A World Health Organization (WHO) preapproved fixed-dose antiretroviral combination pill is safe and effective in clinical practice, according to a study published in the May edition of AIDS. The international relief agency, Medicins Sans Frontieres, conducted an analysis of the use of a fixed-dose pill comprising 3TC/d4T/nevirapine in 21 treatment centres in resource-limited settings and on the basis of their findings recommend the rapid implementation and funding of this fixed-dose treatment as first-line HIV therapy in resource-limited settings.
WHO recommend a fixed-dose combination pill comprising two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) as first-line antiretroviral therapy in resource-limited settings. The advantages of fixed-dose treatment are easier adherence and cost. However, only one NRTI/NNRTI, which includes 3TC, d4T and nevirapine was prequalified by WHO.
The safety, tolerability and effectiveness of this fixed-dose combination is not universally accepted and its use is not supported by all agencies. It is well known that 3TC and nevirapine show a low genetic barrier to resistance; that nevirapine can be associated with rash and liver toxicity; and, that d4T can cause severe side-effects such as peripheral neuropathy, lactic acidosis and lipodystrophy.
Doctors from Medicins Sans Frontieres therefore conducted a review looking at the use of 3TC/d4T/nevirapine fixed-dose treatment. They monitored the clinical and immunological outcome of over 6,500 individuals receiving this treatment. In addition, doctors anaylsed safety data for a subset of 655 patients who had received at least twelve months of therapy.
Treatment was provided to patients with advanced symptoms of HIV infection or with a CD4 cell count below 200 cells/mm3. Three quarters of the Medicins Sans Frontiers treatment programmes were in Africa, 24% in Asia, and 1% in Central America.
Median age of patients receiving free antiretroviral therapy was 34 years, and 61% were women. The majority of patients (88%) had never taken any antiretroviral drugs before prior to commencing fixed-dose therapy. Advanced HIV disease was a notable feature of patients starting treatment. A little over 33% of patients had AIDS, a similar percentage had a body mass index below 18kg/m2 and 32% had moderate or severe anaemia. Only 4,900 patients had a CD4 cell count available prior to the initiation of antiretroviral therapy, and amongst these individuals the median CD4 cell count was only 89 cells/mm3, with 33% having a CD4 cell count below 50 cells/mm3.
Median follow-up was available for a little over four months. A total of 413 patients (6%) died, 328 (5%) were lost to follow-up and 128 (2%) stopped antiretroviral therapy. The overwhelming majority, 5,992 (87) remained on antiretroviral therapy and all but 476 of these were taking their initial fixed-dose combination.
The investigators noted that of the 413 deaths that occurred, the vast majority (69%), occurred during the first three months of anti-HIV treatment, before antiretroviral therapy had had an opportunity to restore the immune system.
Amongst patients for whom data were available, the investigators recorded a median increase in CD4 cell count of 102 cells/mm3 after six months of treatment and a median increase of 173 cells/mm3 after 18 months of therapy.
Overall mortality was 14.2 per 100 person years and factors significantly associated with an increased risk of death included AIDS at baseline (HR, 3.86); a body mass index below 18 kg/m2 (HR, 2.38); haemoglobin below 80g/l (HR, 2.62) and a CD4 cell count count below 50 cells/mm3 (HR, 2.54).
The investigators then looked in detail at the subset of individuals who had at least twelve months efficacy and safety data after starting fixed-dose treatment. These 655 patients had a median baseline CD4 cell count of 79 cells/mm3. After a year, 13% had died, 9% were lost to follow-up and 1% had stopped fixed-dose therapy. A total of 503 patients (77%) were still taking their initial fixed-dose treatment. Once again, the majority of deaths (63%) occurred during the first three months of antiretroviral therapy. Median increase in CD4 cell count after twelve months was 133 cell/mm3. No individual switched to an alternative antiretroviral combination because of clinical or immunological failure during the first year.
Of the 52 patients who discontinued fixed-dose treatment, all but one switched to an alternative anti-HIV treatment regimen. Difficulties with nevirapine caused 42 individuals to stop treatment, and nine stopped because of side-effects associated with d4T. Treatment was stopped a median of 29 days after initiation if nevirapine was the reason and 215 days after initial commencement if d4T toxicity was the cause.
Efficacy and safety data were also available for 126 patients extending to 18 months. A total of 22 (18%) of these patients had died; six (5%) were lost to follow-up and one (1%) had stopped anti-HIV therapy. Of the 97 individuals still taking anti-HIV treatment, 75 were taking their initial fixed-dose therapy. CD4 cell counts were available for 39 patients and these individuals had a median increase in their CD4 cell count at month 18 of 165 cell/mm3.
The investigators were encouraged by these results and write, “despite the fact that these patients were severely immunocompromised we found that 76.8% ...were still on HAART at 1 year. Only...12.5% of severely ill patients had died, most during the first months of therapy.” They add, “the present study shows the benefit of fixed dose combination extends beyond satisfactory surrogate markers, giving survival results comparable to those initiating antiretroviral therapy in developing countries and in developed countries in the early era of HAART.”
When the investigators looked at the reasons for treatment discontinuation, they noticed that a third were due to the commencement of anti-tuberculosis therapy. They conclude that “these MSF cohort results confirm the efficacy and safety of generic fixed-dose combination in preventing AIDS-related death in resource-poor settings. Funding and implementing agencies should support without reservation the rapid scale up of this simple first-line treatment in resource-poor settings."
Calmy A et al. Generic fixed-dose combination antiretroviral treatment in resource-poor settings: multicentric observational cohort. AIDS 20: 1163 - 1169, 2006.