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).
1. Adelman CC. Ensuring the safety of HIV/AIDS generics. Lancet 2005; 365:1926.
2. Narang VS, Lulla A, Malhotra G, Purandare S. A combined-formulation tablet of lamivudine/nevirapine/stavudine: bioequivalence compared with concurrent administration of lamivudine, nevirapine, and stavudine in healthy Indian subjects. J Clin Pharmacol 2005; 45:265–274.
3. World Health Organization. Procurement, quality and sourcing project: access to HIV/AIDS drugs and diagnostics of acceptable quality.
Available at: http://mednet3.who.int/prequal/
2001. Accessed: 28 April 2006.
4. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoué N, Bourgeois A, Calmy A, et al. 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. Lancet 2004; 364:29–34.
5. Laurent C, Ngom Gueye NF, Ndour CT, Gueye PM, Diouf M, Diakhaté N, et al. Long-term benefits of highly active antiretroviral therapy in Senegalese HIV-1-infected adults. J Acquir Immune Defic Syndr 2005; 38:14–17.
6. Coetzee D, Hildebrand K, Boulle A, Maartens G, Louis F, Labatala V, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18:887–895.
7. Martinez V, Marcelin A-G, Morini J-P, Deleuze J, Krivine A, Gorin I, et al. HIV-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS 2005; 19:1065–1069.
8. Nettles RE, Kieffer TL, Kwon P, Monie D, Han Y, Parsons T, et al. Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. JAMA 2005; 293:817–829.
9. Sungkanuparph S, Overton ET, Seyfried W, Groger RK, Fraser VJ, Powderly WG. Intermittent episodes of detectable HIV viremia in patients receiving nonnucleoside reverse-transcriptase inhibitor-based or protease inhibitor-based highly active antiretroviral therapy regimens are equivalent in incidence and prognosis. Clin Infect Dis 2005; 41:1326–1332.
10. Van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17:987–999.
11. Gulick RM, Mellors JW, Havlir D, Eron JJ, Meibohm A, Condra JH, et al. 3-Year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000; 133:35–39.
12. Kumarasamy N, Solomon S, Chaguturu SK, Mahajan AP, Flanigan TP, Balakrishnan P, et al. The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS 2003; 17:2267–2269.
13. Pujari SN, Patel AK, Naik E, Patel KK, Dravid A, Patel JK, et al. Effectiveness of generic fixed-dose combinations of highly active antiretroviral therapy for treatment of HIV infection in India. J Acquir Immune Defic Syndr 2004; 37:1566–1569.
14. Kumarasamy N, Vallabhaneni S, Cecelia AJ, Yepthomi T, Balakrishnan P, Saghayam S, et al. Reasons for modification of generic highly active antiretroviral therapeutic regimens among patients in Southern India. J Acquir Immune Defic Syndr 2006; 41:53–58.
15. Van Oosterhout JJ, Bodasing N, Kumwenda JJ, Nyirenda C, Mallewa J, Cleary PR, et al. Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi. Trop Med Int Health 2005; 10:464–470.
16. Veldkamp AI, Weverling GJ, Lange JMA, Montaner JSG, Reiss P, Cooper DA, et al. High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals. AIDS 2001; 15:1089–1095.
17. Gonzalez de Requena D, Bonora S, Garazzino S, Sciandra M, D'Avolio A, Raiteri R, et al. Nevirapine plasma exposure affects both durability of viral suppression and selection of nevirapine primary resistance mutations in a clinical setting. Antimicrob Agents Chemother 2005; 49:3966–3969.
18. Oyugi JH, Byakika-Tusiime J, Charlebois ED, Kityo C, Mugerwa R, Mugyenyi P, et al. Multiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr 2004; 36:1100–1102.
19. Ramachandran G, Perloff ES, von Moltke LL, Swaminathan S, Wanke CA, Greenblatt DJ. Analysis of generic antiretroviral formulations manufactured in India. AIDS 2004; 18:1482–1484.
20. Penzak SR, Acosta EP, Turner M, Tavel JA, Masur H. Analysis of generic nevirapine products in developing countries. JAMA 2003; 289:2648–2649.
This article has been cited 15 time(s).
Journal of Infectious DiseasesRate of Accumulation of Thymidine Analogue Mutations in Patients Continuing to Receive Virologically Failing Regimens Containing Zidovudine or Stavudine: Implications for Antiretroviral Therapy Programs in Resource-Limited SettingsJournal of Infectious Diseases
Acta Clinica Belgica
Generics: Need for Clinical Concern?
Acta Clinica Belgica, 64(5):
Evaluation of transmitted HIV drug resistance among recently-infected antenatal clinic attendees in four Central African Countries
Antiviral Therapy, 14(3):
Lancet Infectious Diseases
Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review
Lancet Infectious Diseases, 10(3):
Stavudine in antiretroviral therapy
Medicina Clinica, 129():
Southern African Journal of Hiv Medicine
Short-term effectiveness and safety of HAART in the form of a generic fixed-dose combination of stavudine, lamivudine and nevirapine (Triviro) in HIV-1-infected adults in zimbabwe
Southern African Journal of Hiv Medicine, ():
Bmc Public HealthHepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in CameroonBmc Public Health
AIDS Research and Human RetrovirusesTolerability and effectiveness of first-line regimens combining Nevirapine and lamivudine plus zidovudine or Stavudine in CameroonAIDS Research and Human Retroviruses
Tropical Medicine & International HealthDeterminants of survival in AIDS patients on antiretroviral therapy in a rural centre in the Far-North Province, CameroonTropical Medicine & International Health
AIDS Research and Human RetrovirusesLow Prevalence of HIV Type 1 Drug Resistance Mutations in Untreated, Recently Infected Patients from Burkina Faso, Cote d'Ivoire, Senegal, Thailand, and Vietnam: The ANRS 12134 StudyAIDS Research and Human Retroviruses
Resistance profiles after different periods of exposure to a first-line antiretroviral regimen in a Cameroonian cohort of HIV type-1-infected patients
Antiviral Therapy, 14(3):
Hiv MedicineViral efficacy maintained and safety parameters improved with a reduced dose of stavudine: a pilot studyHiv Medicine
Double-Boosted Protease Inhibitor Antiretroviral Regimens What Role?
International Journal of PharmaceuticsThe effect of temperature and moisture on the amorphous-to-crystalline transformation of stavudineInternational Journal of Pharmaceutics
JAIDS Journal of Acquired Immune Deficiency SyndromesAdherence to Antiretroviral Therapy Assessed by Drug Level Monitoring and Self-Report in CameroonJAIDS Journal of Acquired Immune Deficiency Syndromes
© 2007 Lippincott Williams & Wilkins, Inc.