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The clinical implications of pretreatment drug resistance -- a moving target.

Drug-resistance testing is not routinely available in the lowand middle-income countries with the highest human immunodeficiency virus (HIV) prevalence. The choice of first-line antiretroviral therapy (ART) regimens in these areas is thus informed by HIV drug resistance surveillance studies in people who initiate therapy. World Health Organization (WHO)–prescribed studies initially quantified transmitted drug resistance (TDR) in recently infected individuals, but these studies were subsequently expanded to assess pretreatment drug resistance (PDR) by including people who present for initial therapy, those in whom ART was interrupted, and those who received ART to prevent mother-to-child transmission. This surveillance strategy reflects the programmatic reality of the WHO’s public health approach that initiates HIV treatment in all people without a documented history of virological failure (VF) on the same first-line regimen [1]. Not surprisingly, PDR rates are usually higher than those of TDR, although there has been a worrisome gradual upward trend in both. Nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated PDR rates approach 10% in Latin America and many parts of Southern and Eastern Africa, with lower rates in Asia and West and Central Africa [2]. NNRTIassociated PDR causes great concern, as any one of several mutations is often sufficient to markedly reduce NNRTI susceptibility. Conversely, some nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI)-associated drug-resistance mutations (DRMs), particularly several of the thymidine analog mutations selected by zidovudine (AZT) and stavudine (d4T), are less likely to compromise an NRTI backbone that contains tenofovir (TDF). The study by Derache and colleagues is the largest to assess the effect of baseline NNRTI resistance on the virological response to the fixed-dose combination of TDF/emtricitabine (FTC)/efavirenz (EFV), one of the WHO-recommended first-line ART regimens [3]. It is also one of the largest studies to quantify PDR prevalence using a next-generation sequencing technology, Illumina MiSeq, in place of the more common dideoxynucleoside Sanger sequencing technology. The authors defined PDR at frequencies of ≥20% and ≥5% to detect 1 or more mutations from a list of WHO-defined surveillance DRMs [4] within a person’s virus population. The 20% threshold approximates the sensitivity of Sanger sequencing, which usually detects mutations in ≥20% of a person’s plasma viruses. The more sensitive 5% threshold is often used to identify lower abundance mutations not typically detected by Sanger sequencing. The prevalence of NNRTI-associated PDR in the cohort of 1148 people undergoing successful resistance testing was 8.8% and 11.1% using the 20% and 5% thresholds, respectively. Both prevalences are similar to recently reported PDR rates from Southern and Eastern Africa [2]. Additional analysis was performed on the 837 people in the cohort who began therapy and had at least 1 follow-up virus load test. Of these, 67 (8.0%) and 82 (9.8%), respectively, had NNRTIassociated PDR using the 20% and 5% thresholds. Five (0.6%) and 7 (0.8%) people had combined NRTI plus NNRTI PDR using these thresholds. Sequencing detected just 1 NNRTI-associated DRM, K103N, in approximately 75% of persons with NNRTI-associated PDR, whereas K103N was detected in combination with a second NNRTI-associated DRM in about 10% of persons. In the few people with combined NRTI plus NNRTI PDR, there was a strong, albeit nonstatistically significant, trend toward a reduced likelihood of achieving virological suppression using both the 20% and 5% detection thresholds. However, at both thresholds and in both unadjusted and adjusted regression models, NNRTI-associated PDR was not associated with a reduced likelihood of virological suppression. In contrast, a high baseline virus load and reduced E D I T O R I A L C O M M E N T A R Y