(FCH/HIV, 22 April 2002)

Application for Inclusion of indinavir/low dose ritonavir (IDV/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 indinavir and low dose ritonavir (IDV/r) is proposed for listing on the WHO Model List of Essential Medicine. Low dose ritonavir is included in this treatment, not for its intrinsic anti-retroviral activity, but because it inhibits the metabolism of indinavir. This is sometimes known as pharmaco-kinetic ‘boosting’. 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.

Extensive library searches compiled by the Cochrane Review Group for HIV/AIDS retrieved a number of studies documenting the nature of the pharmacokinetic interaction between indinavir and ritonavir, and a modest number of clinical studies reporting on the efficacy and safety of this combination treatment.

This pharmaco-kinetic interaction between IDV and RTV leads to increased minimum concentrations of indinavir (without major changes to maximum plasma drug concentrations or area under the plasma concentration/time curve). This allows the combination treatment to be given twice daily (in contrast to three times daily with indinavir used alone), without dietary restrictions.

Indinavir in full doses is known to be an effective protease inhibitor with a potent anti-retroviral action (in combination with other drugs – usually 2 nucleoside reverse

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2transcriptase inhibitors), and has been studied in a substantial number of randomised clinical trials, which are reviewed in other submissions to the Expert Committee (see main body of this submission).

However the literature on IDV/r is more limited. The literature search uncovered only one randomised clinical trial comparing IDV/r with full dose TDS IDV treatment, one non-randomised comparative study, and 7 uncontrolled studies. These studies covered a range of different doses of IDV and RTV (see main body of text for details) and the protease inhibitor combination was given with other anti-retroviral agents, usually two nucleoside reverse transcriptase inhibitors (NRTIs). These studies provide some evidence that IDV/r is probably equi-efficacious to IDV in full doses. It is less clear whether combination therapy is associated with less toxicity than full dose IDV, and it seems safer to assume that there is no clear advantage in this respect. However, the convenience of twice daily therapy is a clear advantage. Presently IDV/r is not available as a fixed dose combination. The annual costs of treatment vary from $US 508 to $US 650, depending on the relative doses of IDV and RTV that are used.

1. Summary statement of the proposal for inclusion, change or deletion.

Indinavir + 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. Indinavir + ritonavir (IDV/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

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. Immunological 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. International Nonproprietary Names: indinavir sulfate, 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.

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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. 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: Double protease inhibitor combinations

Note: in the sub-therapeutic doses recommended here ritonavir is not being administered for its intrinsic anti-retroviral activity but because its co-administration with indinavir results in a beneficial pharmacokinetic interaction, sometimes referred to as ‘boosting’ (see section 8.4).

In clinical use, a reduced dose of indinavir (800 or 1600 mg daily - compared with 2400 mg at full doses) combined with low dose ritonavir (100 – 400 mg twice daily) increases the dosing interval from every 8 hours to twice-daily, results in a low rate of ritonavir side-effects, and alleviates both food restrictions and fluid requirements for indinavir. While indinavir in general should not be taken with 2 hours of a fatty meal, indinavir when taken in combination with low-dose ritonavir has no restrictions.

Dosage:

Adults: The regimen that provides the greatest efficacy and least toxicity has not been established. The most commonly used regimens are:

* 400 mg indinavir (BID) + 400 mg ritonavir (BID)* 800 mg indinavir (BID) + 200 mg ritonavir (BID)* 800 mg indinavir (BID) + 100 mg ritonavir (BID)

Indinavir is available in 200 mg, 333 mg and 400 mg capsules. Ritonavir is available in 100 mg capsules and 600 mg/7.5 ml solution.

Concomitant Antiretroviral Therapy: indinavir + ritonavir must be given in combination with other antiretroviral medications.

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Duration: Antiretroviral treatment is usually regarded as life-long.

Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited Settings”10 recommends ritonavir + indinavir (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 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 Embaseo AIDSLINEo CENTRAL

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: indinavir, ritonavir

oStudy 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)

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8Trials 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, 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.

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 draft WHO Antiretroviral Guidelines for Resource Limited Settings10. The summary of regimens recommended in this document is in Table 1.

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10Table 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 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 indinavir plus ritonavir? (Level 2 evidence)

Indinavir is a well studied and effective protease inhibitor. In full doses it has been included in a substantial number of trials that are the basis of submissions for other anti-retroviral drugs included in the agenda for the Expert Committee meeting (see for instance submissions for nelfinavir, stavudine, and zidovudine/lamivudine for ‘full dose’ indinavir trials).

However, in the conventional regimen indinavir is associated with certain disadvantages and toxicities. It needs to be taken with a low-fat, low-calorie, meal or at least 1 hour before, or 2 hours after, a meal. Dosing is three times per day. Toxicities include nephrolithiasis, which may be related to maximum plasma concentration (Cmax).

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.

In pharmacokinetic studies with healthy volunteers ritonavir was shown to decrease the Cmax of indinavir, increase its Cmin and not alter its area under the curve (AUC) when administered simultaneously (Hsu 1998a-c22, Saah 199923, 200124). In studies in HIV-infected patients, similar pharmacokinetic characteristics were demonstrated (Bani-Sader25 2001, Burger 199926, Hugen 199927, 200028, Mallolas 2000a-b29, van Heeswijk RPG 199930, van Rossum 200031). In particular, the Cmin of indinavir, when combined with low-dose ritonavir, has in most studies exceeded the therapeutic level needed to suppress HIV replication. It should be noted that in these studies in HIV-infected patients ritonavir does not reach therapeutic levels; its effect is due primarily to its inhibition of indinavir metabolism.

Inidinavir and low-dose ritonavir have been studied clinically in two dosage formulations, indinavir 800 mg + ritonavir 100-200 mg bid and indinavir 400 mg + ritonavir 400 mg bid.

These combinations are used in three different clinical settings: (1) as initial therapy, (2) as salvage therapy for patients failing highly active antiretroviral therapy and (3) as switch therapy to simplify regimens for patients on indinavir three times per day.

There is only one randomized controlled trial that has compared indinavir and low-dose ritonavir with full dose indinavir (Boyd, 2001)32. Boyd compared zidovudine and lamivudine + indinavir 800 mg + ritonavir 100 mg twice daily to zidovudine and lamivudine twice daily + indinavir 800 mg three times per day in nucleoside reverse-transcriptase-experienced patients. They found that viral suppression and immunologic improvement were equivalent between the two study arms at 48 weeks. Adverse events were slightly higher in the indinavir plus low-dose ritonavir arm, but permanent treatment discontinuation was equivalent between the arms.

In addition to this trial one non-randomized trial (Barreiro 2000)33 and seven uncontrolled prospective studies (Burger 200034, Casado 200035, Estrada 200036, Kempf 200137, Mallolas 2000a-b29, Moreno 200038, Workman 1999d39, 1999f40) measured virologic and/or immunologic endpoints.

Barreiro and colleagues compared the 800 mg/100 mg regimen of indinavir and ritonavir to the 400 mg/400 mg regimen but presented results for the two arms combined33.

The prospective studies found significant decreases in HIV plasma viral load from baseline and significant increases in CD4 cell counts. The longest running of these studies (Workman 1999f40) reported two patients at 2 years of therapy; the majority are in the 16 to 24 week range.

There are also two clinical series that reported high levels of viral suppression in antiretroviral therapy-naïve patients and patients switched from three times daily indinavir (Matthews 200041) and the absence of, or resolution of, nephrotoxicity (Workman 1999 a-c42). There were several different dosages used in all these studies (see table).

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12There is also a prospective cohort study, reported by Burger and colleagues (2001)43, of Dutch patients who sent serum for antiretroviral level monitoring. This study was able to compare the 800 mg/100 mg regimen of indinavir and ritonavir to the 400 mg/400 mg regimen directly. In examining the subset of patients who switched from indinavir 800 mg three times per day, they found that viral suppression was equivalent (78% and 70% respectively by intention to treat analysis) and that rates and types adverse events were comparable.

Table. Uncontrolled clinical trials of indinavir and low-dose ritonavirStudy Patients N IDV

doseRTV dose

Proportion with undetectable HIV RNA

Barreiro (2000)33 HAART failures

51 800 100 22% at 24 weeks400 400

Burger (2001)43 Mixed 9 1200 400 67% at 1 monthCasado (2000)35 HAART 59 800 100 38% at 24 weeks

43 Burger DM; Hugen PW; Aarnoutse RE; et al. A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J Acquir Immune Defic Syndr 2001 Mar 1; 26(3): 218-24.

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

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

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

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

11 National Health and Medical Researcg 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

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

failuresEstrada (2000)36 Mixed 56 800 100 43% at 12 weeksHavlir (2000)44

Hsu (2001)45

Kempf (2001)37

Shulman (2000)46

IDV switch

35 400 400 53% at 16 weeks (on-treatment analysis)

Mallolas (2000a, 2000b)

Naïve 27 800 200 94% at 32 weeks

Moreno (2000) HAART failure

32 Mixed Mixed 1.8 log10 decrease in HIV RNA at 6 months

Rockstroh (1998, 1999a, 1999b, 2000)

Naïve 90 400 400 71% at 24 weeks

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

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

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

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.

22 a) Hsu A, Granneman GR, Cao G et al. Pharmacologic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998; 42:2784-91.b) Hsu A, Granneman R, Heath-Chiozzi M, et al. Indinavir can be taken with regular meals when administered with ritonavir. Int Conf AIDS 1998;12:336 (abstract no. 22361).c) Hsu A, Granneman R, Molla A, et al. Ritonavir-indinavir combination regimen offers potential synergistic antiviral effects in addition to substantially improved pharmacokinetic profile. HIV Pathog Treat Conf 1998 Mar 13-19;:58 (abstract no. 2048).

23 Saah AJ, Winchell G, Seniuk M, Deutsch P. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) ritonavir (RTV) combinations in healthy volunteers. 6th Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4; 6:136 (abstract no. 362).

24 Saah AJ, Winchell GA, Nessly ML, Senluk MA, Rhodes RR, Deutsch PJ. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrob Agents Chemother 2001 Oct; 45(10): 2710-5.

25 Bani-Sadr F; Perré P; Peytavin G; et al. Association indinavir-ritonavir: résultats pharmacologiques et tolérance chez les patients infectés par le VIH. Presse Med 2001 Apr 21; 30(15): 731-5.

13

14Workman (1999d, 1999f)

Naïve 33 400 400 93% at 12 weeks (on-treatment analysis)

HAART, highly active antiretroviral therapy; IDV, indinavir; RTV, ritonavir

There is an ongoing trial comparing indinavir and low-dose ritonavir to efavirenz listed in AIDSTRIALS (U.S. National Library of Medicine). AIEDRP AI-07-001 is examining the safety and antiviral activity of a stavudine + didanosine + indinavir 800 mg + ritonavir 100 mg regiment to a protease-sparing stavudine + didanosine + efavirenz regimen in patients with acute and early HIV infection. 26 Burger DM; Hugen PW; Aarnoutse RE; et al. A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J Acquir Immune Defic Syndr 2001 Mar 1; 26(3): 218-24.

27 Hugen PW; Van de Ende ME; Reiss P; Lange JM; Burger DM; Prins JM. Pharmacokinetics of an indinavir/ritonavir 800/100mg bid regimen. 6th Conf Retroviruses Opportunistic Infect 1999 Jan 31-Feb 4; 6: 136 (abstract no. 363).

28 Hugen PW; Burger DM; ter Hofstede HJ; et al. Dose-finding study of a once-daily indinavir/ritonavir regimen. J Acquir Immune Defic Syndr 2000 Nov 1; 25(3): 236-45.

29 a) Mallolas J, Blanco JL, Sarasa M, et al. A dose-finding study of once-daily indinavir/ritonavir plus combivir in HIV-infected patients. 7th Conf Retroviruses Opportunistic Infect 2000 Jan 30-Feb 2;7:172 (abstract no. 512). 

b)Mallolas J; Blanco JL; Sarasa M; et al. Dose-finding study of once-daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients. J Acquir Immune Defic Syndr 2000 Nov 1; 25(3): 229-35.

30 van Heeswijk RP; Veldkamp AI; Hoetelmans RM; et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. AIDS 1999 Oct 1; 13(14): F95-9.

31 van Rossum AM; de Groot R; Hartwig NG; Weemaes CM; Head S; Burger DM. Pharmacokinetics of indinavir and low-dose ritonavir in children with HIV-1 infection [Letter]. AIDS 2000 Sep 29; 14(14): 2209-10.

32 Boyd M, Duncombe C, Newell M, et al. Indinavir/ritonavir vs indinavir in combination with AZT/3TC for treatment of HIV in nucleoside- experienced patients: a randomised, open-label trial. Conf Retroviruses Opportunistic Infect 2001 Feb 4-8;8:143 (abstract no. 335). 

33 Barreiro P; Soriano V; Oller V; González-Lahoz J. Potent activity but limited tolerance of ritonavir plus indinavir in salvage interventions [Letter]. J Acquir Immune Defic Syndr 2000 Aug 15; 24(5): 488.

34 Burger DM; Hugen PW; van der Ende ME; et al. Once-daily indinavir plus ritonavir: preliminary results of the PIPO study. AIDS 2000 Nov 10; 14(16): 2621-3.

35 Casado JL, Moreno A, Sabido R, et al. A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response. HIV Clin Trials. 2000 Jul-Aug;1(1):13-9.

36 Estrada V, De Gorgolas M, Roca V, De Villar N, Tellez MJ. Tolerance and efficacy of indinavir 800mg plus ritonavir 100mg bid in addition to nucleoside analogues in HIV infected patients. Int Conf AIDS. 2000 Jul 9-14;13: (abstract no. TuPeB3232).

37Kempf D, Hsu A, Jiang P, et al. Response to ritonavir (RTV) intensification in indinavir (IDV) recipients is

9. Comparative evidence on safety (See Attachment 1 for results from clinical studies of indinavir and low dose ritonavir):

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, neutropaenia, lymphocytopaenia; elevated cholesterol, triglycerides, CPK, AST, ALT.

b) indinavir (Note: these are adverse events as reported with a 800 mg q8h dose)

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.

highly correlated with virtual inhibitory quotient. Conf Retroviruses Opportunistic Infect. 2001 Feb 4-8;8:200 (abstract no. 523). 38 Moreno A, Casado JL, Marte-Belda P, et al. Efficacy of the combination of ritonavir plus indinavir plus a nonnucleoside reverse transcriptase inhibitor in patients failing multiple antiretroviral regimens: pharmacokinetic and resistance data (NIVELPROT study). Int Conf AIDS. 2000 Jul 9-14;13:abstract no. WePeB4159.

39 Workman C, Whittaker W, Forrester J, Dyer W, Sullivan J. Combining ritonavir (RTV) & indinavir (IDV) decreases IDV-associated urinary & renal adverse events (AES). Annu Conf Australas Soc HIV Med 1999d Dec 9-11;11:145 (abstract no. P40).

40Workman C, Whittaker W, Forrester J, Dyer W, Sullivan J. Virologic & immunologic response to combination protease inhibitor (PI) therapy with ritonavir (RTV) & indinavir (IDV) in antiretroviral naive HIV+ patient. Annu Conf Australas Soc HIV Med. 1999f Dec 9-11;11:48 (abstract no. OR18). 41 Matthews G, Gazzard B, Nelson M. Combination indinavir/ritonavir in clinical practice. Int Conf AIDS 2000 Jul 9-14;13:(abstract no. WePeB4135). 

42 a) Workman C, Whittaker W, Dyer W, Sullivan J. Combining ritonavir and indinavir decreases IDV associated nephrolithiasis. 6th Conf Retroviruses Opportunistic Infect 1999a Jan 31-Feb 4; 6:195 (abstract no. 677).

b) Workman C, Whittaker W, Dyer W, et al. Combining ritonavir (RTV) & indinavir (IDV) decreases IDV-associated urinary & renal adverse events (AES). Eur Conf Clin Aspects Treatment HIV Infect 1999b Oct 23-27; 7: (abstract no. 116).

c) Workman C, Whittaker W, Dyer W, et al. Virologic & immunologic response to combination protease inhibitor (PI) therapy with ritonavir (RV) & indinavir (IDV) in antiretroviral naïve HIV+ patients. Eur Conf Clin Aspects Treatment HIV Infect 1999c Oct 23-27; 7: (abstract no. 6201).

15

16Laboratory abnormalities (Grade 3 or 4): neutropaenia, anaemia, thrombocytopaenia; elevations in total serum bilirubin, ALT, AST, amylase, glucose, creatinine.

Warnings:

Nephrolithiasis/Urolithiasis: Nephrolithiasis/urolithiasis has occurred with indinavir therapy. The frequency of nephrolithiasis, as reported in clinical trials, is substantially higher in paediatric patients (29%) than in adult patients (9.3%). However in adults nephrolithiasis has been reported in up to 43% of recipients of full dose indinavir47. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without haematuria or microscopic haematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered.

Also, although the early reports of indinavir with low dose ritonavir didn’t report nephrolithiasis, the BEST study found nephrolithiasis in 20% of the ind/rit BID arm vs. 7% of the ind q8H arm48

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.

Haemolytic anaemia: Acute haemolytic anaemia, including cases resulting in death, has been reported in patients treated with indinavir. Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be instituted, including discontinuation of indinavir.

Precautions:

Hepatic impairment and toxicity: Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug 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.

Hepatitis: Hepatitis, including cases resulting in hepatic failure and death, has been reported in patients treated with indinavir. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between indinavir and these events has not been established

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.

Hyperbilirubinaemia: Indirect hyperbilirubinaemia has occurred frequently during treatment with indinavir and has infrequently been associated with increases in serum transaminases. It is not known whether indinavir will exacerbate the physiologic hyperbilirubinaemia seen in neonates

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 indinavir + 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.

17

18Drugs which require a dose reduction when coadministered with indinavir + 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 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 ritonavir:ritonavir increases plasma concentrations of dihydropyridine calcium channel blockers (felodipine, nifedipine, nicardinpine) and HMG-CoA reductase inhibitors (atorvastatin and cerivastatin).

Other potentially clinically significant drug interactions with ritonavir + indinavir: carbamazepine, phenobarbital, phenytoin, and dexamethasone may decrease indinavir plasma concentrations. Plasma concentrations of estrogen-based hormonal contraceptives are decreased by ritonavir; alterative or additional contraceptive measures should be used.

Coadministration of ritonavir with other antiretrovirals:

Dosing of didanosine and 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. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 2.]

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. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 15.]

10. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:

No fixed dose combinations of indinavir and low dose ritonavir are available. Based on the most recent data from MSF the costs of ‘typical’ regimens will be:IDV 800mg BD (Merck) + RTV 100mg BD (Abbott) $US 508/ yearIDV 800mg BD (Merck) + RTV 200mg BD (Abbott) $US 617/ yearIDV 400mg BD (Merck) + RTV 400mg BD (Abbott) $US 633/ yearIn comparison:‘Full dose’ IDV (2400mg/day) costs $US 600/ yearand full dose RTV (1200mg/day) costs $US 650/ yearThe 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

19

20

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

(Pages 18 – 23)

Attachment 1: Results of indinavir plus low-dose ritonavir (IDV/r) trialsAUTHOR METHODS BENEFITS TOLERABILITY AND ADVERSE EFFECTS

PATIENTS DETAILS IDV/r regimen Comparator regimen IDV/r regimen Comparator regimenBarreiro et al 200033

PI experienced, HAART failures

Non randomizedNRTIs plus1. IDV 800

mg + RTV 100 mg bid

2. IDV 400 mg + RTV 400 mg bid

N=51

HIV RNA undetectable at 24 weeks Discontinuation of therapy <3 monthsIDV/r (both arms) 22% (ITT), 75% on-treatment analysis

No comparison arm 22 (43%)

Nausea/vomiting 15Dyspepsia 3Diarrhea 2Elevated LFTs 1Renal stones 1

No comparison arm

Increase in CD4 cells/ml at 6 months (patients with successful viral suppression only)

IDV/r (both arms) 199 ± 89

No comparison arm

Boyd et al 200132

NRTI experienced (≥3 months ZDV at entry)

N=104

RCTOpenZDV+3TC and1. IDV 800

mg tid2. IDV 800

mg/RTV 100 mg bid

Virologic response at 48 weeks Drug interruptions/dose reductionsDecrease in log10 HIV RNA:IDV/r 1.6 (0.3-2.6) (NS)

% of patients with VL < 50 copies IDV/r 66% (NS)

IDV tid 2.0 (0.4- 2.)

IDV tid 70%

IDV/r 20/50 (40%) (p=0.09)

Adverse events:Nausea

IDV/r 68% (p=0.04) Dry mouth

IDV/r 46% (p=0.02). Hyperbilirubinaemia (>2.5*ULN)

IDV/r 34% (p=0.09) Nephrolithiasis (± flank/back pain ± haematuria ± dysuria) was seen in 20 patients IDV/r 17% (p=0.08).

IDV tid 14/54 (26%)

IDV tid 48%

IDV tid 24%

IDV tid 20%

IDV tid 22%Increase in CD4+ cells/ml Permanent treatment discontinuation

IDV/r 70 (-11-128) 57 (-1-128) IDV/r 8/50 (16%) IDV tid (9/54) 17%

21

22

Burger et al 200126

Registry of Dutch patients on HAART who sent serum for drug monitoring

N=132

Questionnaire response rate 72% in 400/400 group and 77% in 800/100 group

Cohort study1. IDV 800

mg + RTV 100 mg (N=100, 10% ART naïve)

2. IDV 400 mg + RTV 400 mg (N=32, 17% ART naïve)

HIV RNA below limit of detection among those who switched from IDV 800 mg tid

Discontinuation of therapy for side effects among those who switched from IDV 800 mg tid

N=41 (2 had HIV-2)IDV/r 800/100 78% (ITT)

Among patients in whom HIV RNA undetectable before switch 24/26 (92%)

Among patients in whom HIV RNA detectable before switch 8/15 (53%)

N=10IDV/ r 400/400 70% (ITT)

Among patient s in whom HIV RNA undetectable before switch 6/6 (100%)

Among patients in whom HIV RNA detectable before switch 1/4 (25%)

N=43IDV/r 800/100 23%

N=10IDV/r 400/400 40%

Side effects reported by >5% (all patients responding to questionnaire)

IDV/R 800/100N=77Nausea/vomiting 22%Nephrotoxicity 14%Lipodystrophy 13%Hyperbilirubinemia 12%Skin reaction 13%

IDV/R 400/400N=23Nausea/vomiting 35%Nephrotoxicity 9%Lipodystrophy 4%

Burger et al 200034

PIPO

6/9 pretreated and failed, 2/9 ART naïve, 1/9 pretreated and suppressed.

N=9

UncontrolledIDV 1.2 gm + RTV 400 mg plus existing NRTIs and NNRTIs

HIV RNA at 1 month <500 copies/ml (baseline 89,000 copies/ml)

Subtherapeutic concentrations only in patients using concurrent NVP or EFV. “Regimen well tolerated with no signs of renal toxicity except slight increase in serum creatinine level, which stabilize after 3 months.”

IDV/r 67% (2/2 ART naïve, 4/6 treatment experienced)

No comparison arm

CD4 cells/ml at 3 months (baseline 70 cells/ml)

IDV/r 170 No comparison arm

Casado et al 200035

HAART experienced, failing therapy (mean duration 44 months; ,78% and 39% had failed regimens with IDV or RTV)

N=59

Uncontrolled2 NRTIs plus IDV 800 mg bid + RTV 100 mg bid

Virologic response at 24 weeks Nephrolitiasis, hematuria, or flank pain 13/59 (22%)

Premature discontinuation 6/59 (10%).

Decrease in HIV RNA >1 log10IDV/r 61%

HIV RNA <50 copies/ml38%

No comparison arm

IDV Cmin plasma levels (mg/L)Median 1.75 mg/L, (IQR 1.07-2.57)

No comparison arm

Estrada et al 200036

26/56 (46%) HAART experienced and failing therapy24/56 (43%) ART naïve6/56 (11%) IDV switch to bid

N=56

Uncontrolled2 NRTIs plusIDV 800 mg + RTV 100 mg bid

HIV RNA <400 copies/ml at 12 weeks “32 patients (57%) discontinued IDV/R 2.92 months after initiation (range 1-10). Main reasons for discontinuation were digestive intolerance in 18 cases (56%) and nephrolithiasis in 6 (18%).”

IDV/r 43%

ART naïve 58%HAART failure 19%

No comparison arm

Increase in CD4 cells/ml at 3 monthsIDV/r +66

ART naïve +148HAART failure +7

Havlir et al 200044

Hsu 200145

Kempf 200149

Shulman 200046

M98-985

HAART experienced, IDV tid switch

N=35

Uncontrolled2 NRTIs plusIDV 400 mg + RTV 400 mg bid

HIV RNA <50 copies/ml at week 16(on-treatment analysis)

“12 of 17 discontinuations at wk 36 were due to drug-related AEs. The most commonly reported AE of at least moderate severity and probable or possible relationship to drug was diarrhea (16 of 37 patients). 22 of 37 patients had Grade 3/4 cholesterol or triglyceride elevations.” (Hsu 2001)

IDV/r 9/17 (53%)IDV Cmin levels µg/ml

IDV/r 0.54 with no change in AUC

23

24

Mallolas et al 2000a29

Mallolas et al 2000b29

ART naïve

N=27

UncontrolledInitial therapy with ZDV + 3TC + IDV 800 mg bid + RTV 100 mg bid. Switch at W8:1. IDV/r

1000/100 qd (N=9)

2. IDV/r 800/200 qd (N=7)

Group 1 switched to 800/200 qd at W12

HIV RNA <5 copies/ml at 32 weeks 11/27 (40%) discontinued in first 4 weeks due to clinical progression (N=3) or grade 1-2 RTV-related side effects (N=8)

IDV/r 800/200 qd 15/16 (94%)

No comparison arm

IDV Cmin <0.1 µg/ml (trough level inconsistent with viral suppression)

IDV/r 800/200 qd 1/16 (6%)

IDV/r 1000/100 qd 4/9 (44%)

Matthews 200041

30/96 (31%) ART naïve, 22/96 (23%) IDV tid switch,44/96 (46%) HAART failures

N=96

Clinical seriesIDV/r in different regimens (66% IDV 800 mg + RTV 100 mg)

HIV RNA <500 copies/ml (<50 copies/ml) at 6 months (ITT)

“Only 6 patients stopped due to virological failure (all in SA [salvage] grp), 24 (25%) stopped due to R[TV] intolerance. Only 1 patient developed nephrolithiasis. Median chol rise was >1.6 mmol in all groups. Doses > 100 mg were stopped twice as often as 100 mg.”

ART naïve 81% (71%)

Switch 86% (86%)

HAART failure 45% (30%)

No comparison arm

Moreno 200038

NIVELPROT

HAART failure29/32 (91%) and 20/32 (63%) had prior IDV and RTV therapy

N=32

UncontrolledNNRTI (EFV [N=25] or NVP [N=7]) plus IDV/r (different doses, 800/100 [N=11] or 400/400 [N=13] most common)

Decrease in HIV RNA at 6 months “Drug-related adverse events appeared in 20 patients (63%), mainly due to gastrointestinal disturbance secondary to RTV liquid formulation, leading to withdrawal in 8 cases (25%). Dose adjustement was necessary in 15 cases (47%), mostly requiring a change from the 400/400 regimen to the 100/800 (8 cases, p = 0.02).”

IDV/r 1.8 log10 (+0.2 to -3)

No comparison arm

IDV Cmin

1.70 µg/ml (range 0.06-4.74)

No comparison arm

Rockstroh 199850

Rockstroh 1999a51

Rockstroh 1999b52

Rockstroh 200053

ART naïve

N=90

Uncontrolled Open2 NRTIs plusIDV 400 mg + RTV 400 mg bid

HIV RNA <500 copies/ml (<80 copies/ml) at 24 weeks

“The quadruple therapy was well tolerated except for mild diarrhoea, initial nausea and increased triglyceride levels. Treatment was stopped in seven (7.7%) patients because of adverse events and three (3.3%) were lost to follow-up.”

IDV/r 87% (71%) No comparison arm

Workman 199754

12/36 (33%) ART naïve,

Controlled trial?

No results in abstract No results in abstract

50 Rockstroh JK, Bergmann F, Wiesel W, Rieke A, Nadler M, Knechten H. Efficacy and safety of bid firstline ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. Intersci Conf Antimicrob Agents Chemother. 1998 Sep 24-27;38:432 (abstract no. I-213).

51 Rockstroh JK, Bergmann F, Wiesel W, Rieke A, Nadler M, Knechten H. Efficacy and safety of bid firstline ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. 6th Conf Retroviruses Opportunistic Infect 1999 Jan 31-Feb 4; 6:186 (abstract no. 631).

49 Kempf D, Hsu A, Jiang P, et al. Response to ritonavir (RTV) intensification in indinavir (IDV) recipients is highly correlated with virtual inhibitory quotient. Conf Retroviruses Opportunistic Infect. 2001 Feb 4-8;8:200 (abstract no. 523).

52 Rockstroh J, Bergmann F, Wiesel W, et al. BID first-line ritonavir/indinavir 400/400 MG plus double nucleoside combination therapy. Eur Conf Clin Aspects Treatment HIV Infect 1999 Oct 23-27; 7: (abstract 452).

53 Rockstroh JK, Bergmann F, Wiesel W, Rieke A, Theisen A. Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. German Ritonavir/Indinavir Study Group. AIDS 2000; 14:1181-5.

25

2612/36 (33%) IDV and RTV naïve, 12/36 (33%) suppressed on SQV/r

N=36

IDV/r (dosage not stated)

Workman 1999a42

Workman 1999b42

Workman 1999c42

On IDV/r therapy, mean 45 weeks, median 40 weeks

N=57

Clinical seriesIDV 400 mg + RTV 400 mg bid

No efficacy data in abstract “No cases of nephrolithiasis, haematuria, flank pain or other urinary or renal AEs [adverse events] were found. No patients experienced creatinine elevations of >20% of baseline values; no patients had sustained elevations of creatinine beyond the normal range.”

Workman 1999d39

Workman 1999f*40

ART naïve

N=33

Uncontrolled Open3TC/d4T plus IDV 400 mg + RTV 400 mg bid

Virologic response <400 copies/ml (except at 12 weeks, <1000 copies/ml; on treatment analysis)

“No cases or urinary or renal adverse events occurred.”

At W12:IDV/r 25/27 (93%)

At W24:IDV/r 23/24 (96%)

At W52:14/14 (100%)

At Wk 104:2/2 (100%)

No comparison arm

Increase in CD4 cells/mlAt W 12:IDV/r 166

At W24:IDV/r 204

At W52:IDV/r 287

No comparison arm

Key: 3TC, lamivudine; ART, antiretroviral therapy; AUC, area under the curve; bid, twice daily; Cmin, trough concentration of drug; HAART, highly active antiretroviral therapy (≥2 drugs from ≥2 classes); IDV, indinavir; IDV/r, indinavir plus low-dose ritonavir (100-400 mg bid); ITT, intention-to-treat analysis; LFT, liver function tests; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; qd, daily; RTV, ritonavir; SQV, saquinavir; ULN, upper limit of normal; ZDV, zidovudine

27

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;* multiple potential drug interactions

28

*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-gel capsule

$814 (including 100% rebate in kind) Roche USA

*well-tolerated;* 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

* 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 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 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

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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

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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.

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.

44 Havlir D, Gallant J, Race E, et al. Ritonavir intensification in indinavir recipients: Tolerance, antiviral effect and pharmokinetics. Int Conf AIDS 2000 Jul 9-14;13:abstract no. WePeB4122.

45 Hsu A, Zolopa A, Shulman N, et al. Final analysis of ritonavir (RTV) intensification in indinavir (IDV) recipients with detectable HIV RNA levels. Conf Retroviruses Opportunistic Infect 2001 Feb 4-8;8:143 (abstract no. 337).

46 Shulman N, Zolopa A, Havlir D, et al. Ritonavir intensification in indinavir recipients with detectable HIV RNA levels. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7:176 (abstract no. 534).

47 Saltel et al. J Urol 2000 Dec;164(6):1895-7

48 Cahn P et al. Continued indinavir versus switching to indinavir + ritonavir in HIV patients having achieved viral load suppression. A randomised study: The BID Efficacy and Safety Trial. Abstract 60. 1st IAS Conference on HIV Pathogenesis and Treatment. July 8-11, 2001. Buenos Aires, Argentina .

54 Workman C, Mussen R, Dyer W, Sullivan J. Indinavir-ritonavir in combination therapy: safety, antiviral and immunological activity. Annu Conf Australas Soc HIV Med. 1997 Nov 13-16;9:134 (poster no. P37).

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