Application for Inclusion of indinavir/low dose ritonavir on who model List of E

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(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 transcriptase 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
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.
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.
1The 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.
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.
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:

  • The Cochrane Data-base of Systematic Reviews

  • The ACP Journal Club reviews of published trials

  • The data-base of reviews of abstracts of reviews of effectiveness (DARE)

  • The Cochrane controlled trials register (CCTR)

  • Medline

  • Embase



Search terms used were:

  • Anti-retroviral or antiretroviral

  • Nucleoside reverse transcriptase inhibitors

  • Non-nucleoside reverse transcriptase inhibitors

  • Protease inhibitors

  • Randomised clinical trial (exploded and as text word)

  • Individual drug names: indinavir, ritonavir

Study selection:

  • Randomised comparative parallel-group controlled clinical trials

  • Examined the performance of indinavir/ritonavir when included in combinations comprising 3 or more drugs, involving concomitant use of NRTIs, NNRTIs or other PIs.

Categorisation of levels of evidence

The following rating scheme was used11:

  • Level 1 – evidence from relevant high quality systematic reviews of unbiased randomised comparative clinical trials

  • Level 2 – evidence from at least one relevant unbiased randomised comparative clinical trial.

  • Level 3 – evidence from relevant controlled observational studies

Additional considerations for use in resource-poor settings

  • Co-morbidity

  • Simplicity (frequency of dosing, number of tablets)

  • Tolerability

  • Cost

  • Prior exposure to ARVs

General therapeutic issues: (common to the therapeutic category of anti-retroviral drugs)

  1. What is the validity of surrogate markers as predictors of morbidity and mortality in patients with HIV/AIDS?

  2. What evidence is there that triple (or quadruple) ARV therapy is superior to single or dual therapy?

Class specific questions

  1. Which combinations of drug classes have the best evidence in relation to benefits and harms?

Agent-specific questions

  1. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations that include didanosine?


  1. What is the validity of surrogate markers as predictors of morbidity

and mortality in patients with HIV/AIDS? (Level 3 evidence)
Trials of anti-retroviral compounds have relied heavily on measuring the effects of drugs on surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA levels. The validity of these markers depends on showing that they are correlated with clinical outcomes, and that they should be able to capture the effects of treatment on the major clinical outcomes12. Both of these markers may be viewed as being on the ‘causal pathway’ between viral infection and disease outcomes, but more directly in the case of viral measures. The viral end-point has come to be regarded as superior to a measure as a prognostic marker, although results have not been entirely consistent. A meta-analysis of trials of 2 NRTIs (plus NNRTI or PI), which included 36 treatment arms, found that baseline CD4 counts were significantly correlated with virologic suppression at 6 and 12 months, whereas a similar correlation was not found with baseline viral load and subsequent viral suppression13. The authors concluded that baseline CD4 cell count was a better predictor of drug induced viral suppression than baseline viral load. In the other meta-analysis of surrogate measures uncovered by the literature search, Hill et al reviewed results from 15 randomised trials that used surrogate markers and also included measures of disease progression14. This review included data from 15038 patients, of whom 3532 patients progressed to clinical outcomes. The analyses documented that there were significant correlations between the relative hazards for clinical progression and changes in both 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.

  1. 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.

  1. 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.

Table 1. Recommended First-Line Antiretroviral

Regimens in Adults


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


- 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

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