1
(FCH/HIV, 22 April 2002)
Application for Inclusion of saquinavir/low dose ritonavir (SQV/ r)
combination on
WHO Model List of Essential Medicines
Drugs are members of the therapeutic class of HIV protease inhibitors
Summary of Proposal
Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated
25 million people have died as a result of HIV infection. Current estimates suggest that
around 40 million persons world-wide are infected with HIV and more than 90% of infected
persons live in the developing world. Growing experience of the provision of anti-retroviral
therapy in resource-poor settings (eg. Brazil, Côte d’Ivoire, Senegal, Haiti, India) indicates
that treatment can be provided in an effective and safe manner. The delivery of antiretroviral treatment in low-income countries has been aided by the development of fixed
drug combinations and substantial reductions in the prices of certain products.
Combination treatment with the protease inhibitors saquinavir and low dose ritonavir
(SQV/r) is proposed for listing on the WHO Model List of Essential Medicine.
A search of several data-bases, including the Cochrane Library, Medline and Embase and
some specialised data-bases, retrieved systematic reviews and articles supporting the use
of HIV-1 RNA levels and CD4 cell counts as valid surrogate measures for changes in the
rates of clinical outcomes during treatment of HIV-infected subjects. The literature search
also provided evidence that combinations of 3 anti-retroviral drugs are superior to dual or
single drug therapy. The latter are no longer regarded as satisfactory treatment, because of
low efficacy rates and the development of resistance.
Ritonavir inhibits the metabolism of saquinavir and is added to improve the bioavailability of
the latter, not as an anti-retroviral drug in its own right. Library searches compiled by the
Cochrane Review Group for HIV/AIDS retrieved details of 6 randomised clinical trials
involving saquinavir/low dose ritonavir (SQV/r). These trials involved different doses of the
two drugs, although 400mg of each, twice daily, was the most common regimen. One trial
documented apparent therapeutic equivalence of a range of doses of the two drugs when
combined with 2 nucleoside reverse transcriptase inhibitors. The SQV/r 400mg/400mg
seemed the most attractive option, as it involved the lowest total does of the drugs, and
appeared better tolerated than the alternatives. In another large trial SQV/r 400/400 was
compared with full dose therapy with indinavir or ritonavir and the SQV/r combination was
at least as effective overall, and was superior in patients who had not been previously
treated with ARVs. The remaining trials provided reasonable insights into the efficacy of
this combination, but tended to involved sub-optimal combinations with SQV/r (eg with only
1 non-nucleoside reverse transcriptase inhibitor (NRTI), or compared the SQV/r-containing
regimen with one that is not recommended in the guidelines. Overall, the evidence appears
to be of reasonable quality, and at least as good as what is available to support the
combined use of indinavir/low dose ritonavir. Adverse effects were typical of what are seen
with protease inhibitor combinations, and there is no evidence that the BD dosing in
combination with ritonavir reduces these. Presently, saquinavir and ritonavir are not
available as a fixed dose combination preparation.
1. Summary statement of the proposal for inclusion, change or deletion.
Saquinavir mesilate + low dose ritonavir are proposed for inclusion on the WHO Model List
of Essential Medicines, as part of a multi-drug antiretroviral regimen for the treatment of
HIV/AIDS within an appropriately monitored program. Saquinavir + ritonavir (SQV/r) should
be viewed as examples of the class of protease inhibitors. Other examples of this group
may sometimes be preferred when local factors such as availability and price are taken into
account.
Antiretroviral therapy is recommended for HIV-infected children, adolescents, and adults
with symptomatic disease, and also for asymptomatic patients with CD4+ cell counts at or
below 200/mm3. Where CD4+ cell testing is unavailable, clinicians can use the presence of
a total lymphocyte count below 1200/mm3, but only in symptomatic patients.1,2
2. Name of the focal point in WHO submitting the application:
HIV/AIDS Department at WHO; the person responsible is Dr Dr Bernhard Schwartländer,
Director of Evidence and Policy.
3. Name of the organization(s) consulted and/or supporting the application:
Supporting letters may be submitted – please contact Dr Robin Gray (WHO/EDM) at
grayr@who.int
4. International Nonproprietary Names: saquinavir mesilate (hard-gel formulation),
saquinavir (soft-gel formulation), ritonavir.
5. Listing Type Requested:
Listing is requested on the Model List of Essential Medicines as examples of the
therapeutic class of HIV protease inhibitors. Other members of this class of drugs may
serve as alternatives, depending on quality, price and local availability.
6. Information supporting the public health relevance of the submission:
Since the first clinical evidence of AIDS was reported over twenty years ago, an estimated
25 million people have died as a result of HIV infection. Current estimates suggest some
40 million persons worldwide are infected with HIV and more than 90% of infected persons
live in the developing world3. In 2001, 5 million persons worldwide became infected with
HIV, and 3 million others died from HIV/AIDS-related causes.
3
In sub-Saharan Africa, the region most severely affected by HIV, 28.1 million individuals
are living with this infection. Eastern Europe — especially the Russian Federation —
continues to experience the fastest-growing epidemic in the world. In 2001, there were an
estimated 250 000 new infections in this region, bringing to 1 million the number of people
living with HIV. In Asia and the Pacific, an estimated 1 million people became infected in
2001; about 7.1 million people in this region are now living with HIV/AIDS 3. More than 1.8
million people in Latin America and the Caribbean are living with HIV/AIDS, including the
190,000 adults and children who became infected in 2001
In countries often already burdened by huge socio-economic challenges, HIV/AIDS
threatens human social welfare, developmental progress, and social stability on an
unprecedented scale. HIV/AIDS cripples the economic development of entire countries,
because it often strikes people during their most productive working years. Of the 14,000
persons who became infected each day in 2001, about 12,000 were aged 15 to 49 years3.
Left untreated, HIV infection results in a period of clinical latency that may last a median of
3 to 10 years. Once symptomatic disease or AIDS develops, without access to
antiretroviral treatment, death results within an average of two years.
In high-income countries, an estimated 1.5 million people live with HIV, many of them
productively, thanks to antiretroviral therapy. In the USA, the introduction of triple
combination antiretroviral therapy in 1996 led to a decline of 42% in deaths attributable to
HIV/AIDS in 1996-973.
The feasibility efficacy and adherence with antiretroviral therapy has been demonstrated in
a number of national and smaller pilot programs in middle- and low-income countries.
In Brazil, the policy of universal access to antiretroviral drugs has reduced the number of
AIDS-related deaths by nearly 50% and cut the incidence of opportunistic infections by 60 80%4. Between 1997 and 2000, Brazil saved approximately US $677 million in averted
hospitalisations and treatment of HIV-related infections.

In Argentina a program similar to that of Brazil provides even greater coverage. A special
fund has been established to pay for antiretroviral drugs for those not covered by social
security (such as street vendors, small business people, the unemployed, low-income
pregnant women) 5.
Through the UNAIDS Drug Access Initiative Pilot Program, 6 treatment centres in Abidjan,
Côte d’Ivoire, offer antiretroviral therapy. Of the patients who received therapy, 72% were
heavily symptomatic upon initiation. Nonetheless, the overall survival rate of was 93% at 6
months, 90% at 12 months, and 86% at 18 months. When survival rates are re-calculated
using a worst-case scenario in which patients lost to follow-up are assumed to have died
immediately after their last clinic visit, 75% survived at 6 months, 64% at 12 months, and
55% at 18 months6.
The Senegal Initiative on Antiretroviral Therapy was launched in August 1998. A
partnership between the Senegalese government and the International Therapeutic
Solidarity Fund, it aims to have 7,000 patients on triple combination therapy by the end of
2007. At the end of 2001, an estimated 550 adults and children had received treatment. A
prospective observational cohort study was undertaken to assess the feasibility,
effectiveness, adherence, toxicity and viral resistance of antiretroviral therapy. The clinical
and biological results of the study were comparable to those seen in western cohorts,
despite differences in HIV-1 subtype and an advanced disease stage when treatment was
initiated. Fifty-eight patients with advanced HIV disease demonstrated by CDC staging (16
patients in CDC Stage B, 42 in CDC Stage C) and CD4+ cell count (median CD4+ cell
count = 108.5, IQR = 34 - 217) were given triple combination antiretroviral therapy (2
nucleoside analogues + 1 protease inhibitor). After 18 months of treatment, participants
gained a median of 180 CD4+ cells and showed a median drop in plasma viral load of 2.8
log10 copies/ml. During the study period, there were 7 clinical AIDS-defining events with 6
deaths from HIV-related infections7. The antiretroviral regimen was complex: indinavir, the
protease inhibitor used in the study, had to be taken in a fasting state every 8 hours, with
maintenance of hydration; didanosine (DDI), the nucleoside analogue given to 86% of
participants, is a buffered preparation which also had to be taken while fasting 1 to 2 hours
after any other medication. Despite the complexity of the regimen, 80% of patients (IQR
72-87%) showed adherence 80% at 18 months.
In Cange, a Haitian village, the non-profit organization Partners in Health has introduced
antiretroviral therapy to a small number of seriously ill AIDS patients, based on their
Directly-Observed Therapy (DOT) programme for multiple-drug resistant tuberculosis. This
DOT programme has been successful, with 90% of all registered TB cases in the Cange
catchment area considered cured, compared with just 26% in other regions of Haiti. Sixtyfive patients were selected to receive triple combination antiretroviral therapy on the basis
of clinical indicators of severe HIV disease (e.g. wasting, recurrent opportunistic infections,
severe neurological complications, etc.). Shortly after initiating treatment, most patients
showed clinical improvement. To counter critics and test the effectiveness of the
programme, blood samples were sent to Boston for viral-load analysis. The results showed
that 83% of patients on triple therapy had unquantifiable viral load measures. For the most
part, side effects have been minimal and easily managed and there are support groups to
encourage adherence.8
At HIV clinics in Pune and Ahmedabad, India, a recent study demonstrated the benefit of
triple combination antiretroviral therapy (nevirapine + 2 nucleoside analogue RTs) in 347
patients with advanced HIV disease. At 12 months, 64.6% of the study participants
experienced an increase of more than 20% in CD4+ cell counts. Twenty-three secondary
clinic events during the study were reported, including 6 deaths (4 TB-related, 1
cryptococcal meningitis, 1 non-Hodgkin’s lymphoma) — an AIDS-associated mortality rate
of 5.7% at six months. This program was also significant for the fact that it relied on generic
drugs supplied by Indian pharmaceutical manufacturers.9
Thus, in addition to the large amount of clinical data from high-income countries, there is a
small but growing body of clinical evidence to support the use of ARVs in developing
countries. Significant price reductions have also been achieved in many developing
countries and new funding and delivery mechanisms are being developed to expand their
availability. These factors warrant the addition of this class of drugs to the Model List of
Essential Drugs (with appropriate consideration of their use in resource-limited settings).
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7. Treatment details:
In clinical use, a reduced daily dose of saquinavir mesilate (SQV-hgc) or saquinavir (SQVsgc) combined with a reduced ritonavir dose improves the bioavailability of saquinavir and
increases the dosing frequency from thrice-daily to twice-daily or (even) once-daily.
Note: in the sub-therapeutic doses described here (100-200 mg daily), ritonavir is not being
administered for its intrinsic anti-retroviral activity, but because its co-administration with
saquinavir or saquinavir mesilate results in a beneficial pharmacokinetic interaction,
sometimes referred to as ‘boosting’.
Dosage:
Adults and adolescents: The regimen that provides the greatest efficacy and least toxicity
has not been established. The WHO Guidelines recommend SQV/r 1000/100mg twice
daily. Either hard or soft gel preparations of SQV can be used when combined with
ritonavir. Another popular and widely studied regimen is: 400 mg saquinavir + 400 mg
ritonavir, twice daily. Other regimens in use and under study include 1600 mg
saquinavir + 100 mg ritonavir once daily.
Saquinavir mesilate and saquinavir are available in 200 mg capsules. Ritonavir is available
in 100 mg capsules and 600 mg/7.5 ml solution.
Concomitant Antiretroviral Therapy: saquinavir + ritonavir must be given in combination
with other antiretroviral medications.
Duration: Antiretroviral treatment is usually regarded as life-long.
Guidelines: The WHO guidelines ‘Scaling up antiretroviral therapy in resource-limited
settings: Guidelines for a public health approach’10 recommends saquinavir + low dose
ritonavir (in combination with two nucleoside analogue reverse transcriptase inhibitors) as a
preferred regimen for the treatment of HIV/AIDS (see Table 1).
Special Requirements: Adequate resources for monitoring and specialist oversight are a
pre-requisite for the introduction of this class of drugs.
8. Comparative effectiveness in clinical settings:
In compiling the evidence for this and related submissions for anti-retroviral drugs we have
created a common ‘stem’ in the form of information that is relevant to all of the antiretroviral
group. This is followed by information that is relevant to use of this class of drug under the
conditions described in this application, followed by information which is specific to the
individual agent under consideration.
Because of time constraints and the growing acceptance of the efficacy of highly active
anti-retroviral drug regimens in the last 5 years, we have relied in part on secondary data
sources – systematic reviews of randomised and non-randomised studies conducted by
the Cochrane Collaboration, or by independent groups who have generally met standards
that are considered appropriate to this type of work. We have relied on individual trials
where these provided data and insights not available from systematic reviews.
Details of literature searches conducted
The principal data-bases that were searched were:
o The Cochrane Data-base of Systematic Reviews
o The ACP Journal Club reviews of published trials
o The data-base of reviews of abstracts of reviews of effectiveness (DARE)
o The Cochrane controlled trials register (CCTR)
o Medline
o Embase
Search terms used were:
o
o
o
o
o
o
Anti-retroviral or antiretroviral
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Randomised clinical trial (exploded and as text word)
Individual drug names: saquinavir, ritonavir
Study selection:
o
o
Randomised comparative parallel-group controlled clinical trials
Examined the performance of indinavir/ritonavir when included in combinations
comprising 3 or more drugs, involving concomitant use of NRTIs, NNRTIs or other
PIs.
Categorisation of levels of evidence
The following rating scheme was used11:
 Level 1 – evidence from relevant high quality systematic reviews of unbiased
randomised comparative clinical trials
 Level 2 – evidence from at least one relevant unbiased randomised comparative
clinical trial.
 Level 3 – evidence from relevant controlled observational studies
Additional considerations for use in resource-poor settings



Co-morbidity
Simplicity (frequency of dosing, number of tablets)
Tolerability
7


Cost
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of anti-retroviral
drugs)
1. What is the validity of surrogate markers as predictors of morbidity and mortality in
patients with HIV/AIDS?
2. What evidence is there that triple (or quadruple) ARV therapy is superior to single or
dual therapy?
Class specific questions
3. Which combinations of drug classes have the best evidence in relation to benefits
and harms?
Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations
that include didanosine?
Results
1. What is the validity of surrogate markers as predictors of morbidity
and mortality in patients with HIV/AIDS? (Level 3 evidence)
Trials of anti-retroviral compounds have relied heavily on measuring the effects of drugs on
surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA levels. The validity of
these markers depends on showing that they are correlated with clinical outcomes, and
that they should be able to capture the effects of treatment on the major clinical
outcomes12. Both of these markers may be viewed as being on the ‘causal pathway’
between viral infection and disease outcomes, but more directly in the case of viral
measures. The viral end-point has come to be regarded as superior to a measure as a
prognostic marker, although results have not been entirely consistent. A meta-analysis of
trials of 2 NRTIs (plus NNRTI or PI), which included 36 treatment arms, found that baseline
CD4 counts were significantly correlated with virologic suppression at 6 and 12 months,
whereas a similar correlation was not found with baseline viral load and subsequent viral
suppression13. The authors concluded that baseline CD4 cell count was a better predictor
of drug induced viral suppression than baseline viral load. In the other meta-analysis of
surrogate measures uncovered by the literature search, Hill et al reviewed results from 15
randomised trials that used surrogate markers and also included measures of disease
progression14. This review included data from 15038 patients, of whom 3532 patients
progressed to clinical outcomes. The analyses documented that there were significant
correlations between the relative hazards for clinical progression and changes in both HIV1 RNA levels and CD4 cell counts. The authors concluded that these markers, together,
were useful in monitoring treatment responses. However the data also indicate the value
of using CD4 cell counts alone. Another meta-analysis has quantified the relationship
between changes in surrogate measures and development of AIDS or death. In an
analysis based on 16 randomised trials of NRTIs, Babiker et al. estimated that the average
hazard reduction was 51% (95% CI 41, 59%) for each reduction in HIV RNA levels of
1*log10, and 20% (95% CI 17, 24%) for each increase of 33% in CD4 cell count15. These
studies are supported by a wealth of observational data from developed countries, showing
that the use of highly active anti-retroviral therapy, tested on the basis of surrogate markers
in many trials, has profoundly influenced the outcomes for patients with HIV infection.
2. What evidence is there that triple (or quadruple) ARV therapy is
superior to single or dual therapy? (Level 1 evidence)
There is extensive clinical experience suggesting that multiple drugs with different modes
of action are necessary to achieve sustained viral suppression (induction). Such
combination treatments are standard recommendations in clinical practice guidelines.
16,17,18 There is insufficient space and time to present all of the relevant studies
documenting the success of multi-drug induction therapy to the Expert Panel. However, a
smaller number of trials have documented the value of various maintenance regimens
introduced after successful induction therapy and these studies are relevant. Four trials
that compared 3 or 4 drug maintenance regimens with 2 drug regimens were included in a
Cochrane Review19. Use of a two-drug maintenance regimen was associated with an odds
ratio for virologic failure (loss of HIV suppression) of 5.55 (95% CI 3.14, 9.80). These
results complement an earlier systematic review, which synthesised data from 6 trials that
compared the results of zidovudine monotherapy with treatment combinations comprising
ZDV with ddI or ddC20. Although mainly of historical interest now, the review studies clinical
outcomes and showed that the addition of ddI to ZDV resulted in a reduced odds of
disease progression and death (OR 0.74, 95% CI 0.67, 0.82) and (0.72, 95% CI 0.64, 0.82)
respectively. The addition of ddC gave similar results: disease progression, 0.86 (95% CI
0.78, 0.94); and death, 0.87 (95% CI 0.77, 0.98). After 3 years the rates of mortality were
ZDV 59%, ZDV+ddC 63% and ZDV+ddI 68%. The reviewers concluded that the
combination of ZDV and ddI was probably superior to ZDV plus ddC.
The most recent review of the importance of multiple drugs in treatment of HIV/AIDS was
published in the BMJ21. These investigators pooled data from 54 randomised clinical trials.
The odds ratio for disease progression with 3 drugs compared with 2 drugs was 0.62 (95%
CI 0.50, 0.78), but data were considered inadequate to determine if there was a further
advantage in adding a fourth drug (this appears to exclude low dose ritonavir).
3. Which combinations of drug classes have the best evidence in
relation to benefits and harms? (Level 2 evidence)
Unfortunately this is a question that is not yet addressed in published systematic reviews.
Enquiries directed to the AIDS/HIV review group in the Cochrane Collaboration revealed
that relevant reviews are underway but results are not yet available. Some of the data from
the limited number of trials comparing different combinations of 3 or more anti-retroviral
drugs will be reviewed in relation to the individual drugs (see below section 8.4). However
there are broad questions about which combinations should be used as first line treatment,
and in what sequence should they be employed. The clinical practice guidelines mentioned
earlier address some of these issues and point out that choice is determined not only by
direct evidence of comparative clinical efficacy, but also by tolerability and toxicity,
presence of co-morbidity, concern about the development of viral resistance, and more
pragmatic considerations such as pill burden and adherence to therapy. With recognition
9
that none of the available regimens eradicates the virus, but suppression is desirable, HIV
infection has come to be regarded as a chronic disease, which requires long-term (albeit
sometimes intermittent) drug therapy. An additional consideration is a wish to ‘preserve’
more active anti-retroviral regimens for later in the course of therapy. This has led to
recommendations to conserve PI-containing regimens, using those based on combinations
of NRTIs and NNRTIs early in therapy. These considerations are reflected in the advice
contained in the WHO Guidelines10. The summary of regimens recommended in this
document is in Table 1.
Table 1. Recommended First-Line Antiretroviral
Regimens in Adults
Regimen
ZDV/3TC plus
EFV* or NVP*
ZDV/3TC/ABC*
ZDV/3TC** plus
RTV enhanced
PI or NFV
Pregnancy
Considerations
- Substitute NVP
for EFV in
pregnant women
or women for
whom effective
contraception
cannot be
assured
- ABC safety
data limited
- LPV/r safety
data limited
- NFV: most
supportive
safety data
Major Toxicities
- ZDV-related anemia
- EFV-associated CNS
symptoms
- Possible teratogenicity
of EFV
- NVP-associated
hepatotoxicity and severe
rash
- ZDV-related anemia
- ABC hypersensitivity
- ZDV-related anemia
- NFV-associated
diarrhea
- IDV-related
nephrolithiasis
- PI-related metabolic
side effects
*ZDV/3TC is listed as the initial recommendation for dual NsRTI component based on efficacy, toxicity,
clinical experience and availability of fixed dose formulation. Other dual NsRTI components can be
substituted including d4T/3TC, d4T/ddI and ZDV/ddI depending upon country-specific preferences.
ZDV/d4T should never be used together because of proven antagonism.
** RTV-PI includes IDV/r, LPV/r, and SQV/r.
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include saquinavir plus ritonavir? (Level 2 evidence)
Claimed advantages of dual Protease Inhibitor therapy: Synergistic antiretroviral activity
has been demonstrated in vitro when ritonavir was combined with indinavir, saquinavir
(both soft-gel and hard-gel formulations), and amprenavir. Ritonavir is a highly potent
inhibitor of cytochrome P450 3A (CYP3A), and, to a lesser extent, CYP2D6; it may also
inhibit the p-glycoprotein system. For further details of this interaction see the
accompanying submissions for indinavir/low dose ritonavir.
Library searches compiled by the Cochrane Review Group for HIV/AIDS retrieved details of
6 randomised clinical trials involving saquinavir/low dose ritonavir (SQV/r). These trials
involved different doses of the two drugs, although 400mg of each, twice daily, was the
most common regimen (see Attachment 1). One trial documented apparent therapeutic
equivalence of a range of doses of the two drugs when combined with 2 nucleoside
reverse transcriptase inhibitors. The combination of SQV/r 400mg/400mg seemed the most
attractive option, as it involved the lowest total does of the drugs, and appeared better
tolerated than the alternatives. In another large trial SQV/r 400/400 was compared with full
dose therapy with indinavir or ritonavir and the SQV/r combination was at least as effective
overall, and was superior in patients who had not been previously treated with ARVs.
The remaining trials provided reasonable insights into the efficacy of this combination, but
tended to involved sub-optimal combinations with SQV/r. The WHO guidelines
recommend that SQV/r is combined with 2 NRTIs10. For instance, Gisolf et al (2000)
combined SQV/r with d4T alone and compared this with SQV/r with no NRTIs. As
expected, 28/104 receiving no NRTI backbone agent needed intensification of their ARV
therapy. Similarly, Smith et al (2001)compared SQV/r plus d4T with SQV plus nelfinavir
(NFV) plus d4T; neither regimen would be considered satisfactory using the WHO
guidelines as the reference, and NFV was used in full doses in this trial. Florence et al
(2001) also combined SQV/r with a single NRTI and compared this with IDV in full does
plus 2 NRTIs, finding the latter to be superior. These studies are not very informative in
assessing the regimen recommended by WHO10.
There are 2 studies that employed alternative doses of the SQV/r combination. In a small
trial Chavanet et al (2001) found SQV/r 600mg/200mg twice daily to be roughly equivalent
to SQV 600mg and NFV 1000 mg, both twice daily. Both regimens were combined with 2
NRTIs. Finally, Cardiello et al (2002) recently published a cross-over study, which
demonstrated that switching 87 subjects from SQV (soft gel capsules) in full doses +2
NRTIs twice daily to a single daily dose of SQV 1600 mg and ritonavir 100 mg led to an
improvement in CD4 cell counts.
Overall, the evidence appears to be of reasonable quality and at least as good as what is
available to support the combined use of indinavir/low dose ritonavir. Adverse effects were
typical of what are seen with protease inhibitor combinations, without the problems of
nephrolithiasis, seen with IDV. Presently, saquinavir and ritonavir are not available as a
fixed dose combination preparation.
9. Comparative evidence on safety :
a) ritonavir (Note: these are adverse events as reported with a 600 mg BID dose)
Adverse effects/reactions: fatigue, nausea, diarrhoea, vomiting, anorexia, abdominal pain,
taste perversion, circumoral and peripheral parasthesias.
Laboratory abnormalities (Grade 3 or 4): anaemia, neutropenia, lymphocytopenia; elevated
cholesterol, triglycerides, CPK, AST, ALT.
b) saquinavir and saquinavir mesilate (Note: these are adverse events as reported with
11
a 600 mg TID dose. Although co-administration of low dose ritonavir significantly increases
the Cmax of saquinavir, the incidence of adverse events appears to remain similar to the
unboosted regimen.)
Adverse effects/reactions: nausea, abdominal pain, vomiting, nephrolithiasis/ urolithiasis,
headache, taste perversion, acid regurgitation, anorexia, dizziness, diarrhoea, pruritus,
fatigue, somnolence, malaise, dyspepsia, dysuria, jaundice, fever, anaemia, cough, rash,
dyspnoea.
Laboratory abnormalities (Grade 3 or 4): neutropenia, thrombocytopenia, anaemia;
elevations in gamma GT, creatine kinase, ALT, AST, glucose, potassium, total bilirubin;
decreased glucose.
Warnings:
Pancreatitis: pancreatitis has been observed in patients receiving ritonavir, including those
who developed marked triglyceride elevations. In some cases, fatalities have been
observed. Although a causal relationship to ritonavir has not been established, marked
triglyceride elevation is a risk factor for the development of pancreatitis. Patients with
advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis,
and patients with a history of pancreatitis may be at increased risk of recurrence during
ritonavir therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting,
abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or
amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs
or symptoms should be evaluated and ritonavir and/or other antiretroviral therapy should
be suspended as clinically appropriate.
Diabetes: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and
hyperglycaemia have been reported during post-marketing surveillance in HIV-infected
patients receiving protease inhibitor therapy. Some patients required either initiation or
dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In
some cases diabetic ketoacidosis has occurred. In those patients who discontinued
protease inhibitor therapy, hyperglycaemia persisted in some cases. Because these events
have been reported voluntarily during clinical practice, estimates of frequency cannot be
made and a causal relationship between protease inhibitor therapy and these events has
not been established.
Precautions:
Saquinavir (soft gelatin capsules) and saquinavir mesilate (hard gel capsules) are not
bioequivalent and cannot be used interchangeably. Only saquinavir soft gel capsules
should be used in an antiretroviral regimen comprised of two nucleoside analogues with a
single protease inhibitor. However it appears that co-prescription of low dose ritonavir
enables the use of hard gel capsules of saquinavir.
Hepatic impairment and toxicity: Saquinavir and ritonavir are principally metabolized by
the liver. Therefore, caution should be exercised when administering these drugs to
patients with hepatic impairment. Patients with underlying hepatitis B or C or marked
elevations in transaminases prior to treatment may be at risk of developing further
transaminase elevations.
Lipid elevations: Treatment with ritonavir has resulted in large increases in the
concentration of total cholesterol and total triglycerides. Cholesterol and triglyceride testing
should be performed prior to initiating treatment with ritonavir at a periodic intervals during
therapy.
Haemophilia: There have been reports of increased bleeding, including spontaneous skin
haematomas and haemarthrosis, in patients with haemophilia type A and B treated with
protease inhibitors. In some patients, additional factor VIII was given. In more than half of
the reported cases, treatment with protease inhibitors was continued or reintroduced. A
causal relationship has not been established.
Redistribution/accumulation of body fat: Redistribution/accumulation of body fat
including central obesity, dorsocervical fat enlargement, peripheral wasting, breast
enlargement, and “cushingoid appearance” have been observed in patients receiving
protease inhibitors. The mechanism and long-term consequences of these events are
currently unknown. A causal relationship has not been established.
Drug Interactions:
Ritonavir is a potent inhibitor of the P450 isozyme CYP3A. Coadministration of ritonavir
and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma
concentrations of the other drug that could increase or prolong both its therapeutic and
adverse effects.
Drugs that must not be coadministered with saquinavir or saquinavir mesilate + ritonavir:
flecainide, propafenone, astemizole, terfenadine, ergot derivatives, midazolam, triazolam,
cisapride, pimozide, lovastatin, simvastatin, rifampin, St. John's wort (Hypericum
perforatum) or St. John's wort-containing products.
Drugs which require a dose reduction when coadministered with saquinavir or saquinavir
mesilate + ritonavir: A dose of at least 75% of the usual 300 mg/day dose of rifabutin (i.e.,
maximum rifabutin dose of 150 mg every other day or three times a week) is necessary if
ritonavir and rifabutin are co-administered. Further reductions in rifabutin dose may be
required.
Co-administration of sildenafil with saquinavir, saquinavir mesilate, and/or ritonavir may
increased sildenafil concentrations (11-fold increase in AUC) and may result in an increase
in sildenfil-associated adverse events, such as hypotension, syncope, visual changes and
prolonged erection.
Drugs which may require a dose increase when coadministered with ritonavir: methadone,
atovaquone.
Drugs which require careful monitoring when coadministered with saquinavir, saquinavir
mesilate and/or ritonavir: dihydropyridine calcium channel blockers (felodipine, nifedipine,
13
nicardinpine) and HMG-CoA reductase inhibitors (atorvastatin and cerivastatin).
Other potentially clinically significant drug interactions with ritonavir: Plasma concentrations
of estrogens-based hormonal contraceptives are decreased by ritonavir; alterative or
additional contraceptive measures should be used.
Coadministration of SQV/r with other antiretrovirals:
Dosing of didanosine and saquinavir + ritonavir should be separated by 2.5 hours in order
to avoid formulation incompatibility.
c) Variation in safety due to health systems and patient factors:
Antiretroviral therapy cannot be successfully introduced in a healthcare system vacuum.
However, facilities and personnel infrastructure can be expanded in parallel with the
implementation of antiretroviral agent delivery programmes. Health care provider and
patient education, an essential health care package, and the ability to do at least limited
clinical and laboratory monitoring are all necessary to try to insure programmatic success.
It is well established that the introduction of any antimicrobial therapy for an infectious
disease is association with the induction and spread of drugs resistance as an inevitable
consequence. Although an obvious concern, this is not a reason to delay introduction of
large-scale antiretroviral therapy programmes. Rather, education of providers and patients,
attention to drug adherence, monitoring the population for drug resistance, and institution
of strategies to try to limit drug resistance are the components of an appropriate response.
It is possible that the risk of the spread of resistant viral strains in the population may be
balanced by the potential for the reduction of HIV transmission by the introduction of
antiretroviral therapy.
10. Summary of available data on comparative cost and cost-effectiveness within the
pharmacological class or therapeutic group:
No fixed dose combinations of saquinavir and ritonavir are available. Based on the
most recent data from MSF the costs of ‘typical’ regimens will be:
SQV 400 mg BID + RTV 400 mg BID (Abbott) $US 795/year
In comparison:
‘Full dose’ saquinavir mesilate (1800mg/day) costs $US 814/ year
and full dose RTV (1200mg/day) costs $US 650/ year. The prices quoted here are
the cheapest for the relevant drugs. Availability of protease inhibitors from generics
suppliers is limited and prices tend to be higher than those from ‘originator’
companies.
11. Summary of regulatory status of the medicine (in country of origin and preferably
in other countries as well): TBA
12. Availability of pharmacopoieal standards: TBA
15
Attachment 1: Results of trials of
saquinavir + low dose ritonavir
(Pages 15 – 16)
Attachment 1: summary of efficacy data
Authors
Patients
Design
SQV/r
intervention
Comparators
Changes in viral load
SQV/r
Changes in viral load
Comparator
Kirk et al
199922
269 ARV
naïve and
experienced
SQV400mg BD+
RTV400mg BD
IDV 800mg TDS
Or
RTV 600mg BD
HIV-1 <200 copies/ml
SQV/r 71% (89% in naïve
pts)
RTV 67% (57% naïve)
IDV 71% (63% naïve)
P=0.07; P<0.01 in naïve pts
Cameron
et al
199923
141 PI-naïve
SQV/r 400/400
BD
SQV/r 400/400
TDS
SQV/r 600/600 BD
SQV/r 400/400 BD –1.9
log10
“better tolerated”
Gisolf et
al 200024
208 mainly
ARV-naive
SQV 400 mg BD
RTV 400 mg BD
3/104 required intensification
of treatment
73
ARVexperienced
-0.26 log10 copies/ml
180 mainly
ARVexperienced
ROCT
(NRTIs as
shown)
SQV_SGC 800 mg
TDS
NFV 750 mg TDS
d4T 40 mg BD
IDV 800 mg TDS
2 NRTIs
- 0.71 log10 copies/ml
Florence
et al
200126
HIV-1 <400 copies/ml
SQV/r 43%
IDV + 2NRTIs 63%
Chavanet
et al
200127
Cardielo
et al
200228
31
PIexperienced
ROCT
SQV 400mg BD
RTV 400 mg BD
D4T 40mg BD
SQV-SGC 400 mg
BD
RTV 400 mg BD
d4T 40 mg BD
SQV-HGC 400
mgBD
RTV 400 mg BD
1 NRTI (NS)
SQV 600 mg BD
RTV 200 mg BD
2 NRTIs recycled
SQV/r 400/400 TDS –1.6
log10
SQV/r 600/600 BD –1.8
log10
28/104 required
intensification of treatment
Smith et
al 200125
ROCT
(all
received 2
NRTIs)
ROCT
(all had 2
NRTIs
added)
ROCT
(NRTIs as
shown)
ROCT
(NRTIs as
shown)
SQV 600 mg BD
NFV 1000 mg BD
2 NRTIs recycled
Viral load ‘stable or
decreased’ 10/16
‘More drop outs’ with SQV/r
+ 1 NRTI
Viral load ‘stable or
decreased’ 8/15
87, all ARVexperienced
Crossover
study, not
randomised
SQV1600mg daily
RTV 100 mg daily
2 NRTIs
Previously treated
with SQV_SGC
1400mg BD
2 NRTIs
CD4 count rose
CD4 count stable
17
Attachment 1: summary of adverse reaction data
Authors
Patients
Design
SQV/r
intervention
Comparators
Reported adverse effects
Kirk et al
199922
269 ARV
naïve and
experienced
SQV400mg BD+
RTV400mg BD
IDV 800mg TDS
Or
RTV 600mg BD
More subjects stopped treatment because of ADRs in the
ritonavir only group (37%) than with SQV/r (16%) or IDV
(8%) (p<0.001)
Cameron
et al
199923
141 PI-naïve
SQV/r 400/400
BD
SQV/r 400/400
TDS
SQV/r 600/600 BD
Gisolf et
al 200024
208 mainly
ARV-naive
SQV 400 mg BD
RTV 400 mg BD
73
ARVexperienced
Florence
et al
200126
180 mainly
ARVexperienced
ROCT
(NRTIs as
shown)
Chavanet
et al
200127
Cardielo
et al
200228
31
PIexperienced
ROCT
SQV 400mg BD
RTV 400 mg BD
D4T 40mg BD
SQV-SGC 400 mg
BD
RTV 400 mg BD
d4T 40 mg BD
SQV-HGC 400
mgBD
RTV 400 mg BD
1 NRTI (NS)
SQV 600 mg BD
RTV 200 mg BD
2 NRTIs recycled
The most common ADRs were diarrhea, parasthesia,
asthenia and nausea. Reversible elevations of
transaminases in 10% of subjects, more commonly with
SQV/r twice daily.
Overall, 10% of subjects discontinued medication because
of adverse events. No difference between groups.
Smith et
al 200125
ROCT
(all
received 2
NRTIs)
ROCT
(all had 2
NRTIs
added)
ROCT
(NRTIs as
shown)
ROCT
(NRTIs as
shown)
87, all ARVexperienced
Crossover
study, not
randomised
SQV1600mg daily
RTV 100 mg daily
2 NRTIs
SQV_SGC 800 mg
TDS
NFV 750 mg TDS
d4T 40 mg BD
IDV 800 mg TDS
2 NRTIs
35% of subjects in SQV/r arm discontinued treatment
because of drug intolerance or toxicity compared with 1%%
for the nelfinavir arm
SQV 600 mg BD
NFV 1000 mg BD
2 NRTIs recycled
No ADR data in abstract
Previously treated
with SQV_SGC
1400mg BD
2 NRTIs
No subject stopped treatment because of ADRs. 8/87
subjects experienced one or more grade 3 or 4 laboratory
ADRs, usually elevated ALT or lipid abnormalities.
Lipodystrophy newly observed in 13/69 subjects after
switching
Abnormal LFTs and increased lipids reported more
frequently with SQV/r than with IDV
Key: ROCT = randomised open-label clinical trial. SQV= saquinavir; RTV= ritonavir. NRTI= nucleoside reverse transcriptase inhibitor. IDV=indinavir;
NFV=nelfinavir; NRTI = nucleoside reverse transriptase inhibitor; d4T = stavudine
18
Attachment 2
Overview of protease inhibitor-based regimens including two nucleoside
analogue reverse transcriptase inhibitors:
Advantages
Disadvantages
*potent, durable antiretroviral
activity
* adherence difficult with original TID dosing
regimens; addition of ritonavir can reduce dosing to
BID or QD.
* clinical benefit established,
confirming validity of
surrogate marker
improvement
* adverse events associated with long-term
antiretroviral use, but a causal relationship has yet
to be established
Characteristics of individual drugs
Non-proprietary
name
Cost p.a. US $
Advantages
Disadvantages
Nelfinavir
$2585 including 15%
rebate in kind (Roche
USA) to $2924
(Aurobindo, India)
* well-tolerated;
* resistance profile may
allow 2nd line PI
regimen;
* twice-daily dosing;
* active against Group
O subtypes;
*mild to moderate
diarrhoea in ca 30% of
patients;
*high level resistance
usually confers crossresistance with other
protease inhibitors;
* high pill burden (10
tablets daily);
* cannot be used with
rifampin:
19
Indinavir
$600 (Merck, US) to
$985 (Hetero, India)
* active against Group
O subtypes;
*only PI to penetrate
blood/brain barrier;
* dosing regimen every
8 hours, empty stomach
or with fat-free, very low
protein snack;
*extra hydration, at
least 2 litres, required
daily;
*nephrolithiasis
reported in 9 - 43% of
users;
* moderate pill burden
(6 capsules daily);
* cannot be used with
rifampin;
* multiple potential drug
interactions
*high level resistance
usually confers crossresistance with other
protease inhibitors
Indinavir +
ritonavir
cost variable,
depending on dose see
above
*combination reduces
cost;
* allows for twice-daily
dosing;
* can be taken with
food;
* reduces hydration
requirement;
* active against GroupO
subtypes
*optimal dosing not
established;
*limited clinical data on
combination available;
* nephrolithiasis
incidence may be
increased;
* cannot be used with
rifampin;
* multiple potential drug
interactions;
Saquinavir softgel capsule
$814 (including 100%
rebate in kind) Roche
USA
*well-tolerated;
* twice daily dosing;
*active against Group O
subtypes;
* mild to moderate
diarrhoea in ca 20% of
patients;
*high pill burden (16
capsules daily);
*soft-gel capsules must
be stored in refrigerator
in warm climates; 3
month shelf-life at room
temperature (25C or
lower);
*cannot be used with
rifampin;
*high level resistance
usually confers crossresistance with other
protease inhibitors
*low level resistance to
saquinavir-sgc with only
one gene mutation will
often allow successful
switching to another
protease inhibitor
combination therapy
20
Saquinavir softgel capsule +
ritonavir
N/A
*combination reduces
cost;
* allows twice-daily
dosing (400 mg SQVsgc + 100 mg RTV);
* allows once daily
dosing (1600 mg SQVsgc + 100 mg RTV);
*optimal once-daily
dose not established;
*limited clinical data on
once-daily dosing;
*soft-gel capsules must
be stored in refrigerator
in warm climates; 3
month shelf-life at room
temperature (25C or
lower);
*cannot be used with
rifampin;
Ritonavir
$650 (Abbott US) to
$3504 (Hetero, India)
*twice-daily dosing;
*active against group O
subtypes
*adverse events mostly
GI-related, can be
severe;
* cannot be used with
rifampin;
*multiple potential drug
interactions;
*both capsule and liquid
formulations contain
alcohol;
*capsules must be
stored in refrigerator;
*liquid has 30 day shelflife at room temperature
20-25C;
*high level resistance
usually confers crossresistance with other
protease inhibitors
(only as low dose
‘boost’ therapy
with other PI
drugs)
(full dose therapy – see
above for costs of
boosted treatment)
21
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