The increasing visibility of the human misery caused by the HIV/AIDS pandemic in poor countries has emphasized the urgency of treatment. The World Health Organization (WHO)/UNAIDS ‘3 by 5’ programme  aims at increasing access to affordable antiretroviral drugs, especially fixed-dose combination generics pre-qualified by WHO. However, accounts of such experience are insufficiently documented. We report the preliminary results from a trial in which a fixed-dose combination of generic antiretroviral drugs is being used in the management of HIV-associated Kaposi's sarcoma (KS). These formulations may have a wider utility if shown to be effective at this extreme end of the HIV/AIDS spectrum.
HIV-associated KS is the commonest malignancy in patients with HIV infection. The dramatic increase in sub-Saharan Africa is a result of the high seroprevalence rates of HIV and human herpes virus 8 and a maturing AIDS epidemic. The survival rates of African HIV-associated KS range from 3.5 to 18 months after diagnosis .
The efficacy of generic highly active antiretroviral therapy (HAART) in HIV-infected African individuals has been demonstrated to a limited extent . There are no published studies in HIV-infected patients from southern Africa. In addition, relevant studies excluded patients on chemotherapy for malignancies [3,4]. We highlight our preliminary results in a cohort of HIV-associated KS patients enrolled in an ongoing HAART/chemotherapy therapeutic trial.
The primary objectives of the study were to assess the efficacy of generic fixed-dose HAART in patients with HIV-associated KS by quantifying viral suppression, determining the time to achieve viral suppression to less than 50 and less than 400 copies/ml, and the change in the CD4 cell count.
The data from the first 50 patients with HIV-associated KS on generic nevirapine, stavudine and lamivudine (Triomune; Cipla, Mumbai, India) were analysed. Twenty-five patients (50%) also received chemotherapy. The HIV-1 viral load (Nuclisens HIV-1 QT kit; Biomerieux, Boxtel, the Netherlands) and CD4 cell counts at days 0, 4, 7, 14, 28, and months 2, 3, 6, 9 and 12 were analysed. Adverse events were documented. Adherence was assessed by 7-day self-report.
The primary outcome was the achievement of an undetectable viral load (< 50 copies/ml). Secondary outcomes were a change in viral and CD4 cell count from baseline, the time to complete viral suppression, incidence rates of deaths and severe adverse events. An intention to treat analysis was used. Non-parametric methods were used to describe and compare log viral loads and CD4 cell counts, Friedman tests were used to examine the change over time, and Kaplan–Meier survival analysis was used to describe the median time to viral lowest detectable limit (LDL). Incidence rates were reported per 10 000 person-days, and were calculated using person-days denominators obtained from the time to the development of a severe adverse event or death, or the total time of follow-up in those who did not develop severe adverse events or die. All analysis was performed using SPSS version 11.5.
All patients had AIDS at baseline, with a median CD4 cell count of 135cells/mm3 [interquartile range (IQR) 69–320, n = 50] and viral loads of 4.7 log10 copies/ml (IQR 4.2–5.1, n = 47). At 52 weeks, the median CD4 cell count was 375 cells/mm3 (IQR 219–514, n = 20) and the viral load was 1.69 log10 copies/ml (IQR 1.69–1.97, n = 20). Twenty patients completed 52 weeks follow-up. For all 20 with valid data at baseline and 52 weeks, the median increase in the CD4 cell count was 126 cells/mm3 (IQR 70–205; P < 0.001). The median decline in log10 viral load was 3.1 (IQR 2.1–3.6; P < 0.001) (see Fig. 1). The viral load was less than 50 copies/ml in 74% and less than 400 copies/ml in 86% of patients after 52 weeks’ follow-up. Fig. 2 shows the proportion of participants at each timepoint who reached the LDL. The proportion with LDL increased steeply until 12 weeks, and thereafter leveled off. The median time to viral suppression below detectable levels was 84.4 days for viral loads of less than 50 copies/ml [95% confidence interval (CI) 60.4–108.3 days] and 28.1 days for viral loads of less than 400 copies/ml (95% CI 26.0–30.3 days). Mean adherence by self-report was 89%.
There were eight deaths and two patients were lost to follow-up. The mortality rate was 8.43 per 10 000 person-days. Five deaths occurred within 8 weeks of therapy as a result of advanced AIDS, two occurred as a result of advanced KS, and one occurred as a result of nevirapine hepatitis. The incidence rates of severe adverse events per 10 000 person-days were: AIDS related 6.22; HAART related 4.07; KS related 2.91, and KS unrelated 0.96, and total 15.18. The median time to a severe adverse event was 404 days. At 52 weeks, six patients (12%) were showing resistance and were changed to second-line therapy.
Our results using the most widely used fixed-dose combination of HAART for the management of advanced HIV/AIDS in this report are comparable with those reported with brand-name antiretroviral drugs. Viral load suppression, CD4 cell responses, drug-related toxicities, and deaths were similar to those obtained with the same HAART regimen utilizing brand-name drugs in less severe forms of HIV/AIDS . At 48 weeks, the median increase in CD4 cell count was 150 cells/mm3, and 74% of patients reached viral loads of less than 50 copies/ml, compared with 126 cells/mm3 and 76% in our cohort with 50% on concomitant chemotherapy, which this study excluded. Our results also compare favourably with a study utilizing a brand-name protease inhibitor-based regimen and chemotherapy for HIV-associated KS , with 49% reaching undetectable viral loads (< 500 copies/ml) and a CD4 cell count increase of 173 cells/mm3 at 52 weeks compared with 86% (< 400 copies/ml) and 126 cells/mm3 in our cohort.
Our early experience indicates that the generic fixed-dose combination of stavudine, lamivudine and nevirapine is effective and holds much promise. Although further studies are required to support their use fully, the available data support their use to achieving widespread access in resource-limited settings, as advocated by the WHO/UNAIDS ‘3 by 5’ strategy.
Conflict of interest
The authors have no commercial associations (consultations, stock ownerships, equity interests, patient-licensing arrangements, etc.) that might pose a potential conflict of interest in connection with the submitted manuscript. The generic fixed-dose HAART Triomune was donated by Cipla, Mumbai, India. Cipla had no part in the conceptualization, study design, implementation or write-up of the results.
Sponsorship: The study received funding from the N.R.F. Thuthuka grant GUN 2054349, Dermatological Society research grant and AMC supplemental grant 5U01 CA70019-09.
1. UNAIDS/WHO. Emergency scale up of antiretroviral therapy in resource limited settings: technical and operational recommendations to achieve 3 by 5. Report of the WHO/UNAIDS International Consensus Meeting on Technical and Operational Recommendations for Emergency Scaling-up of Antiretroviral Therapy in Resource-Limited Setting
. Lusaka, Zambia, 18-21 November 2003. Geneva: World Health Organisation; 2003.
2. Thomas JO. Acquired immunodeficiency syndrome-Associated cancers in Sub-Saharan Africa. Semin Oncol 2001; 28:198–206.
3. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue 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.
4. Van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomized open-label trial, the 2NN study. Lancet 2004; 363:1253–1263.
5. Dupont C, Vasseur E, Beauchet A, Aegerter P, Berthe H, de Trucis P, et al
. Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. AIDS 2000; 14:987–993.