Long-term safety, effectiveness and quality of a generic fixed-dose combination of nevirapine, stavudine and lamivudine
Laurent, Christiana; Kouanfack, Charlesb; Koulla-Shiro, Sinatab; Njoume, Maguyc; Nkene, Yvette Mawambab; Ciaffi, Laurad; Brulet, Charlottec; Peytavin, Gillese; Vergne, Laurencea; Calmy, Alexandrad; Mpoudi-Ngolé, Eitelc; Delaporte, Erica
aIRD, UMR 145 (IRD/University of Montpellier 1), Montpellier, France
bCentral Hospital, Yaoundé, Cameroon
cProjet PRESICA, Military Hospital, Yaoundé, Cameroon
dMédecins Sans Frontières, Geneva, Switzerland
eLaboratoire de Toxicologie et de Dosage de Médicaments, Centre Hospitalier Universitaire Bichat Claude Bernard, Paris, France.
Received 2 May, 2006
Revised 24 May, 2006
Accepted 4 June, 2006
Correspondence to Christian Laurent, Institut de Recherche pour le Développement (UMR 145), 911 Avenue Agropolis, BP 64501, 34394 Montpellier cedex 5, France. E-mail: christian.Laurent@mpl.ird.fr
We assessed the long-term safety, effectiveness and quality of a fixed-dose combination of nevirapine, stavudine and lamivudine (triomune). HIV-1-infected adults initially enrolled in a one-year, open-label, single-arm, multicentre trial in Cameroon were followed for 2 years. Our results support the safety and effectiveness of the triomune combination for first-line treatment of HIV infection. Virological effectiveness appeared to wane somewhat during the second year of treatment, however, and plasma nevirapine concentrations were relatively high.
The safety of the easy-to-use fixed-dose combination of nevirapine, stavudine and lamivudine remains controversial despite bioequivalence data and World Health Organization approval [1–3]. We have previously documented the quality, safety and effectiveness of this drug (triomune; Cipla, Mumbai, India) in HIV-1-infected patients enrolled in a clinical trial in Cameroon . Our results supported its use as first-line antiretroviral treatment in developing countries, but were only preliminary (6 months of follow-up). Long-term data are urgently needed to determine when best to switch to second-line regimens. Here we report the clinical, biological and pharmacological results of the Cameroonian study after 2 years of follow-up.
The study was initially designed as a one-year, open-label, single-arm trial conducted in two major hospitals in Yaoundé, the capital of Cameroon. The methods have been described extensively elsewhere . After the initial study, patients were managed, free of charge, in the same hospitals, according to the Cameroonian national guidelines. All the patients received one tablet of triomune twice a day (nevirapine was started with a lead-in dose). If necessary, patients were switched to other regimens available in the national AIDS programme.
Sixty HIV-1-infected adults were enrolled between November 2002 and April 2003 (median age 35 years; 41 women). Most patients were at Centers for Disease Control and Prevention stages B or C (42% in each group). The median plasma HIV-1-RNA level was 104 736 copies/ml [interquartile range (IQR) 40 804–243 787] and the median CD4 cell count was 118 × 106 cells/l (IQR 78–167).
Six patients were lost to follow-up, at months 4, 11, 15, 17 (n = 2) and 20, respectively. Treatment was changed in three patients because of adverse effects (n = 2) or resistance (n = 1). In four other patients, nevirapine was temporarily replaced by efavirenz at months 1, 3, 7 and 16, respectively, because they were prescribed rifampicin for tuberculosis.
Although the proportion of patients with viral loads below 400 copies/ml remained stable over time on triomune in the as-treated analysis (90–94% from month 12 onwards), the proportion of patients with viral loads below 50 copies/ml decreased at month 24 (Table 1). Therefore, 15 and 26% of patients had values between these two thresholds at months 12 and 24, respectively (one-sided Fisher's test P = 0.1). The median increase in the CD4 cell count from baseline was 117 and 213 × 106 cells/l at the same timepoints, respectively. Nine patients died (15%), on day 13 and at months 1, 2 (n = 2), 6, 11, 16, 17 and 18; all had baseline CD4 cell counts below 100 × 106 cells/l. Five deaths occurred among the nine patients with baseline CD4 cell counts below 50 × 106 cells/l, who had a lower survival probability than other patients: 44 compared with 92% at month 24 (log-rank test P < 0.001).
Ten patients had viral loads above 1000 copies/ml during treatment. Major genotypic mutations were detected in three of them (5% of all patients), conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI; mutation Y181C) at month 3, lamivudine and NNRTI (M184V and K103N) at month 3, and lamivudine and NNRTI (M184V and K103N) at month 9, respectively. No thymidine analogue-associated mutations were found.
One woman with a baseline CD4 cell count of 307 × 106 cells/l developed generalized urticaria, fever, and an elevated alanine aminotransferase level (274 U/l) 13 days after starting treatment, and nevirapine was therefore replaced by indinavir. Another woman reported severe peripheral neuropathy at month 13, and stavudine was replaced by zidovudine. Other severe adverse effects included elevated alanine aminotransferase (n = 4) and amylase (n = 1), with no clinical signs. No deaths were related to adverse effects. Nine cases of mild or moderate peripheral neuropathy occurred. No lipodystrophy was observed.
Plasma drug concentrations were undetectable in four patients at month 12 and in three patients at month 24 (Table 1). One other patient at month 12 and two other patients at month 24 had subtherapeutic nevirapine concentrations. Nevirapine concentrations above 8000 μg/l were observed in 56 and 36% of patients at months 12 and 24, respectively.
Compared with the expected doses, the median quantities of the three triomune components in the 26 dispensed batches were nevirapine 96% (range 84–114), stavudine 89% (range 75–104), and lamivudine 90% (range 72–103).
This study shows that triomune is safe and effective for at least 2 years. Virological effectiveness was similar to that seen in other African studies in which branded or generic drugs were used [5,6]. The proportion of patients with viral load values between 50 and 400 copies/ml increased during the second year of treatment. Although most of these values could reflect only intermittent episodes of detectable viraemia (‘blips’) [7–9], it is unclear why this proportion reached such a level [10,11]. If this reflects a loss of virological effectiveness, then a switch to second-line treatment might be required to head off resistance, as we observed a low frequency of genotypic resistance, and no thymidine analogue-associated mutations.
The tolerability of triomune was acceptable after 2 years. In particular, adverse effects potentially related to stavudine (e.g. peripheral neuropathy and lipodystrophy) or nevirapine (e.g. rash and transaminase elevation) were as observed in Indian studies [12,13]. Our results also compare well with those of studies in which other drugs were used . Only two patients (3%) had to switch treatment because of adverse effects, compared with 13% in India and 9% in Europe and north America [10,14].
As previously reported in Malawi , we found relatively high plasma concentrations of nevirapine. High-level exposure to nevirapine has been associated with the suppression of HIV replication and with the infrequent emergence of nevirapine resistance mutations [16,17], as in our study. On the other hand, high nevirapine concentrations (> 8000 μg/l) were rarely toxic in our study. The small proportion of patients with subtherapeutic drug concentrations (in accordance with low rates of detectable viral load and resistance) suggests good adherence to triomune, as seen in Uganda . As did other authors, we found that the content of triomune tablets was adequate [19,20].
Further studies on the long-term virological effectiveness and tolerance of stavudine and the possible clinical repercussions of high plasma nevirapine concentrations in African patients are required.
The authors would like to thank all the patients and staff of the Military and Central Hospital in Yaoundé who participated in the study, and the National AIDS Program, Yaoundé, Cameroon.
Sponsorship: The study was supported by a grant from the French National Agency for Research on AIDS (ANRS 1274).
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