Efavirenz has proved more durable than nevirapine in an African cohort study. Efavirenz use also resulted in better adherence levels and fewer discontinuations than nevirapine use; however, the virologic results were not dependent on these alone. The results (which expand on those presented at last year’s CROI) were published in the October 18 issue of AIDS.
In Africa and other resource-limited settings, drug combinations based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) are frequently used as first-line antiretroviral therapy (ART), and nevirapine (Viramune) is more widely used than efavirenz (Sustiva). While head-to-head comparisons of the two drugs (such as the 2NN study) have tended to favour efavirenz, results have arguably not been completely decisive.
In this cohort study, researchers evaluated records from 2817 HIV-positive adults in nine countries of southern Africa, who received treatment through a private-sector HIV/AIDS programme, Aid for AIDS. People enrolled on the programme were eligible for ART with either a CD4 cell count repeatedly below 350 cells/mm3 or a confirmed AIDS-defining illness. Participants were included in the study if they were 18 years or older, ART-naïve, had no previous documented viral load below 400 copies/ml, and began either nevirapine-based or efavirenz-based therapy between January 1998 and September 2004. Choice of treatment was decided by the treating physician.
Of the 2817 patients included in the study, 1822 (64.7%) were started on efavirenz and 995 (35.5%) on nevirapine. At baseline, those on nevirapine were younger (mean, 36.0 versus 37.5 years), more likely to be female (67.5% versus 60.3%), had higher median CD4 cell counts (171 cells/ mm3 versus 136 cells/mm3), lower median viral loads (5.1 log10 copies/ml versus 5.2 log10 copies/ml), started treatment earlier in calendar time, and were more likely to receive AZT/3TC (87.0% versus 72.5%) (p
The median follow-up period was two years. The primary outcome was time to virologic failure (two viral loads ≥ 400 copies/ml). Secondary outcomes included all-cause mortality, time to viral load
By this broad measure of adherence, 100% adherence rates were less frequent with nevirapine than with efavirenz (30.2% versus 38.1%, p
In univariate analysis, those who started on nevirapine were more likely to experience virologic failure (20.4% versus 13.8%) or to discontinue their NNRTI without virologic failure (15.4% versus 8.9%). After controlling for other factors in multivariate analysis, nevirapine was still associated with a higher risk of virologic failure (hazard ratio [HR] 1.52; 95% confidence interval [CI], 1.24-1.86) and discontinuation (HR, 1.67; 95% CI, 1.32-2.11), as well as a higher overall risk of death (HR, 2.17; 95% CI, 1.31-3.60, p
Faster time to failure was seen in people with lower baseline CD4 cell counts (HR 1.52; 95% CI, 1.16-1.99, p = 0.004, for ≤ 50 versus > 200 cells/ mm3), initial use of d4T/ddI (HR 1.48; 95% CI, 1.15-1.91, p = 0.001, versus AZT/3TC) or AZT/ddI (HR 2.35; 95% CI, 1.07-5.18, p = 0.03), calendar year of antiretroviral initiation (HR 1.57; 95% CI, 1.29-1.90, p
A secondary analysis looked at outcomes in the 177 patients who switched NNRTIs (123 before reaching suppression, 54 after). Switching from nevirapine to efavirenz had no significant effect on failure or time to failure. However, switching from efavirenz to nevirapine resulted in significantly slower time to suppression (HR 0.58; 95% CI, 0.35–0.93) in those who switched before suppression, and faster time to failure (HR 3.92; 95% CI, 1.61-9.55) in those who were suppressed. Due to the limited sample size, the investigators urged caution in interpreting these results.
Possible confounders and explanations have already been reported from lead investigator Jean Nachega’s CROI presentation. As NNRTI selection was at the discretion of individual physicians, there may have been selection biases: nevirapine use, for instance, was more widespread near the beginning of the study. The use of single-dose nevirapine for prevention of mother-to-child transmission (PMTCT) was not thought to be a significant factor, as short-course HIV treatment was the standard of care for PMTCT in the population studied.
The investigators concluded that these findings, “consistent with comparable studies from the developed world”, demonstrate that “in initial highly active antiretroviral therapy regimens, efavirenz was associated with superior virologic and clinical outcomes than nevirapine”. However, due to potential limitations and the observational nature of the study, they also cited the “critical need for a large, randomized, clinical trial to definitively compare the outcomes of efavirenz and nevirapine,” and for “acceleration of efforts to develop lower cost formulations of efavirenz, including generic, fixed-dose combinations”.
Reference:
Nachega JB et al. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 22:2117–2125, 2008.