(FCH/HIV, 22 April 2002)

Application for Inclusion of lopinavir/low dose ritonavir (LPV/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 lopinavir and low dose ritonavir (LPV/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 lopinavir. 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 details of 5 randomised clinical trials involving LPV/r. The clinical evidence for LPV/r appears more comprehensive than for another protease inhibitor combination being considered for listing – indinavir/ritonavir (IDV/r). Three trials in ARV-naïve subjects documented high rates of viral suppression when LPV/r was combined with two NRTIs, usually a combination of d4T and 3TC. LPV/r, as a single dose, is equi-effective to the drug given twice daily, and in combination with d4T and 3TC, LPV/r was found to be superior to a nelfinavir-containing combination. In two trials, LPV/r was found to be a potent rescue therapy in subjects who had increased viral loads despite treatment with multiple ARVs.

1

Presently LPV/r is available as a fixed dose combination from 2 manufacturers. The annual costs of treatment vary from $US 650 to $US 1916.

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

Combination treatment with lopinavir and ritonavir is 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. Lopinavir and low dose ritonavir (LPV/r) is marketed as a fixed dose combination product. Other examples of the protease inhibitor group may sometimes be preferred when local factors such as availability and price are taken into account.

Antiretroviral therapy is recommended for HIV-infected children, adolescents, and adults with symptomatic disease, and also for asymptomatic patients with CD4+ cell counts at or below 200/mm3. Where CD4+ cell testing is unavailable, clinicians can use the presence of a total lymphocyte count below 1200/mm3, but only in symptomatic patients.1,2

2. Name of the focal point in WHO submitting the application:

HIV/AIDS Department at WHO; the person responsible is Dr Dr Bernhard Schwartländer, Director of Evidence and Policy.

3. Name of the organization(s) consulted and/or supporting the application:

Supporting letters may be submitted – please contact Dr Robin Gray (WHO/EDM) at grayr@who.int

4. International Nonproprietary Name: Co-formulated lopinavir + ritonavir

5. Listing Type Requested:

Listing is requested on the Model List of Essential Medicines as an example 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

2

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.

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

3

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

4

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

Recommended Dosage: Adults and adolescents over the age of 12 years: 400 mg lopinavir with 100 mg ritonavir twice daily taken with food. LPV/r comes in fixed dose combination capsules containing 133mg Lopinavir/33mg Ritonavir each. The recommended standard dose is therefore 3 capsules PO BID. LPV/r also comes as an oral solution containing 80mg LPV/20mg RTV/mL.

Doses in children: Children 6 months to 12 years: 12 mg/Kg lopinavir with 3 mg/Kg ritonavir for children 7 to <15 Kg, and 10 mg/Kg lopinavir with 2.5 mg/Kg ritonavir for those 15 to 40 Kg, twice daily taken with food, to a maximum dose of 400 mg lopinavir with 100 mg ritonavir in children >40 Kg twice daily.

Concomitant Antiretroviral Therapy: Lopinavir/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

indicates lopinavir/ritonavir (in combination with two nucleoside analogue reverse transcriptase inhibitors) as a first-line or alternative regimen for the treatment of HIV/AIDS.

Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs.

8. Comparative effectiveness in clinical settings:

In compiling the evidence for this and related submissions for anti-retroviral drugs we have created a common ‘stem’ in the form of information that is relevant to all of the antiretroviral group. This is followed by information that is relevant to use of this class of drug under the conditions described in this application, followed by information which is specific to the individual agent under consideration.

Because of time constraints and the growing acceptance of the efficacy of highly active anti-retroviral drug regimens in the last 5 years, we have relied in part on secondary data sources – systematic reviews of randomised and non-randomised studies conducted by the Cochrane Collaboration, or by independent groups who have generally met standards that are considered appropriate to this type of work. We have relied on individual trials where these provided data and insights not available from systematic reviews.

Details of literature searches conducted

The principal data-bases that were searched were:o The Cochrane Data-base of Systematic Reviews

5

o 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 AIDSLINE o AIDSTRIALS o AIDSDRUG

Search terms included:

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: lopinavir, ritonavir

Study selection:

o Randomised comparative parallel-group controlled clinical trialso Examined the performance of lopinavir/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?

6

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

7

Class specific questions3. Which combinations of drug classes have the best evidence in relation to

benefits and harms?

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

combinations that include didanosine?

Results1. What is the validity of surrogate markers as predictors of morbidity and mortality in patients with HIV/AIDS? (Level 3 evidence)

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

8

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 5.6 (95% CI 3.1, 9.8). 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

9

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

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 combined therapy with lopinavir/ritonavir? (Level 2 evidence)

The combined formulation of Lopinavir 400mg/Ritonavir 100mg (henceforth referred to as LPV/r) is the most powerful protease inhibitor available, achieving trough plasma levels more than 30-fold above the EC50 of the drug for wild-type HIV. This is due both to the potency and bioavailability of LPV, and the inhibition of LPV metabolism by low-dose Ritonavir, which does not itself exert much antiretroviral activity at the 100mg dose (see submission for indinavir for more details of pharmacokinetic interactions with low dose ritonavir).

10

However LPV/r is associated with some disadvantages. It requires 3 pills twice a day, with food. Its use is associated with increased transaminases, triglycerides, and cholesterol in a substantial minority of patients (up to 22%). Because LPV/r inhibits the CYP3A4 microsomal enzyme system, dose adjustments are often necessary in medications given concurrently.

LPV/r has been studied in two main clinical settings: (1) as initial therapy for HIV infection; and (2) as rescue therapy in multiple PI-experienced patients with viral rebound.

Three randomized, blind, controlled trials (Murphy, 200122; King, 200123; Eron, 200224) have established the antiviral efficacy of LPV/r in treating ART-naïve patients (see Attachment 1 for details of the trials). In a dose-ranging study of LPV/r+d4T+3TC, Murphy found that as many as 86% of patients randomized to LPV/r 400/100mg BID had HIV VL<50 copies/mL after 48 weeks of treatment, without drug-related discontinuations for clinical or laboratory abnormalities, despite the occurrence of elevated cholesterol, triglycerides, and transaminases. A recent study by Eron demonstrated that once daily dosing of LPV/r (800/200mg) was roughly as effective as standard BID dosing over 48 weeks. Finally, a comparison of LPV/r with the protease inhibitor Nelfinavir, both given with d4T and 3TC, showed a statistically significant increase in the proportion of patients with undetectable VL, at both the 400c/mL and 50c/mL thresholds, among patients randomized to LPV/r.

Two randomized trials (Danner, 200125; Benson, 200226) and one open-label (Ruiz, 200227) trial have demonstrated the usefulness of LPV/r as the backbone of rescue therapy in patients with extensive history of ARV therapy (see Attachment 1), including multiple PI failures, with up to 67% of patients having a VL<400c/mL at 72 weeks (Benson). The study by Danner showed a dose response between the number of LPV mutations present and a decline in efficacy: patients with 6-7 pre-study mutations still had a 71% probability of suppressing viral load to below 400c/mL, while those with 8-10 pre-study mutations had a 33% probability of doing so.

11

9. Comparative evidence on safety (See attachment 1 for results from clinical trials of co-formulated lopinavir/ritonavir):

Adverse effects/reactions: Adults: diarrhea, nausea, asthenia, headache, abnormal stools, vomiting, abdominal pain, rash, insomnia.

Laboratory abnormalities in adults (Grade 3 or 4) include neutropenia; elevated cholesterol, triglycerides, AST, ALT, GGT, glucose, uric acid.

Adverse effects/reactions in children: Rash (2%) was the only drug-related clinical adverse event of moderate or severe intensity reported in 2% of paediatric study subjects.

Laboratory abnormalities in children (Grade 3 or 4) include thrombocytopaenia, neutropaenia; elevations in AST, ALT, amylase, total bilirubin, total cholesterol; hyponatraemia.

Warnings: Co-formulated lopinavir/ritonavir must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen.

Pancreatitis: pancreatitis has been observed in patients receiving lopinavir/ritonavir, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to lopinavir/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 lopinavir/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 lopinavir/ritonavir and/or other antiretroviral therapy should be suspended as clinically appropriate.

Diabetes: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia 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, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Precautions:

Hepatic impairment and toxicity: Lopinavir and ritonavir are 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

12

C or marked elevations in transaminases prior to treatment may be at risk of developing further transaminase elevations.

Lipid elevations: Treatment with lopinavir/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 lopinavir/ritonavir at a periodic intervals during therapy.

Haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis, in patients with haemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.

Redistribution/accumulation of body fat: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Drug Interactions: Ritonavir is a potent inhibitor of the P450 isozyme CYP3A. Coadministration of lopinavir/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.

Lopinavir/ritonavir is itself metabolized by CYP3A. Coadministration of lopinavir/ritonavir and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect. Coadministration of lopinavir/ritonavir and drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drugs that must not be coadministered lopinavir/ritonavir: flecainide, propafenone, astemizole, terfenadine, ergot derivatives, midazolam, triazolam, cisapride, pimozide, lovastatin, simvastatin, rifampin, St. John's wort (Hypericum perforatum) or St. John's wort-containing products.

Drugs which require a dose reduction when coadministered with lopinavir/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 lopinavir/ritonavir and rifabutin are co-administered. Further reductions in rifabutin dose may be required. When co-administered with lopinavir/ritonavir, sildenafil dose should be reduced to 25 mg every 48 hours with increased monitoring for adverse events.

Drugs which may require a dose increase when coadministered with lopinavir/ ritonavir: methadone, atovaquone.

Drugs which require careful monitoring when coadministered with lopinavir/ritonavir:lopinavir/ritonavir increases plasma concentrations of dihydropyridine calcium

13

channel blockers (felodipine, nifedipine, nicardinpine) and HMG-CoA reductase inhibitors (atorvastatin and cerivastatin).

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

Coadministration of lopinavir/ritonavir with other antiretrovirals:

When administered with efavirenz or nevirapine, the lopinavir dose should be increased from 400 mg to 533 mg and ritonavir increased from 100 mg to 133 mg, twice daily with food.

When administered with didanosine, the didanosine dose should be taken either one hour before or two hours after lopinavir/ritonavir.

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:

Lopinavir + Ritonavir (Trade name KaletraTM) is available from Abbott at $US650/year; the price quoted by Hetero (India) is 1916 USD/year for the same combination.

14

11. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): TBA

12. Availability of pharmacopoieal standards: TBA

15

Attachment 1: results of clinical trials of lopinavir/ritonavir. Pages 15- 18

16

Author Study Details Benefits Tolerability/Adverse EffectsLpv/r Regimen Comparator Lpv/r Regimen Comparator

Murphy et al.200122

RCTGroup 1: RTV 100mg + LPV 200mg vs. 400mg q12h x 3 wks, then d4T+3TC added.

Group 2: RTV 100mg vs. 200mg + LPV 400mg q12h + d4T + 3TC.

N=100 ART-naïve, HIV VL>5000c/mL followed for 48 weeks.No baseline differences in HIV VL, CD4. Mean VL=4.9 log10; Mean CD4= 398(group1); 310(group2).

Pts w/ VL<50c/mL @ Wk48:

No comparator regimen --No drug-related discontinuations

(clinical or laboratory-related).--7 withdrawals (2 LTFU; 2non-compliance; 1 personal reasons; 1 lymphoma; 1 relocation).--incidence of diarrhea, nausea, vomiting similar among arms, except significantly higher in group 2 arm receiving 200mg Ritonavir.--Most common grade III/IV lab abnormalities: -elev. triglycerides -elev. total cholesterol -elev. liver enzymes.

Grp1 LPV/r 200/100mg: 100% LPV/r 400/100mg: 50% (p=0.002)* Grp2 LPV/r 400/100mg: 86% LPV/r 400/200mg: 73%

Mean change in CD4 @ w48:Grp1: +244/mm3Grp2: +213/mm3

*6/8 pts in 400/100 group w/ VL>50c/mL at wk48 had VL<50c/mL at next visit.

King et al.200123

M98-863 Study

RCTLPV 400mg/rtv 100mg BID vs. NEL 750mg TID (double blinded) + d4T/3TC (open label).

N=653 ART-naïve pts.

Pts w/ virologic suppression at 48 weeks: No genotypic/phenotypic resistance among 37 LPV/r failures.

<400c/mL:75%(p=0.001)

<50c/mL: 67%(p<0.001)

<400c/mL: 63%

<50c/mL: 52%

17

Author Study Details Benefits Tolerability/Adverse EffectsEron et al.200224 Randomized (no blinding info in

abstract) trial.D4T+3TC BID, plus LPV/r 800/200mg OD vs. LPV/r 400/100mg BID x 48 weeks.N=38 ART-naïve pts with median baseline VL 4.7 log10 c/mL, CD4 264/mm3.

Pts. with HIV VL<50c/mL at 48 weeks:--Comparable frequency of nausea, asthenia, diarrhea across groups.

--2 grade III cholesterol elevations.--3 grade III triglyceride elevations.

OD LPV/r: 74%Median Ctrough/IC50: 40.BID LPV/r: 79%Median Ctrough/IC50: 84.Adherence (MEMS-caps) similar across groups

No comparator regimen.

Danner et al.200125

M98-957 Study

RCT

LPV/r 400/100mg BIDvs. 533/133mg BID plus open EFV + NRTIs; converted to open-label LPV/r 533/133mg BID after week 24.

N=57 multiple-PI-experienced, NNRTI-naïve; VL on ART>1000c/mL.

Median BL HIV VL 4.5 log10c/mL.

Pts. with HIV VL <400c/mL at week 72:13 pts withdrew by week 72--4 for LPV/r-related events--5 for virologic failure

Most common EA: diarrhea; asthenia; lipid elevations.

Pooled arms: 67% (ITT, missing = failure).

No comparator regimen

Antiviral efficacy stratified by BL # LPV mutations:

# mutations: pts w/VL<400c/ml@72wks: 0-5 91% 6-7 71% 8-10 33%

18

Author Study Details Benefits Withdrawals/Adverse Events

Benson et al.200226

RCT(Blinded) LPV/r 400/100mg vs. 400/200mg substituted for prior PI, followed by addition of open-label NVP + new NRTI(s) on day 15.

N=70 pts, naïve to NNRTI and at least one NRTI, with HIV VL 1000-100,000c/mL on stable PI-containing ART x 12 weeks.

No significant baseline demographic, immunologic, virologic, or antiretroviral differences between arms.

Pts. with suppressed HIV VL at 48 weeks:No statistically significant difference in incidence rates of adverse events between 400/100mg and 400/200mg groups.--Most common adverse events: diarrhea (19% and 24%); asthenia (3% and 9%).

Significantly increased total cholesterol (30 and 38mg/dL, p<.001); triglycerides (135 and 124 mg/dL, p<.05) vs. baseline.

No withdrawals due to lab abnormalities.

<400c/mL:LPV/r 400/100mg: 67%LPV/r 400/200mg: 74%

<50c/mL:LPV/r 400/100mg: 56%LPV/r 400/200mg: 68%No significant difference between dosages.

Mean CD4 change @ 48 weeks:LPV/r 400/100mg:+140/mm3LPV/r 400/200mg:+108/mm3No significant difference between dosages.

No comparator regimen

19

Ruiz et al.200227

Open-label randomized prospective trial.

Rescue therapy consisting of LPV/r+SQV+3TC+ABC+ddI with (group a) or without (group b) a preceding 3-month treatment interruption.

N=46 pts. with HIV VL>1000c/mL on >2 three-drug ART regimens and with resistance mutations to all three classes of antiretroviral drugs.

At Baseline: Mean #prior drugs: 8Mean years of prior ART: 5.7Mean VL: 4.3 log10 c/mLMean CD4/mm3: (a)396; (b) 322

Pts with HIV VL<80c/mL at 24 weeks:

Adverse events and withdrawals not reported in abstract.(a):47%

(b):36%No significant difference.

Abstract does not state reason for choosing 80c/mL as threshold for undetectability.

Baseline VL <20,000c/mL associated with better virologic suppression.

No comparator regimen.

20

Attachment 2 Overview of protease 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 diarrhea 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*high level resistance usually confers cross-resistance with other

21

protease inhibitors

Indinavir + ritonavir

cost variable, depending on dose

*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;

* mild to moderate diarrhea in ca 20% of patients;*high pill burden (16

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.

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

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

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

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

9 S. Pujari, E. Naik, A. Patel, and S. Bhagat. Safety, Tolerability, and Efficacy of Nevirapine-Based HAART amongst Antiretroviral Naïve HIV-1-Infected Patients in India. Paper presented at the 9 th Retrovirus Conference, Washington State Convention and Trade Center, Seattle, February 24th-28th 2002. Available at www.retroconference.org10

? World Health Organisation. ‘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

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

22

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

capsules daily);*soft-gel capsules must be stored in refridgerator 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

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

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

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

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

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

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

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

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

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

22 Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. Aids 2001;15(1):F1-9.

23 King, B. Bernstein, D. Kempf, J. Moseley, K. Gu, and E. Sun. Comparison of Time To Achieve HIV RNA <400 Copies/ mL and <50 copies/mL in a Phase III, Blinded, Randomized Clinical Trial of ABT-378/r vs. NFV in ARV-Naive Patients. In: 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 24-28, 2000; Chicago, IL; 2001.

24 Eron JJ, , B. Bernstein, M. King, L. Manning, R. Bertz, G. Beall, F. Carpio-Cedraro, J. Feinberg, H. Horowitz, D. Wheeler, H. Kessler, D. Mildvan, P. Ruane, B. Yangco, C. Renz, S. Mayer, and E. Sun. Once-Daily vs Twice-Daily Kaletra (Lopinavir/Ritonavir) in Antiretroviral-Naïve HIV+ Patients: 48-Week Follow-Up. In: 9th COnference on Retroviruses and Opportunistic Infections; 2002 Feb 24-28, 2002; Seattle, WA; 2002.

25 Danner S, S. Brun, J. Sylte, J. Isaacson, A. Lazzarin, P. M. Girard, J. Rockstroh, S. Becker, G. Pantaleo, F. Bergmann, N. Clumeck, D. Ho, R. Tubiana, G. Carosi, R. Bertz, A. Hsu, M. King, B. Richards, D. Kempf, E. Sun, E. Kaletra (lopinavir/ritonavir) and Efavirenz: 72 Week Safety/Efficacy Evaluation andPhenotypic/Genotypic Breakpoints in Multiple PI Experienced Patients. In: 41st ICAAC; 2001 12/16/01

23

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 refridgerator 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)

*twice-daily dosing;*active against group O subtypes

*adverse events mostly GI-related, can be severe;* cannot be used with rifampin;*multiple potential drug interactions;*both capsule and liquid formulations contain alcohol;*capsules must be stored in refridgerator;*liquid has 30 day shelf-life at room temperature 20-25C;*high level resistance usually confers cross-resistance with other protease inhibitors

through 12/19/01; 2001.

26 Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, et al. Safety and Antiviral Activity at 48 Weeks of Lopinavir/Ritonavir plus Nevirapine and 2 Nucleoside Reverse-Transcriptase Inhibitors in Human Immunodeficiency Virus Type 1--Infected Protease Inhibitor--Experienced Patients. J Infect Dis 2002;185(5):599-607.

27 Ruiz L, E. Ribera, A. Bonjoch, J. Martinez-Picado, M. Díaz, J. Romeu, S. Marfil, E. Negredo, J. García-Prado, C. Tural, T. Puig, G. Sirera, and B. Clotet. Virological and Immunological Benefit of a Salvage Therapy that Includes Kaletra plus Fortovase Preceded or not by Antiretroviral Therapy Interruption (TI) in Advanced HIV-Infected Patients (6-Month-Follow-up). In: 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24-28, 2002; Seattle, WA; 2002

24

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.

25