(See the Review Article by Tang et al, on pages 862–75.)
The rollout of antiretroviral therapy (ART) in resource-limited settings has had a profound impact on AIDS-related morbidity and mortality. According to the World Health Organization, >5 million human immunodeficiency virus (HIV)–infected persons in low- and middle-income countries were receiving ART at the end of 2009, the most recent year for which data are available . In South Africa alone, the availability of ART has reduced mortality from AIDS by 3.3% since the peak in 2006, saving an estimated 700000 life years .
Despite this impressive progress, the World Health Organization estimates suggest that only one-third of persons who meet guidelines for ART are receiving treatment . Funding for ART has come from the US President’s Emergency Plan for AIDS Relief (PEPFAR), the Global Fund for AIDS, Tuberculosis and Malaria, other donor programs and, in many countries, local governments. The increasing number of patients in need of ART and the growing number requiring more costly second-line regimens have strained the budgets of AIDS treatment programs at the same time that the global economic crisis has sapped the resources of donor countries. Rising healthcare costs and shrinking revenues have constrained AIDS budgets in wealthy countries, too. As a result, pressure is mounting to make greater use of less-expensive regimens in order to maximize access to ART.
One concern about financial pressures to use the least-expensive ART regimens is that data may be lacking to substantiate their activity. In this issue of Clinical Infectious Diseases, Tang et al raise concerns about the efficacy of tenofovir, lamivudine, and nevirapine as an initial ART regimen . They conducted a systematic review of 33 studies that assessed the efficacy of tenofovir plus lamivudine or emtricitabine administered with nevirapine or efavirenz. The tenofovir-lamivudine-nevirapine combination was the least well-studied of the 4 possible regimens based on these drugs and appeared to be the least efficacious. Two prospective trials of this regimen were halted due to unacceptably high early failure rates, and a retrospective cohort study of regimens administered in 4 Nigerian clinics through the PEPFAR program found tenofovir-lamivudine-nevirapine to have a significantly higher rate of virologic failure as compared with tenofovir-lamivudine-efavirenz or tenofovir-emtricitabine-efavirenz. Regimens that included tenofovir-emtricitabine plus nevirapine fared somewhat better: in randomized clinical trials, tenofovir-emtricitabine-nevirapine had similar virologic efficacy to the comparator regimens, which included tenofovir-emtricitabine plus ritonavir-boosted atazanavir or ritonavir-boosted lopinavir. In the Nigerian PEPFAR cohort study, however, tenofovir-emtricitabine-nevirapine was less efficacious than either zidovudine-lamivudine-nevirapine or tenofovir-emtricitabine-efavirenz.
It should be emphasized that the PEPFAR cohort study is not a randomized trial and, as noted by Tang et al , comparison of treatment outcomes is subject to the usual caveats regarding analyses of such data. The main concerns are residual confounding and confounding by indication. That is, despite the apparent similarity of pretreatment characteristics, patients treated with tenofovir-lamivudine-nevirapine may have differed in important ways from other patients in the cohort, particularly those who received zidovudine-lamivudine-nevirapine or tenofovir-emtricitabine-efavirenz, and factors associated with treatment outcome but not accounted for in the analysis may have influenced clinicians’ decisions to select one regimen or the other. It is also important to note that tenofovir-lamivudine–based and tenofovir-emtricitabine–based regimens were not available in the earlier years of the ART rollout in Nigeria, and therefore differences in calendar year of treatment initiation could be an important covariate not controlled for in the analyses reported here. A fuller understanding of these results must await publication of a more comprehensive analysis of the PEPFAR data.
It is also important to note that although the rate of virologic failure was significantly greater in the once-daily tenofovir-lamivudine-nevirapine arm compared with the twice-daily zidovudine-lamivudine-nevirapine arm in the DAUFIN trial , the failure rate of the 2 regimens is not significantly different in an intention-to-treat analysis that counts regimen discontinuation and loss to follow-up as treatment failure (15 [42%] of 36 vs 13 [37%] of 35 for the tenofovir-lamivudine-nevirapine and zidovudine-lamivudine-nevirapine arms, respectively; P = .88 by χ2 test [our analysis]). It is possible that poor tolerability of the zidovudine-containing regimen counterbalanced the lower virologic failure rate of that regimen. This possibility is supported by the findings of the AIDS Clinical Trials Group A5175 trial, which found similar virologic efficacy of tenofovir-emtricitabine-efavirenz and zidovudine-lamivudine-efavirenz but significantly higher treatment switches and toxicity rates in the zidovudine-lamivudine-efavirenz arm .
Tang et al  propose a number of plausible explanations for why tenofovir-lamivudine-nevirapine may be less potent than other regimens, including intrinsic differences in potency, genetic barrier to resistance, and plasma and intracellular pharmacokinetics of the component drugs compared with those of drugs in other combination regimens. As the authors remind us, seemingly potent combinations of antiretroviral drugs have produced disappointing results in the past , and the efficacy of some regimens may be less than the sum of their parts . Toxicities associated with nevirapine, including rash and hepatotoxicity, may also limit overall efficacy .
With increasing competition among manufacturers of generic drugs, the price of nucleoside and nonnucleoside reverse-transcriptase inhibitors continues to fall. A strategy to identify the most efficacious treatment regimen, focus global treatment guidelines on a simplified regimented treatment approach, and scale up generic competition to meet the procurement demand has led to significant decreases in the annual per-patient cost of drugs . Nevertheless, it is likely that nevirapine-based regimens will continue to be an important component of ART in some resource-limited settings because of the large number of women of childbearing age who need effective, safe, inexpensive, and convenient ART. The concerns raised by Tang et al  emphasize the need for adequately powered, prospective, randomized trials to establish the efficacy of tenofovir-lamivudine-nevirapine before that regimen can be recommended with confidence as an alternative to other established, albeit more costly, regimens. International bodies proposing treatment guidelines and the generic drug manufacturers who market antiretroviral drugs in resource-limited settings have an obligation to provide the resources needed to conduct such studies.