Generic fixed-dose combinations (FDC) have been pre-qualified by the World Health Organization (WHO) to treat HIV-infected patients in resource-limited countries where access to antiretroviral drugs is a public health priority. These combinations have not yet been approved by the U.S. Food and Drug Administration due to lack of data on their formulation, pharmacokinetic properties, safety and efficacy.

WHO currently recommends 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI) as these combinations have proven efficacy and tolerability and are relatively inexpensive and easy to adhere to.¹

Triomune, a generic FDC of nevirapine (NVP, Viramune), stavudine (d4T, Zerit) and lamivudine (3TC, Epivir) produced by Cipla Ltd. in Mumbai, India, is one of the most frequently used generic combinations in African countries, despite the lack of clinical trials assuring quality and efficacy.²

The objective of this study was to determine the quality of plasma concentrations (C_min) achieved, adherence, safety and effectiveness of FDC tablets of nevirapine, stavudine and lamivudine administered to HIV-1-infected African patients in a prospective ANRS (the French National Agency for AIDS) study in Cameroon, a central African country that has 15 million inhabitants and a rapidly rising HIV prevalence.

The study was an open-label, single-arm, prospective multi-center trial in which all patients received 1 tablet of the study treatment twice daily. Each tablet contained 200 mg of nevirapine, 40 mg of stavudine (30 mg for patients weighing less than 60 kg) and 150 mg of lamivudine. To minimize the risk of adverse effects from the nevirapine, patients received 1 tablet of the study treatment once daily plus 1 tablet of lamivudine (Lamivir, Cipla Ltd., Mumbai, India) and stavudine (Zerit, Bristol-Myers Squibb, New York, U.S.A.) 12 hours later for the first 14 days of treatment.

Patients were eligible for the study if they had confirmed HIV-1 group M infection, were age 18 years or older, lived less than 50 miles from Yaounde, Cameroon, and were HAART (highly active antiretroviral therapy) naive (with the exception of drugs used to prevent mother-to-child transmission). They were required to have clinical AIDS according to the 1993 revised Centers for Disease Control and Prevention (CDC) classification (CDC group C); or mild symptoms (CDC group B) or pulmonary tuberculosis, and a CD4+ cell count below 350 cells/mm³; or no symptoms (CDC group A) and a CD4+ cell count below 200 cells/mm³; and a Karnofsky score of at least 50%.

Adherence to study treatment during the previous 7 days was self-reported by the patients to their physicians at every visit with assessment of adequate minimal effective plasma (C_min) levels at weeks 2, 4 and 24. Pooled samples were used to calculate a mean elimination half-life to allow plasma drug level sampling at varied times post-dosing. Twelve-hour plasma concentrations were calculated for each patient with respect to reported interval from last dosing. The primary endpoint was the percentage of patients who had a plasma viral load below 400 copies/mL at week 24 by intent-to-treat (ITT) analysis.

The quality of the generic double-coated tablet was first assessed macroscopically and then by weight. Seven batches of Triomune were then analyzed for nominal quantity of the 3 component drugs as compared to the corresponding European-approved equivalent brand name drug.

Sixty patients were enrolled with 68.3% women and 96.7% antiretroviral therapy naive. The median age was 34.5 years and the median body weight was 63.0 kg. A median of 12.2 months had passed since HIV diagnosis. CDC clinical stages A/B/C comprised 16.6, 41.7 and 41.7% of the enrolled patients, respectively. The median CD4+ cell count and viral load were 118 cells/mm³ and 104,736 copies/mL, respectively. 18.3% had antibodies to hepatitis C and 8.3% had antibody evidence of chronic active hepatitis B.

The quality of 7 batches of Triomune was examined and compared to the expected nominal values. The median concentrations of nevirapine, stavudine and lamivudine were 95.5%, 89.0% and 99.3% of expected nominal values, respectively.

The mean self-reported adherence rate was 98.8% with only 9 patients reporting lapses in adherence. Overall median plasma concentrations expressed as C_min were: nevirapine = 5,008 ng/mL (range <50-19,122, n=161), stavudine = 16 ng/mL (range <10-107, n=138), lamivudine = 172 ng/mL (range 12-890, n=138).

At both weeks 2 and 4 only 2 patients had all 3 drug levels be too low to measure. Adequate minimal effective nevirapine levels (nevirapine C_min) were reached by 78.6, 92.9 and 84.0% of patients at study weeks 2, 4 and 24, respectively.

Looking at ITT analysis of the 60 enrolled patients at week 24, 80.0% had an HIV viral load less than 400 copies/mL and 65.0% less than 50 copies/mL. Looking at the as-treated analysis for the 49 patients still on therapy at week 24, 91.8% were less than 400 and 73.5% less than 50 copies/mL. The median change in plasma viral load and CD4+ cell count were -3.1 log copies/mL and +83 cells/mm³, respectively. Eight patients had a documented HIV viral load >1,000 copies/mL once (n=6) or twice (n=2) during the study. Major viral resistance mutations were found by genotyping in 2 of these patients. Incidence rates of disease progression, serious adverse effects and genotypic resistance mutations were 32.0, 17.8 and 7.1 per 100 person-years, respectively.

This open-label clinical trial of Triomune, one of the most commonly prescribed FDCs, shows good drug quality with efficacy and tolerability similar to that reported with other HAART regimens in comparable patients.

One key issue with these generic preparations has been quality, with little reported data on the purity and consistency of these compounds, which, of course, could have a dramatic impact on tolerability, efficacy and viral resistance.

The unit dose of each component in the 7 batches dispensed to patients in the study was as claimed, adding to the increasing body of proof of the quality of these generic compounds. Despite wide intersubject variability of the 3 drugs' plasma concentrations, the ranges were within those expected and consistent with those previously described for the dosing of their individual brand-name components.

These results confirmed the excellent self-reported adherence (98.8%) and are similar to those obtained with once-a-day didanosine (ddI, Videx)/lamivudine/efavirenz (EFV, Sustiva, Stocrin) therapy in Senegal.³ Virologic and immunologic efficacy was similar to that obtained in industrialized countries.

Tolerability of the medications was also good, and treatment was stopped in only 1 case for a nevirapine rash. Four cases of Grade 1-2 neuropathy were reported secondary to stavudine. Hepatic tolerability to nevirapine was good with only transient, mild-moderate transaminitis reported.

This is the first study to show the quality, safety and efficacy of a generic fixed-dose antiretroviral combination. While long-term studies in large and varied populations are needed, the results of this study support the continued use of generic FDCs, which is welcome news for those infected and affected by HIV in the developing world.

Footnotes

1. WHO. Scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach. 2003 revision.

2. Henry K, Brundage R, Weller D, Akinsete O, Shet A. Comparison of generic zidovudine + lamivudine (Cipla, Duovir) and the GlaxoSmithKline brand (Combivir) tablets. JAIDS. April 15, 2004;35(5):537.

3. Landman R, Schiemann R, Thiam S, et al. Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal. AIDS. May 2, 2003;17(7):1017-1022.