
0.04
0
Cryptosporidiosis
0.09
0
Cryptococcal meningitis
0.04
0
Urinary tract infection
1.29
0.96
Deaths
Deaths by Cohort Year
6
5
4
Frequency of
3
Deaths
2
A
Series1
1
0
Year 1
Year 2
Year 3
Summary
Enrollment
Hospitalisation
Median
CD4%
Deaths
ARV Uptake
Growth
2002
2003
2004
2005
Conclusions
• Improved survival of HIV-infected children
and adolescents
• Improved their quality of life
Conclusions
• Developed an ambulatory surveillance model for Paediatric
HIV/AIDS treatment & care in a developing country
• Focused on a Public Health Approach
• Integrated with existing resources in Jamaica
• Fostered an excellent collaboration with Jamaica MOH & National
HIV/AIDS Program
Future Directions
Future Directions
• Reducing MTCT to < 2%
• Strengthening paediatric HIV/AIDS treatment &
care capacity in rest of Jamaica
• Palliative care issues
• Challenges
– Issue of viral resistance
– Limitations for treatment options
– Maturing cohort of infected adolescents – transition to
adult life
– Sustainability of treatment and laboratory monitoring
Acknowledgements
MOH, National AIDS Program
All participating and facilitating institutions
KPAIDS Team
Children and their caregivers