Interplay Between Transmitted and Acquired HIV Type 1 Drug Resistance: Reasons for a Disconnect

Despite the impressive achievements of antiretroviral treatment (ART), human immunodeficiency virus type 1 (HIV-1) drug resistance remains a relevant obstacle to effective control of HIV-1 replication at both the individual and population levels. Suboptimal treatments and medication nonadherence are the major causes for selection of acquired drug resistance (ADR) in treated patients. Consequent to the development of ADR, drug-resistant HIV-1 can be transmitted to ART-naive individuals (transmitted drug resistance [TDR]), both from treated patients and from other untreated subjects carrying TDR mutations (so-called onward transmission). After an initial increase in the rate of HIV-1 drug resistance, more-recent population studies from resource-rich settings have documented a decreasing prevalence of ADR mutations in patients with virological failure while receiving ART (ie, those who do not achieve or maintain undetectable plasma HIV-1 RNA levels). This phenomenon is observed for all the 3 historical drug classes (nucleoside reverse transcriptase inhibitors [NRTIs], nonnucleoside reverse transcriptase inhibitors [NNRTI], and protease inhibitors [PIs]) in several European cohorts [1, 2]. Despite this decrease in the prevalence of ADR mutations, which represents the initial source of circulating HIV-1 drug resistance, the prevalence of TDR mutations has remained stable, at around 8%–10%, in these countries over the years [3]. As a possible explanation for this apparent paradox, TDR can be significantly fed by onward transmission of drug-resistant strains among clusters of untreated individuals [4, 5]. Moreover, resistant mutants have shown multiple rounds of onward transmission, sometimes occurring over several years [6]. In addition, different resistant variants are transmitted with different efficiency. Indeed, the reverse transcriptase mutation M184V is highly prevalent in patients who are not responding to treatment but rarely observed in untreated patients [7], because of its marked reduction in viral fitness and transmission efficacy [8]. Understanding the dynamics and interplay between ADR and TDR at a population level is necessary to optimize the effectiveness of ART-based interventions and appropriately target critical issues. In this issue of The Journal of Infectious Diseases, Yang et al, from the Swiss HIV cohort Study (SHCS), present their work trying to explain the apparent paradox between the decreasing prevalence of ADR mutations and stable or fluctuating prevalence of TDR mutations in their country [9]. The SHCS is highly representative of the whole country’s epidemic, and the authors performed a number of retrospective resistance tests on stored samples, allowing them to obtain an accurate picture of the prevalence of TDR mutations even in calendar years when testing was not yet routinely performed. It is sometimes difficult to obtain correct estimates of the prevalence of TDR mutations, owing to the waning of drug-resistant variants over time, but Yang et al tested a large number of recently infected patients, more accurately reflecting true estimates of the prevalence TDR mutations, another strong point of their study. The authors examined 2421 recently infected, treatment-naive patients and 5399 nonresponding patients. They correlated the prevalence of TDR mutations with that of ADR mutations observed during the previous calendar year. Their major observations were that ADR mutation prevalences, after peaking at 85% in 1998, dropped continuously Received and accepted 5 January 2015; electronically published 9 January 2015. Correspondence: Andrea De Luca, MD, UOC Malattie Infettive Universitarie, Azienda Ospedaliera Universitaria Senese, Viale M Bracci 16-53100 Siena, Italy (deluca.andrea2308@ icloud.com). The Journal of Infectious Diseases 2015;212:5–7 © The Author 2015. 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 anyway, and that thework is properly cited. For commercial re-use, please contact journals.permissions@oup. com. DOI: 10.1093/infdis/jiv008