(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 anti-retroviral 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

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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.

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/AIDS3. 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.

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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. Sixty-five 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).

7. Treatment details:

In clinical use, a reduced daily dose of saquinavir mesilate (SQV-hgc) or saquinavir (SQV-sgc) 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

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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 Reviewso The ACP Journal Club reviews of published trialso The data-base of reviews of abstracts of reviews of effectiveness (DARE)o The Cochrane controlled trials register (CCTR)o Medlineo Embase

Search terms used were:

o Anti-retroviral or antiretroviralo Nucleoside reverse transcriptase inhibitorso Non-nucleoside reverse transcriptase inhibitorso Protease inhibitorso Randomised clinical trial (exploded and as text word)o Individual drug names: saquinavir, ritonavir

Study selection:

o Randomised comparative parallel-group controlled clinical trialso 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 evidenceThe 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 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 questions3. Which combinations of drug classes have the best evidence in relation to benefits

and harms?

Agent-specific questions4. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations

that include didanosine?

Results1. 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 HIV-1 RNA levels and CD4 cell counts. The authors concluded that these markers, together,

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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 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 Pregnancy Considerations

Major Toxicities

ZDV/3TC plus EFV* or NVP*

- Substitute NVP for EFV in pregnant women or women for whom effective contraception cannot be assured

- ZDV-related anemia- EFV-associated CNS symptoms- Possible teratogenicity of EFV- NVP-associated hepatotoxicity and severe rash

ZDV/3TC/ABC* - ABC safety data limited

- ZDV-related anemia- ABC hypersensitivity

ZDV/3TC** plus RTV enhanced PI or NFV

- LPV/r safety data limited - NFV: most supportive safety data

- 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 besubstituted 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)

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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 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

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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, 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:

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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/ yearand 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

Attachment 1: Results of trials of saquinavir + low dose ritonavir

(Pages 15 – 16)

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Attachment 1: summary of efficacy data

Authors Patients Design SQV/r intervention

Comparators Changes in viral loadSQV/r

Changes in viral loadComparator

Kirk et al 199922

269 ARV naïve and experienced

ROCT(all received 2 NRTIs)

SQV400mg BD+RTV400mg BD

IDV 800mg TDSOrRTV 600mg BD

HIV-1 <200 copies/mlSQV/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 ROCT(all had 2 NRTIs added)

SQV/r 400/400 BD

SQV/r 400/400 TDSSQV/r 600/600 BD

SQV/r 400/400 BD –1.9 log10“better tolerated”

SQV/r 400/400 TDS –1.6 log10SQV/r 600/600 BD –1.8 log10

Gisolf et al 200024

208 mainly ARV-naive

ROCT(NRTIs as shown)

SQV 400mg BDRTV 400 mg BDD4T 40mg BD

SQV 400 mg BDRTV 400 mg BD

3/104 required intensification of treatment

28/104 required intensification of treatment

Smith et al 200125

73 ARV-experienced

ROCT(NRTIs as shown)

SQV-SGC 400 mg BDRTV 400 mg BDd4T 40 mg BD

SQV_SGC 800 mg TDSNFV 750 mg TDSd4T 40 mg BD

- 0.71 log10 copies/ml -0.26 log10 copies/ml

Florence et al 200126

180 mainly ARV-experienced

ROCT(NRTIs as shown)

SQV-HGC 400 mgBDRTV 400 mg BD1 NRTI (NS)

IDV 800 mg TDS2 NRTIs

HIV-1 <400 copies/mlSQV/r 43%

IDV + 2NRTIs 63%

‘More drop outs’ with SQV/r + 1 NRTI

Chavanet et al 200127

31 PI-experienced

ROCT SQV 600 mg BDRTV 200 mg BD2 NRTIs recycled

SQV 600 mg BDNFV 1000 mg BD2 NRTIs recycled

Viral load ‘stable or decreased’ 10/16

Viral load ‘stable or decreased’ 8/15

Cardielo et al200228

87, all ARV-experienced

Crossover study, not randomised

SQV1600mg dailyRTV 100 mg daily 2 NRTIs

Previously treated with SQV_SGC 1400mg BD2 NRTIs

CD4 count rose CD4 count stable

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

ROCT(all received 2 NRTIs)

SQV400mg BD+RTV400mg BD

IDV 800mg TDSOrRTV 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 ROCT(all had 2 NRTIs added)

SQV/r 400/400 BD

SQV/r 400/400 TDSSQV/r 600/600 BD

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.

Gisolf et al 200024

208 mainly ARV-naive

ROCT(NRTIs as shown)

SQV 400mg BDRTV 400 mg BDD4T 40mg BD

SQV 400 mg BDRTV 400 mg BD

Overall, 10% of subjects discontinued medication because of adverse events. No difference between groups.

Smith et al 200125

73 ARV-experienced

ROCT(NRTIs as shown)

SQV-SGC 400 mg BDRTV 400 mg BDd4T 40 mg BD

SQV_SGC 800 mg TDSNFV 750 mg TDSd4T 40 mg BD

35% of subjects in SQV/r arm discontinued treatment because of drug intolerance or toxicity compared with 1%% for the nelfinavir arm

Florence et al 200126

180 mainly ARV-experienced

ROCT(NRTIs as shown)

SQV-HGC 400 mgBDRTV 400 mg BD1 NRTI (NS)

IDV 800 mg TDS2 NRTIs

Abnormal LFTs and increased lipids reported more frequently with SQV/r than with IDV

Chavanet et al 200127

31 PI-experienced

ROCT SQV 600 mg BDRTV 200 mg BD2 NRTIs recycled

SQV 600 mg BDNFV 1000 mg BD2 NRTIs recycled

No ADR data in abstract

Cardielo et al200228

87, all ARV-experienced

Crossover study, not randomised

SQV1600mg dailyRTV 100 mg daily 2 NRTIs

Previously treated with SQV_SGC 1400mg BD2 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

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

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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 cross-resistance with other protease inhibitors;* high pill burden (10 tablets daily);* cannot be used with rifampin:

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;

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* multiple potential drug interactions*high level resistance usually confers cross-resistance 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 soft- $814 (including 100% *well-tolerated; * mild to moderate

1 Blatt SP et al. Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIV-infected persons. JAMA 1993 Feb 3;269(5):622-6

2 French N, Mujugira A, Nakiyingi J, Mulder D, Janoff EN, Gilks CF. Imunological and clinical staging in HIV-1-infected Ugandan adults are comparable and provide no evidence of rapid progression but poor survival with advanced disease. J AIDS 1999;22:509-516.

4 AIDS Drug Policy. Ministry of Health Brazil. Available at http://www.aids.gov.br/assistencia/aids_drugs_policy.htm

5 Improving access to antiretroviral therapy in Latin America. reference to Argentina program. Family Health International. Available at http://www.fhi.org/en/aids/impact/iohiv/ioh11/ioh16.html

6 Djomad G, Roels T, Chorba T, Diomandé F, Nkengasong J, Monga B, Maurice C, Wiktor SZ. HIV/AIDS Drug Access Initiative: Preliminary report covering the period August 1998-March 2000. Ministère de la Santé, Programme National de Lutte contre le SIDA/MST/TUB, République de Côte d’Ivoire, May 2000. Available at: www.unaids.org/publications/documents/care/UNAIDS_DAI/cote_ivoire_drug_access_initiative.doc

8 d’Adesky A-C, HIV meds come to rural Haiti, The AmFAR Treatment Insider, October-November 2001 2(5):5-8. Available at: http://199.105.91.6/treatment/HIV+/insidermenu.html.

9 S. Pujari, E. Naik, A. Patel, and S. Bhagat. Safety, Tolerability, and Efficacy of Nevirapine-Based HAART amongst Antiretroviral Naïve HIV-1-Infected Patients in India. Paper presented at the 9 th Retrovirus Conference, Washington State Convention and Trade Center, Seattle, February 24th-28th 2002. Available at www.retroconference.org

10 World Health Organisation. ‘Scaling up antiretroviral therapy in resource-limited settings: Guidelines for a public health approach’. WHO 2002.

11 National Health and Medical Research Council of Australia. How to use the evidence: assessment and application of scientific evidence. Available at: http://www.nhmrc.gov.au/publications/pdf/cp69.pdf

12 Gilbert, PB et al. Virologic and Regimen Termination Surrogate End Points in AIDS Clinical Trials. JAMA 2001; 285: 777-784

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gel capsule rebate in kind) Roche USA

* twice daily dosing;*active against Group O subtypes;

*low level resistance to saquinavir-sgc with only one gene mutation will often allow successful switching to another protease inhibitor combination therapy

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 cross-resistance with other protease inhibitors

Saquinavir soft-gel capsule + ritonavir

N/A *combination reduces cost;* allows twice-daily dosing (400 mg SQV-sgc + 100 mg RTV);* allows once daily dosing (1600 mg SQV-sgc + 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

13 Skowron, G. Base Line CD4 Cell Count, Not Viral Load, Correlates with Virologic Suppression Induced by Potent Antiretroviral Therapy. Journal of Aquired Immune Deficiency Syndrome 2001; 28: 313-319

14 Hill, AM et al. Meta-Analysis of Antiretroviral Effects on HIV-1 RNA, CD4 Cell Count and Progression to AIDS or Death. Antiviral Therapy 1998; 3: 139-145.

15 Babiker A et al. Human immunodeficiency virus type I RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis. AIDS Research and Human Retroviruses 2000; 16: 1123-1133.

16 Carpenter, CCJ et al. Antiretroviral Therapy in Adults: Updated Recommendations of the International AIDS Society – USA Panel (Consensus Statement). JAMA: 2000; 283: 381-390

17 Gallant, JE. Strategies for Long-term Success in the Treatment of HIV Infection. JAMA 2000; 283: 1329-1334

18 World Health Organization. Safe and Effective Use of Antiretroviral Treatments in Adults with particular reference to resource limited settings. WHO/HSI/2000.04

19 Rutherford, GW et al. Three- or Four- versus Two-Drug Antiretroviral Maintenance Regimens for HIV Infection. Cochrane Database of Systematic Reviews. Issue 1, 2002

20 Darbyshire, J et al. (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV Infected Adults. Cochrane Database of Systematic Reviews. Issue I, 2002

21 Jordan et al. Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy. BMJ 2002;324: 1-10

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lower);*cannot be used with rifampin;

Ritonavir(only as low dose ‘boost’ therapy with other PI drugs)

$650 (Abbott US) to $3504 (Hetero, India)

(full dose therapy – see above for costs of boosted treatment)

*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 shelf-life at room temperature 20-25C;*high level resistance usually confers cross-resistance with other protease inhibitors

22 Kirk O et al . Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999; 13: F9-F16

23 Cameron DW et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999; 13: 213-224

24 Gisolf EH et al. The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine. Prometheus Study Group. AIDS 2000; 14: 405-413

25 Smith D et al. A randomised trial of nelfinavir, ritonavir, or delavirdine in combination with saquinavir-SGC and stavudine in treatment-experienced HIV-1 infected patients. HIV Clin Trials 2001; 2: 97-107

26 Florence E et al. Antivir Ther 2001; 6: 255-262

27 Chavanet P et al. Randomized salvage therapy with saquinavir-ritonavir versus saquinavir-nelfinavir for highlyb protease inhibitor-experienced HIV-infected patients. HIV Clin Trials 2001; 2: 408-412

28 Cardielo PG et al. Simplifying protease inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/ritonavir (1600/100mg): HIVNAT 001.3 study. J AIDS ;29: 464-470

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3 Joint United Nations Programme on HIV/AIDS. ‘AIDS epidemic update -- December 2001.’ Available at: http://www.unaids.org/epidemic_update/report_dec01/index.html

7 Source: Laurent C, Diakhaté N, Ngom Gueye NF, Touré MF, Sow PS, Faye MA, Gueye M, Lanièce I, Touré Kane TC, Liégeois F, Vergne L, Mboup S, Badiane S, Ndoye I, Delaporte E. The Senegalese government HAART initiative: an 18- month follow- up study of feasibility, effectiveness, adherence, toxicity and viral resistance. [Abstract and Poster 460-W] 9th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, USA, February 24 - 28, 2002.

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