 |
|
|
| |
Generic HAART Studied in Cameroon: d4T/NVP/3TC, 80% <400 copies/ml
|
| |
| |
|
|
| |
| |
 |
|
| |
| |
Cheap Indian AIDS pill as good as pricey brands
By Ben Hirschler
LONDON (Reuters) - A cheap three-in-one generic AIDS pill from India is just as good as more expensive branded medicines and should be widely used in developing countries, researchers said on Friday.
Lack of scientific evidence about the clinical effectiveness of such generic fixed-dose combinations has until now caused some international AIDS donors to refuse to fund their use.
But a team from the French national agency for AIDS research and Swiss charity Medecins sans Frontieres said Cipla's Triomune performed as well as brand drugs in the first open clinical study in a developing country.
They found that 80 percent of HIV-infected patients given the tablet twice a day had undetectable levels of virus in their blood after six months treatment.
Results of the study involving 60 patients in Cameroon, 92 percent of whom had full-blown AIDS, were published in The Lancet medical journal.
"This generic fixed-dose combination (FDC) gives results comparable to those seen in the developed world using triple-drug therapy comprising brand name drugs," said study co-ordinator Eric Delaporte.
"It is now no longer possible to raise scientific uncertainty as an objection to the widespread utilisation of FDCs in the developing countries."
In addition to being cheaper, drugs like Triomune -- which contains GlaxoSmithKline's lamivudine, Bristol-Myers Squibb's stavudine and Boehringer Ingelheim's nevirapine -- are simpler to use since patients need to take only two pills a day.
As such, they have a major role to play in meeting the World Health Organisation's goal of getting antiretrovirals to three million people in the developing world by the end of 2005, N. Kumarasamy of the YRG Centre for AIDS Research and Education in Madras wrote in a commentary accompanying the research.
Industry analysts at ABN AMRO said the news was a slight negative for makers of patented drugs but the profitability of AIDS drugs was already weak, limiting the commercial impact on Western firms.
Shares in Cipla rose three percent in late trade in Bombay while GSK and Roche held steady in a firmer European drugs sector.
CONTROVERSY
The WHO has judged Triomune and another Indian combination called Triviro, from Ranbaxy Laboratories, to be safe and effective under a scheme that "prequalifies" them for use.
But both products -- which use compounds still covered by patents -- remain controversial.
Washington has barred groups receiving U.S. government funds from buying them, insisting only drugs approved by the Food and Drug Administration be used.
U.S. officials and Western pharmaceutical executives argue health providers are taking a risk by using medicines which have not passed the rigorous standards of the U.S. drugs watchdog.
Worries about the quality of Indian medicines were fuelled last month when the WHO removed two Cipla products -- though not Triomune -- from its prequalification list because they had not been proven to be equivalent to the original prooducts.
Cipla says it is collecting data from new studies, which should lead to the drugs being re-instated.
In Cameroon, where drugs are subsidised by the government, the cost of one month's Triomune is $20, compared to $35 for the equivalent brand name therapy, even after heavy discounting by big pharmaceutical companies.
Elsewhere, cost differences can vary by as much as 100 percent, according to Medecins sans Frontieres.
PUBLISHED STUDY IN THE LANCET
Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial
Christian Laurent, Charles Kouanfack, Sinata Koulla-Shiro, Nathalie Nkoué, Anke Bourgeois, Alexandra Calmy, Bernadette Lactuock, Viviane Nzeusseu, Rose Mougnutou, Gilles Peytavin, Florian Liégeois, Eric Nerrienet, Michèle Tardy, Martine Peeters, Isabelle Andrieux-Meyer, Léopold Zekeng, Michel Kazatchkine, Eitel Mpoudi-Ngolé, Eric Delaporte, for the ANRS 1274 study group
Lancet 2004; 364: 29-34
See Comment below
Institut de Recherche pour le Développement and Department of International Health, University of Montpellier (UMR 145), Montpellier, France (C Laurent PhD, A Bourgeois MD, F Liégeois, M Peeters PhD, Prof E Delaporte MD); Central Hospital, Yaoundé, Cameroon (C Kouanfack MD, Prof S Koulla-Shiro MD, V Nzeusseu MD, M Tardy MD); Projet PRESICA/PARVY, Military Hospital, Yaoundé, Cameroon (N Nkoué MD, B Lactuock MD, R Mougnutou MD, F Liégeois, E Mpoudi-Ngolé MD); Médecins Sans Frontières, Geneva, Switzerland (A Calmy MD, B Lactuock, I Andrieux-Meyer MD); Laboratoire de Toxicologie et de Dosage de Médicaments, Centre Hospitalier Universitaire Bichat Claude Bernard, Paris, France (G Peytavin PhD); Centre Pasteur, Yaoundé, Cameroon (E Nerrienet MD); Laboratoire de Santé et d'Hygiène Mobile, Yaoundé, Cameroon (L Zekeng PhD); National AIDS Program, Yaoundé, Cameroon (L Zekeng); and French National Agency for Research on AIDS (ANRS), Paris, France (Prof M Kazatchkine MD)
Summary
Background: Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine.
Methods: 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis.
Findings: At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per µL (IQR 78-167) and median plasma HIV-1 RNA was 104 736 copies per mL (40 804-243 787). The proportion of patients with undetectable viral load (<400 copies per mL) after 24 weeks of treatment was 80% (95% CI 68-89). Median (IQR) change in viral load was -3·1 log10 copies per mL (-2·5 to -3·6) and in CD4 count 83 cells per µL (40-178). The probability of remaining alive or free of new AIDS-defining events was 0·85 (95% CI 0·73-0·92). Frequency of disease progression was 32·0 (95% CI 16·6-61·5), severe adverse effects 17·8 (7·4-42·7), and genotypic resistance mutations 7·1 (1·8-28·4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine.
Interpretation: Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.
Introduction
Access to antiretroviral drugs for HIV-infected patients in developing countries is a global public health priority. With the support of multilateral and bilateral programmes, non-governmental organisations, and national authorities, WHO has the ambitious objective to treat 3 million people with highly active antiretroviral therapy (HAART) by 2005.1 WHO currently recommends first-line therapy with two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI (NNRTI), a combination with good efficacy, tolerability and simplicity, low cost, and good adherence to treatment.2
Generic fixed-dose combinations of such regimens are widely regarded as crucial for scaling-up AIDS treatment in developing countries. These treatments improve adherence owing to the fewer daily doses relative to individual formulations. Supply, storage, and distribution are also easier because the range of products is smaller. Generic drugs are generally much cheaper than brand-name formulations. Several generic fixed-dose combinations have been prequalified by WHO3 after assessment of manufacturers' product data (including data for purity of all ingredients, stability of the finished products, and results of in-vivo bioequivalence tests), actual pharmacological composition, and manufacturing practices. However, these formulations are not yet recommended by some of the major donor agencies, such as the US government's multi-billion dollar PEPFAR (President's emergency plan for AIDS relief funding) programme for developing countries.4 In addition to political considerations, particularly on the legitimacy and consequences of using generic instead of brand-name drugs, this situation is partly explained by the absence of clinical studies showing the efficacy and tolerability of generic fixed-dose combinations. Quality control of different drug batches is also a difficulty in most developing countries.
The generic fixed-dose combination of nevirapine, stavudine, and lamivudine (Cipla, Mumbai Central, Mumbai, India) is one of the most frequently prescribed treatments in African countries. In Cameroon, a central African country with more than 15 million inhabitants, the prevalence of HIV infection is increasing rapidly, with up to 11·8% of town-dwelling pregnant women infected.5 HIV-1 predominates, and HIV-1 groups M, N, and O and many subtypes and circulating recombinant forms cocirculate.6 A national antiretroviral access programme is ongoing, with more than 7500 people currently receiving HAART, most usually based on the generic combination of nevirapine, stavudine, and lamivudine owing to its low price (US$20 monthly).
A pilot project on access to antiretroviral drugs in Yaoundé, the capital of Cameroon, was initiated by the country's National AIDS Program, the Military and Central Hospitals, Médecins Sans Frontières in Switzerland, and the Institut de Recherche pour le Développement in France. This project gave us the opportunity to do a clinical trial aimed at assessing the short-term effectiveness and tolerability of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine and to control the quality of the different drug batches actually received by the patients.
DISCUSSION
Generic fixed-dose combinations of two NRTIs and one NNRTI are now among the most widely prescribed first-line antiretroviral regimens in developing countries, yet we are aware of no clinical trials assessing their effectiveness, safety, and quality in field conditions. Brief reports have been presented but these have omitted important data such as virological efficacy, adherence, and viral resistance. In our open clinical trial, we have documented the quality of a commonly prescribed generic fixed-dose combination and shown that its effectiveness and tolerability are similar to that reported with other HAART regimens in patients with comparable baseline HIV disease status.
One key issue about the use of generic fixed-dose combinations is their quality. Very few data on the purity of generic antiretroviral drugs have been published,16 yet incorrect dosing could have a major negative effect on tolerability, efficacy, and viral resistance. We tested all seven batches dispensed to our patients and noted that the unit dose of every component (lamivudine, stavudine, nevirapine) was as claimed.
Despite wide intersubject variability of the plasma concentrations of the three drugs in the fixed-dose combination, the ranges were as expected and consistent with those previously described for the approved drugs. Only two patients presented at both weeks 2 and 4 with nevirapine, stavudine, and lamivudine plasma concentrations lower than the respective limits of quantification, suggesting some adherence difficulties. These results accord with the excellent self-reported adherence (99%), and this finding was corroborated by the good virological response. Many factors can affect adherence to treatment, such as social support, cost, and tolerability, but treatment simplicity is one of the most important. Fixed-dose combinations therefore have a clear advantage in terms of number of pills and cost. In Cameroon, the cost of the fixed-dose combination we assessed here is US$20 per month, whereas the same combination with brand-name drugs in the ACCESS programme (http://www.unaids.org) costs around $35, and six pills have to be taken instead of two with fixed-dose combinations. Our results for adherence are similar to those obtained with once-a-day didanosine-lamivudine-efavirenz therapy in Senegal.
The virological and immunological efficacy of the regimen used by us was at least as good as that obtained with HAART in industrialised countries; for example, in a trial of a triple-drug regimen--including a protease inhibitor (indinavir)--in patients with CD4 counts less than 200 cells per µL, a virological success rate (viral load <500 copies per mL) of 60% and an increase in CD4 count of 91 cells per µL were reported at 24 weeks. The effectiveness of the combination of nevirapine, stavudine, and lamivudine has also been shown. Compared with African therapeutic cohorts in which most patients also have advanced HIV disease at enrolment our results are highly satisfactory. They also compare well with those of a cohort of African patients treated in London, UK. Comparison with other studies, such as use of generic drugs in India, is more difficult since the study design differs and the number of variables analysed is limited.
Nevirapine and stavudine can have troublesome adverse effects. Tolerability was good in our trial, both overall and specifically with respect to nevirapine, and was even slightly better than that usually seen in developed-world cohorts. Treatment was stopped in only one individual for a cutaneous reaction to nevirapine. Hepatic tolerability was good, especially considering that 18% of patients were infected by hepatitis C virus and 8% by hepatitis B virus, with only transient or moderate rises of hepatic transaminases found.
Our results for the emergence of resistance are only preliminary owing to the fairly short follow-up (24 weeks). Virological failure (>1000 copies per mL) happened in eight patients. Only one instance of genotypic resistance to NNRTIs was recorded at week 12, in a non-compliant patient who was subsequently lost to follow-up. The other example is intriguing--a woman with a viral load of 1092 copies per mL and the Met184Val and Lys103Asn mutations at week 12 who had received nevirapine to prevent mother-child transmission. In a report in Thailand, the virological success of HAART with nevirapine in such women was only 46% at week 24 because of a high rate of resistance mutations after one dose of nevirapine.28 Despite these two mutations, viral load at week 24 was less than 400 copies per mL (it was still below this level at treatment week 48).
The open-label one-arm design used in this study is not as powerful as a controlled trial to show the efficacy and safety of fixed-dose combinations but it can be used to assess efficacy of treatment regimens because it preserves size, power, and simplicity.
In conclusion, we have documented the quality, safety, and effectiveness of a generic fixed-dose antiretroviral combination in an African setting. Although controlled trials including more patients and longer follow-up will be important, our results lend support to the use and funding of generic fixed-dose combinations as first-line antiretroviral treatment in developing countries.
Comment
Generic antiretroviral drugs--will they be the answer to HIV in the developing world?
Christian Laurent and colleagues, in today's Lancet, report on the efficacy and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon. Highly active antiretroviral therapy (HAART) has led to dramatic reductions in HIV-related morbidity and mortality in the USA and in India. The use of HAART has led to cost-effective public-health programmes in countries such as Brazil, because there are now fewer episodes of illness and hospital admission.3 The cost of combination HIV-antiretroviral treatment has plummeted in the past 12 months, such that HAART can now be bought for less than US$250 a year from Cipla and other generic companies. Cipla is a drug company in Mumbai, India, that launched the first generic antiretroviral drug, zidovudine, in 1994. Since then ,Cipla has launched ten different antiretroviral and fixed-dose combinations of antiretroviral drugs as single pills. Falling prices of therapy are enabling physicians in the developing world to offer triple antiretroviral regimens to greater numbers of patients, who desperately need the life-saving drugs. The safety, tolerability, and efficacy of generic antiretroviral regimens for HIV-infected Indians has been shown.4 Also there were earlier reports that generic antiretroviral drugs were successfully used in HIV-infected patients in Africa.
The bioequivalency of the generic drugs is equivalent to proprietary drugs.6 Most of the studies and reports used CD4 cell-counts and clinical markers to assess the efficacy of generic antiretroviral treatment. Laurent and colleagues used HIV-RNA to measure efficacy in African patients and found viral suppression with the generic regimen. These investigators recruited 60 patients in an open-label one-arm 24-week trial. All patients received, twice daily, one tablet of Triomune, which is a fixed-dose combination of stavudine, lamivudine, and nevirapine. The primary endpoint of the study, the proportion of patients with HIV-RNA below 400 copies per mL at 24 weeks was achieved in 80%. The probability of remaining alive or free of new AIDS-defining events was 0·85. Incident rates of disease progression, severe adverse effects, and genotypic resistance-mutations were, respectively, 32·0, 17·8, and 7·1 per 100 person-years. Mean adherence rate was 99%. Median nevirapine, stavudine, and lamivudine concentrations in tablets were 96%, 89%, and 99% of expected values, respectively.
Similar reductions in viral load with generic drugs made by Cipla were seen in a clinical trial in southern India. On the basis of these reports there is no question about safety and efficacy of generic antiretrovirals. Generic antiretrovirals will have a major role in WHO's scaling-up of antiretroviral delivery in their 3-by-5 plan in resource-constrained settings. Because of patents by proprietary companies, newer antiretrovirals may not be manufactured by the generic companies, which might be a major obstacle to patients getting drugs in such settings.
Adherence to these antiretroviral drugs is crucial to suppress virus levels and prevent resistance. In clinical settings, maintaining absolute adherence is a monumental task. In resource-constrained settings, where many patients buy antiretrovirals from a pharmacy because such drugs are not available in government programmes, such patients might stop taking their drugs when they can no longer afford them, which could lead to the emergence of multidrug-resistant HIV. Directly-observed HIV therapy is the key to success.
The cost of first-line combination generic antiretrovirals is less than $250 a year. But the cost of the second-line combinations with protease inhibitors is ten times that amount. This large disparity in price will present a great challenge in resource-constrained settings in the scaling-up of antiretroviral delivery. Maintaining the cold chain to store protease inhibitors will also be a challenge in such settings where refrigerators are not available or which suffer power cuts with no backup.
Immunological and virological monitoring of HIV-infected patients on HAART are critical. The cost of a CD4 cell-count is around $25 a test, and measuring viral load costs $100 a test. The cost of monitoring is higher than the cost of generic antiretrovirals. Mixed results were seen in studies which evaluated usefulness of low-cost total lymphocyte counts in first assessment and monitoring of HIV-infected patients for HAART. Thus there is an urgent need to evaluate cost-effective simple techniques to measure CD4 cell-count and HIV-RNA.
In developing countries, patients who need antiretrovirals often have multiple opportunistic and concomitant infections. There are several interactions between drugs for opportunistic infections and antiretrovirals including those leading to varying serum concentrations of drugs. Some interactions such as hepatitis, may be fatal, especially those between protease inhibitors and drugs for tuberculosis.
Starting, monitoring, and managing the toxicities of antiretroviral drugs is an art and needs tremendous experience and dedication. Physicians need to be trained properly before we scale-up antiretroviral programmes. We need to emphasise that physicians should adhere strictly to standard treatment guidelines to avoid antiretroviral failure and resistance which will be a future public-health challenge in the presence of increasing use of generic antiretroviral drugs.
N Kumarasamy
YRG Centre for AIDS Research and Education, VHS, Chennai-600113, India
I am the principal investigator for ACTG/NIH trials for the Chennai site.
|
| |
|
|
|
|
|
