Assessments of HIV Drug Resistance Mutations in Resource-Limited Settings

At the end of 2009, 5.25 million persons were receiving antiretroviral therapy (ART) worldwide, representing an 10fold increase over a period of 5 years [1]. The global scale-up of ART has led to an inevitable increase in HIV drug resistance (HIVDR) and a pool of resistant virus available to establish new infections. The report by Sungkanuparph et al in this issue highlights the need for strengthened national, regional, and global surveillance of HIVDR for the purpose of informing public health policy [2]. Because .739,000 persons are receiving ART in East, South, and Southeast Asia [3], the paucity of data on emergence of HIVDR in populations taking ART in this region is striking. Broadly, there are 3 categories of HIVDR. Acquired HIVDR occurs when resistance mutations are selected for by drug selective pressure in individuals receiving ART. In individuals receiving ART, acquired HIVDR may emerge because of suboptimal adherence, treatment interruptions, inadequate plasma drug concentrations, or the use of suboptimal drug or drug combinations. Transmitted HIVDR occurs when previously uninfected individuals are infected with drug-resistant virus. The term ‘‘transmitted HIVDR’’ is appropriately applied only to HIVDR detected in recently infected individuals. The third category is HIVDR detected in individuals with chronic infection in which drug resistance can be either transmitted or acquired. This last category is important because it is the focus of the analysis presented by Sungkanuparph et al. Transmitted HIVDR may persist for many months or years in the absence of drug selective pressure (ie, in individuals naive to ART), although duration varies by mutation. For example, the reverse transcriptase (RT) mutation M184V, which confers resistance to the nucleoside reverse-transcriptase inhibitors (NRTI) lamivudine and emtricitabine, reduces viral fitness, whereas the K103N and Y181C mutations that cause resistance to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP) and efavirenz (EFV) have little impact on viral fitness [4]. In an individual infected with a virus with drug resistance mutations that only modestly reduce fitness, most but not all mutant species are likely to persist over long periods. Specifically, M41L, T69N, K103N, and some T215 variants show little tendency to revert to wild-type over time. However, it is theoretically possible that some transmitted drug-resistant HIV strains may have reverted to wildtype before genotypic assessment [5–7] or have decreased to levels below the threshold of detection by populationbased sequencing, persisting as minority variants or archived resistance in proviral DNA [8]. Sungkanuparph et al rightly indicate that this may result in an underestimation of transmitted resistance in chronically infected patients. However, some HIVDR detected in chronically infected patients may be acquired because of previous ART exposure not elicited at the time of testing because of social desirability bias, desire of individuals to participate in a particular study, or interviewer bias. Nonetheless, there is value in surveying HIVDR in populations starting ART in settings where transmitted drug resistance is known to occur at high levels, and results provide data about the likely efficacy of currently available regimens in patients starting ART. An important consideration in determining the prevalence of HIVDR is the method used to classify mutations. When assessing transmitted HIVDR, the Received 17 January 2011; accepted 25 January 2011. Correspondence: Michael Jordan, MD, MPH, Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, 800 Washington St, Box 41, Boston, MA 02111 (mjordan@tuftsmedicalcenter.org). Clinical Infectious Diseases 2011;52(8):1058–1060 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. 1058-4838/2011/528-0017$14.00 DOI: 10.1093/cid/cir093