The combination of AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and tenofovir (Viread) is an effective first-line regimen in adult HIV patients in Africa, according to a cohort study published in the 26th June edition of AIDS. The study found that most patients starting HIV treatment with this combination achieve viral suppression over the first year of therapy, supporting its use as first-line therapy in resource-limited settings.
The most commonly used HIV treatment combinations in the developing world consist of two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI), usually nevirapine (Viramune). Although the World Health Organization (WHO) endorses this approach, NNRTI side-effects can be more severe in patients receiving treatment for tuberculosis and in people with high CD4 cell counts, particularly in women. In addition, efavirenz (Sustiva), the other available NNRTI, is not recommended for use during pregnancy.
To avoid these risks, WHO recommends an alternative ‘simplification strategy’ where the NNRTI is replaced with a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI / NtRTI). This preserves NNRTIs for use in second-line therapy, is well tolerated and requires patients to take a small number of pills every day.
Studies in the developed world have found that some triple nucleoside / nucleotide combinations are less potent than combinations including an NNRTI, due to the emergence of drug resistance and treatment failure. However, few studies have examined the combination of AZT, 3TC and tenofovir as first-line therapy, particularly in resource-limited settings.
Accordingly, investigators from the DART trial analysed the response of 300 adult patients starting this anti-HIV drug combination over the first 48 weeks of treatment. All of the patients started with a CD4 cell count below 200 cells/mm3, with a median viral load of 280,000 copies/ml.
After 24 weeks, 59% of the patients had viral loads below 50 copies/ml, rising to 61% by 48 weeks. This was mirrored by CD4 cell count increases of 103 and 127 cells/mm3 at 24 and 48 weeks, respectively, from a median of 101 cells/mm3.
Nineteen (6%) of the patients died before week 48.
“We demonstrate good antiviral efficacy of AZT / 3TC / tenofovir over 48 weeks, in the context of a population in Africa with advanced HIV disease and a high prevalence of opportunistic infections infected with subtypes A, C and D,” the investigators conclude. “These data support the use of such a drug combination as first-line therapy within resource-limited settings.
“Our results compare favourably with data derived from similarly immunosuppressed individuals in other cohorts,” they comment.
The investigators discovered that patients with higher CD4 cell count at the start of treatment were more likely to achieve a suppressed viral load by 48 weeks (p = 0.009). Being female and being older were also linked to viral suppression, but there was no significant impact of viral load before treatment.
The researchers also carried out resistance analysis of HIV from 20 of the 24 patients with viral loads above 1000 copies/ml at week 24 of treatment. Eighteen of the samples had major resistance mutations in the gene for reverse transcriptase, with 14 of these having the M184V mutation that is associated with 3TC resistance. Ten of these also had one to four nucleoside analogue mutations (NAMs), which cause resistance to all NRTIs.
Only three samples had the K65R mutation, which is linked to tenofovir resistance. The investigators believe that this mutation’s low rate of occurrence was due to the patients also taking AZT. In contrast to its effect on other NRTIs, K65R is thought to increase the potency of AZT.
DART is a large, randomised study assessing strategies for antiretroviral therapy at multiple sites in Uganda and Zimbabwe. Its main aim is to determine the effectiveness and feasibility of adding laboratory analysis of blood samples to simple clinical monitoring in the care of people with HIV. To date, almost three quarters of the participants in DART have started treatment with AZT, 3TC and tenofovir.
DART Virology Group and Trial Team. Virological response to a triple nucleoside / nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS 20: 1391-1399, 2006.