Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population

Clinical Infectious Diseases MAJOR ARTICLE Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population 1 Division of Infectious Diseases, Department of Medicine, Stanford University, 2Department of Internal Medicine, Kaiser Permanente Northern California, San Francisco, 3Department of Infectious Diseases, Kaiser Permanente Northern California, San Leandro, 4Department of Infectious Diseases, Kaiser Permanente Northern California, Oakland, and 5Department of Pathology, Stanford University, California; 6Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts; 7Division of Research, Kaiser Permanente Northern California, Oakland; and 8 Department of Biology, Temple University, Philadelphia, Pennsylvania Background. There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the United States. Methods. Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequences were obtained from 4253 antiretroviral therapy (ART)–naive individuals in a California clinic population from 2003 to 2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs. Results. From 2003 to 2016, there was a significant increase in overall (odds ratio [OR], 1.05 per year [95% confidence interval {CI}, 1.03–1.08]; P < .001) and nonnucleoside RT inhibitor (NNRTI)–associated TDR (OR, 1.11 per year [95% CI, 1.08–1.15]; P < .001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7% to 19.2%, and class-specific rates ranged from 10.0% to 12.8% for NNRTIs, 4.1% to 8.1% for nucleoside RT inhibitors (NRTIs), and 3.6% to 5.2% for protease inhibitors. The thymidine analogue mutations, M184V/I and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. Thirty-seven percent of TDR strains clustered with other TDR strains sharing the same DRMs. Conclusions. Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-naive individuals. Keywords. HIV-1 transmission; HIV-1 drug resistance; mutation; reverse transcriptase; protease. In the United States, routine human immunodeficiency virus type 1 (HIV-1) genotypic resistance testing at the time of diagnosis or prior to starting antiretroviral therapy (ART) began about 15 years ago [1, 2]. Although there have been several US studies of transmitted drug resistance (TDR) prevalence, few large studies have characterized the evolution of TDR, the drug resistance mutations (DRMs) responsible for TDR, and the predicted clinical significance of these DRMs [3–11]. Received 22 February 2018; editorial decision 15 May 2018; accepted 25 May 2018; published online May 26, 2018 Correspondence: S.-Y. Rhee, Division of Infectious Diseases, Stanford University Medical Center, 1000 Welch Rd, Suite 202, Stanford, CA 94304 (). Clinical Infectious Diseases®  2019;68(2):213–21 © The Author(s) 2018. Published by Oxford University Press for 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 the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact DOI: 10.1093/cid/ciy453 In this study, we examined the changing prevalence of TDR from 2003 to 2016 in a large clinic population in a region with high ART coverage. We also characterized the specific DRMs responsible for TDR, and the likely clinical significance of TDR in an era in which nonnucleoside reverse transcriptase inhibitor (NNRTI)–containing regimens are no longer preferred regimens for initial therapy, and in which thymidine analogues are rarely used. We performed phylogenetic analyses to determine how much TDR emanates from established circulating drug-resistant strains as opposed to multiple independent episodes of acquired drug resistance and to identify selection pressures at DRM positions in viruses from ARTnaive individuals. METHODS Study Cohort and Virus Samples The study cohort comprised all ART-naive adults in Kaiser Permanente Northern California (KPNC) undergoing dideoxynucleotide genotypic resistance testing of HIV-1 reverse Transmitted HIV-1 Drug Resistance • CID 2019:68 (15 January) • 213 Soo-Yon Rhee,1 Dana Clutter,1 W. Jeffrey Fessel,2 Daniel Klein,3 Sally Slome,4 Benjamin A. Pinsky,5 Julia L. Marcus,6 Leo Hurley,7 Michael J. Silverberg,7 Sergei L. Kosakovsky Pond,8 and Robert W. Shafer1 transcriptase (RT) and protease between January 2003 and December 2016 at the Stanford University Healthcare Diagnostic Virology Laboratory. KPNC is estimated provide care to approximately 25% of the insured population in Northern California [12]. Cohort individuals were characterized by age, gender, race, HIV acquisition risk factor, and baseline plasma HIV-1 RNA level and CD4 count. For ART-naive individuals having >1 resistance test, the virus sequence of the first test was analyzed. Sequences from 13 individuals not encompassing protease positions 10–90 and RT positions 40–240 were excluded. The Stanford University and KPNC institutional review boards approved this study. TDR was defined as the presence of 1 or more mutations from the World Health Organization 2009 list of 93 surveillance DRMs (SDRMs) at 43 positions, including 34 nucleoside reverse transcriptase inhibitor (NRTI)–, 19 NNRTI-, and 40 protease inhibitor (PI)–associated DRMs [13]. We determined the proportion of individuals with TDR to each class and with multiclass TDR. We used generalized binomial logistic regression models to assess the relationship between sample year and TDR and calculated the odds ratio for yearly increases in TDR prevalence. A subset of the NRTI-associated SDRMs were classified as thymidine analogue mutations (TAMs) including M41L, D67N/G, K70R, L210W, T215Y/F, K219Q/E/R/N, and the T215 revertants T215C/D/E/I/S/V (which evolve from T215F/Y in the absence of selective drug pressure). Several additional DRMs not on the SDRM list were analyzed including (1) the primarily tenofovir disoproxil fumarate (TDF)–selected DRMs A62V, K65N, and K70G/N/Q/S/T [14] and (2) the primarily rilpivirine (RPV)–selected DRMs E138A/G/K/Q, of which E138A is polymorphic, occurring in 1%–4% of viruses from ART-naive individuals [15, 16]. The Stanford H (...truncated)