Generic fixed-dose combination pill effective, safe, and of high quality, Lancet reports

A generic fixed-dose combination of nevirapine, lamivudine (3TC), and stavudine (d4T), which is widely used in antiretroviral treatment programmes in Africa, is effective and safe, according to a study published in the July 3^rd edition of the Lancet. The investigators also established that drug concentrations within fixed doses tablets were within expected values. An editorial in the same edition of the Lancet says that the study leaves no doubt about the efficacy and safety of generic fixed-dose antiretrovirals.

Fixed-dosed generic combinations are regarded as crucial for scaling up access to antiretroviral treatment in resource limited settings. Several generic fixed-doses have been prequalified by the World Health Organisation for use in their “3 X 5” treatment initiative. However, major donor agencies have not always offered similar endorsement, most notably the US government’s Presidential Emergency Plan for AIDS Relief Funding (PEPFAR). Although political issues can partly explain this situation, not least pressure from research-based pharmaceutical companies for their own cut price antiretrovirals to be favoured, there is also a lack of clinical data showing the efficacy and safety of fixed-dose generic combinations.

Accordingly investigators in Cameroon conducted an open-label, single-arm, 24 week study to evaluate the efficacy and safety of the Indian generic manufacturer Cipla’s fixed-dose combination of nevirapine, lamivudine and stavudine.

The study’s primary endpoint was the proportion of patients with an HIV viral load below 400 copies/ml after 24 weeks of treatment. Data were also gathered on the proportion of patients with a viral load below 50 copies/ml at this point, the rate of HIV disease progression, adverse events, and levels of adherence. The quality of the generic tablets was also assessed.

A total of 60 HIV-positive adults were recruited to the study between November 2002 and April 2003. At baseline median CD4 cell count was 118 cells/mm³ and median viral load was a little above 100,000 copies/ml. All the patients were naïve to antiretroviral therapy with the exception of two women who had taken a single dose of nevirapine to prevent mother-to-baby transmission of HIV.

After 24 weeks 80% of patients had achieved a viral load below 400 copies/ml, with 65% having a viral load below 50 copies/ml. The median increase in CD4 cell count at this point was 83 cells/mm³ and 50% of patients had a CD4 cell count above 230 cells/mm³.

The frequency of HIV disease progression was 32.0 per 100 patient years of follow-up. Four patients experienced new AIDS-defining events and eight patients died. All but one of the individuals who died did so within the first nine weeks of treatment. The cumulative probability of remaining alive and AIDS free at 24 weeks was 0.85.

Five instances of severe adverse events were recorded providing an incidence of 17.8 per 100 patient years. These severe side-effects included one instance of rash and liver enzyme elevation, two cases of liver enzyme elevation, and a case of pancreatic enzyme elevation. No clinical hepatitis was reported despite the 18% prevalence of hepatitis C coinfection in this cohort. Individuals coinfected with HIV and hepatitis C may be particularly prone to hepatic side effects of nevirapine.

Optimal levels of adherence were reported by patients, with a mean rate of 99%. Plasma blood concentration monitoring, which was performed at weeks two, four and 24, confirmed that individuals were highly adherent to their therapy with only two patients having plasma concentrations of the study medications below the limits of quantification.

The quality of the fixed-dose generic combination pills was high. Compared with expected doses, the median concentration of nevirapine was 96%, the median concentration of stavudine 89% and the median concentration of lamivudine 99%. All upper and lower concentrations were within the 80% - 125% range usually used by regulatory authorities to determine whether drugs contain quantities of a drug which match the product labelling.

”In our open clinical trial, we have documented the quality of a commonly prescribed 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," write the investigators. They add that the plasma ranges of the three drugs were “as expected and consistent with those previously described for the approved drugs.” Further, “the virological and immunological efficacy of the regimen used by us was at least as good as that obtained with HAART in industrialised countries.”

The investigators conclude, “our results lend support to the use and funding of generic fixed-dose combinations as first-line antiretroviral therapy in developing countries.”

This conclusion is endorsed by an accompanying editorial, which notes the bioequivalency of the generic drugs used in the study was equivalent to the proprietary drugs. The editorial emphasises “on the basis of these reports there is no question about the safety and efficacy of generic antiretrovirals.”

Further information on this website

International standards on fixed dose combinations for HIV published - news story