Editorial Commentary: Comparative Efficacy of Lamivudine and Emtricitabine: Comparing the Results of Randomized Trials and Cohorts

Over the last decade, World Health Organization (WHO) guidelines for human immunodeficiency virus (HIV)/AIDS treatment and care have evolved toward simplifying recommendations for firstline antiretroviral therapy (ART) to promote a public health approach to treatment scale-up [1].Whereas in 2002, WHO recommended 5 different treatment options for first-line ART, the latest guidelines released in 2013 recommend a single first-line regimen comprising tenofovir, efavirenz, and either lamivudine or emtricitabine, preferably as fixed-dose combinations [2]. These last 2 nucleoside analogues were recommended as interchangeable based on the results of a systematic review and meta-analysis of randomized trials showing no difference in rates of virological suppression, virological failure, or the development of resistance mutations [3]. Lamivudine is available from multiple generic sources and is cheaper than emtricitabine [4]. In this issue of Clinical Infectious Diseases, an analysis from Rokx et al and the AIDS Therapy Evaluation in the Netherlands nationwide HIV cohort (ATHENA) HIV treatment cohort in the Netherlands suggests better virological responses to emtricitabine compared with lamivudine as part of first-line ART. The authors of this nonrandomized cohort study conclude that using lamivudine instead of emtricitabine may result in additional morbidity and costs associated with virological failure and the development of drug resistance [5]. To date, 3 randomized clinical trials (n = 1242) have directly compared lamivudine and emtricitabine; the pooled results of these trials found no difference in terms of virological suppression (relative risk [RR], 1.03; 95% confidence interval [CI], .96–1.10) or virological failure (RR, 0.93; 95% CI, .74–1.18). In comparison, the risk of virological failure in the ATHENA cohort was three times higher for patients receiving lamivudine compared with efavirenz (RR, 2.99; 95% CI, 2.08–4.30). How should clinical guidelines respond to this seemingly contradictory evidence from 3 randomized trials vs a nonrandomized cohort study? The development of clinical guidelines by WHO and an increasing number of national guidelines follows the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, which rates the quality of evidence supporting a recommendation according to 5 criteria: risk of bias, imprecision, inconsistency, indirectness, and publication bias [6].Randomized trials are generally rated as high-quality evidence but can be downgraded if key methodological issues arise. According to the GRADE approach, observational studies are usually rated as low-quality evidence but can be upgraded based on the quality of evidence under certain exceptional conditions [7]. Adequately powered randomized clinical trials are also required for the marketing approval of new antiretrovirals by the US Food and Drug Administration and other regulatory authorities; cohort studies in which different treatments are compared are not acceptable for such approvals [8]. Observational studies have made invaluable contributions in the field of HIV/AIDS, providing evidence of the feasibility of delivering ART at scale, giving insights into innovations in service delivery that could help efforts to support further ART scale-up, and generating datasets on adverse drug reactions that may not be apparent in trial settings. However, randomized trials remain the gold standard Received 17 September 2014; accepted 23 September 2014; electronically published 1 October 2014. Correspondence: Nathan Ford, PhD, World Health Organization, 20 Avenue Appia, 1211 Geneva, Switzerland ( fordn@ who.int). Clinical Infectious Diseases 2015;60(1):154–6 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of thework, in anymedium, provided theoriginalwork is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup. com. DOI: 10.1093/cid/ciu767