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      Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

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      1 , * , 2 , 3 , 4 , 5 , 1 , 6 , 7 , 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 16 , 32 , 33 , 34 , 35 , 36 , 1 , 37 , 38 , 39 , 40 , 11 , 34 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 12 , 38 , 50 ,   51 , 52 , 53 , 36 , 54 , 55 , 32 , 37 , 52 , 42 , 56 , 15 , 57 , 58 , 40 , 33 , 59 , 60 , 5 , 61 , 1
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          Abstract

          Background

          Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.

          Methods and Findings

          We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.

          Conclusions

          Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

          Abstract

          In this individual patient and sequence-level meta-analysis, Soo-Yon Rhee and colleagues measure regional trends in HIV-1 transmitted drug resistance prevalence and investigate the specific mutations responsible for TDR in different regions and in different virus subtypes.

          Editors' Summary

          Background

          About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells and leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years of infection. Then, in 1996, effective antiretroviral (ARV) therapy—drug combinations that suppress HIV replication by inhibiting reverse transcriptase and other essential viral enzymes—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ARV therapy was expensive, HIV/AIDS remained fatal in low- and middle-income countries (LMICs). In 2003, the international community began to work towards achieving universal access to ARV therapy. Now, more than 10 million HIV-positive individuals in LMICs receive ARV therapy, usually as a fixed-dose combination of two nucleoside reverse transcriptase inhibitors (NRTIs), such as tenofovir and lamivudine, plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz or nevirapine.

          Why Was This Study Done?

          The global scale-up of ARV therapy has reduced deaths from HIV/AIDS and the incidence of HIV infection in LMICs, but the development of resistance to ARV therapy is threatening these advances. HIV rapidly accumulates genetic changes (mutations), some of which make HIV resistant to ARV therapy. Up to 30% of patients receiving a fixed-dose NRTI/NNRTI combination develop virological failure, and a high proportion of these patients develop mutations associated with resistance to the ARVs in their regimen. Moreover, the proportion of newly infected, ARV-naïve individuals with transmitted drug resistance (TDR) is also increasing. Organizations involved in HIV/AIDS control need to understand the regional and temporal mutational patterns of TDR to inform the development of guidelines for first-line ARV therapy and of inexpensive resistance mutation assays for use in LMICs. Here, using a statistical approach called meta-analysis to combine information from individual patients about the resistance mutations they carry, the researchers investigate the molecular epidemiology of TDR (the patterns of molecular changes underlying TDR in populations) and identify the HIV drug-resistance mutations most responsible for TDR in different world regions.

          What Did the Researchers Do and Find?

          The researchers identified 287 studies published between 2000 and 2013 from 111 countries that included the reverse transcriptase sequences of HIV viruses from 50,870 ARV-naïve, HIV-positive individuals. The researchers analyzed each virus sequence for the presence of 93 surveillance drug-resistance mutations (SDRMs) previously shown to be specific indicators of TDR. Meta-analysis of these data indicated that the average overall prevalence of TDR (the proportion of ARV-naïve, HIV-positive individuals infected with a virus carrying one or more SDRMs) ranged from 2.8% in sub-Saharan Africa to 11.5% in North America. In sub-Saharan Africa, the odds (chance) of TDR increased 1.09-fold per year following national ARV scale-up; this increase was attributable to an increase in NRTI- and NNRTI-associated resistance. By contrast, in LMICs in south/southeast Asia, the odds of TDR remained unchanged following ARV scale-up. In Latin America/Caribbean, North America, Europe, and upper-income Asian countries, the odds of TDR have increased by around 1.10-fold per year since 1995, mainly as a result of increased NNRTI resistance. Four NNRTI-associated and 16 NRTI-associated SDRMs accounted for most NNRTI- and NRTI-associated TDR, respectively, in all regions. Notably, in sub-Saharan Africa and south/southeast Asia, most of the NNRTI-associated SDRMs detected were associated with high-level resistance to nevirapine or efavirenz. Finally, the researchers report that 95% of TDR viruses in sub-Saharan Africa and south/southeast Asia were unrelated and had therefore arisen independently.

          What Do These Findings Mean?

          Because many drug-resistance mutations reduce HIV’s fitness and tend to be lost rapidly in individuals not exposed to ARV therapy, differences among the datasets used in this meta-analysis with respect to how long each ARV-naïve patient had been infected with HIV before virus sampling may limit the accuracy of these findings. Nevertheless, the finding that most of the TDR strains detected in sub-Saharan Africa and south/southeast Asia arose independently suggests that improved patient adherence to ARV therapy and the use of ARV regimens that contain drugs to which HIV rarely develops resistance (regimens with a high genetic barrier to resistance) should reduce the generation of new ARV-resistant strains and mitigate TDR increases. In addition, the finding that a few NNRTI-resistance mutations were responsible for most cases of transmitted high-level resistance suggests that an inexpensive assay that detects these specific mutations may be useful for pre-therapy screening in LMICs with high TDR levels.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001810.

          Related collections

          Most cited references24

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          Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review.

          Following large-scale roll-out of antiretroviral therapy in sub-Saharan Africa, the non-clinical efficacy of antiretroviral therapy has received little attention. We aimed to systematically review virological efficacy and drug-resistance outcomes of programmes of antiretroviral therapy in sub-Saharan Africa. 89 studies with heterogeneous design, definitions, and methods were identified. Overall, in on-treatment analysis, 10 351 (78%) of 13 288 patients showed virological suppression after 6 months of antiretroviral therapy, 7413 (76%) of 9794 after 12 months, and 3840 (67%) of 5690 after 24 months. Long-term virological data are scarce. Genotyping results were available for patients with virological failure (HIV-1 RNA greater than 1000 copies per mL). Most patients (839 of 849; 99%) were infected with a non-B HIV-1 subtype. However, drug-resistance patterns were largely similar to those in subtype B. Resistance profiles were associated with the antiretroviral drugs commonly used: the lamivudine-associated M184V mutation was most common, followed by K103N which is associated with non-nucleoside reverse transcriptase inhibitors. Thymidine-analogue mutations and the K65R mutation were less common. First-line antiretroviral therapy regimens used in sub-Saharan Africa are effective. Profiles of drug resistance suggest that a second-line treatment regimen based on protease inhibitors, with a backbone of nucleoside reverse transcriptase inhibitors, is a reasonable option for patients with HIV in sub-Saharan Africa who experience first-line treatment failure. 2010 Elsevier Ltd. All rights reserved.
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            Is Open Access

            The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance

            Summary: The calibrated population resistance (CPR) tool is a web-accessible program for performing standardized genotypic estimation of transmitted HIV-1 drug resistance. The program is linked to the Stanford HIV drug resistance database and can additionally perform viral genotyping and algorithmic estimation of resistance to specific antiretroviral drugs. Availability: http://cpr.stanford.edu/cpr/index.html Contact: robjgiff@gmail.com
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              • Abstract: found
              • Article: not found

              A comparison of summary patient-level covariates in meta-regression with individual patient data meta-analysis.

              To compare meta-analysis of summary study level data with the equivalent individual patient data (IPD) analysis when interest lies in identification of binary patient characteristics related to treatment efficacy. A simulation study comparing meta-regression with IPD analyses of randomized controlled trials. Twenty-seven different meta-analysis situations were simulated with 1000 repetitions in each case. The following parameters were varied: (1) the treatment effect magnitude for different patient risk groups; (2) sample sizes of individual studies; and (3) number of studies. The meta-regression and IPD results were then compared for each situation. The statistical power of meta-regression was dramatically and consistently lower than that of IPD analysis, with little agreement between the parameter estimates obtained from the two methods. Only in meta-analyses of large numbers of large trials, did meta-regression detect differential treatment effects between risk groups with any consistency. Meta-analysis of summary data may be adequate when estimating a single pooled treatment effect or investigating study level characteristics. However, when interest lies in investigating whether patient characteristics are related to treatment, IPD analysis will generally be necessary to discover any such relationships. In these situations practitioners should try to obtain individual-level data.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                7 April 2015
                April 2015
                : 12
                : 4
                : e1001810
                Affiliations
                [1 ]Department of Medicine, Stanford University, Stanford, California, United States of America
                [2 ]Hospital Clinic Universitari–Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
                [3 ]Tufts University School of Medicine, Boston, Massachusetts, United States of America
                [4 ]Department of Statistics, Stanford University, Stanford, California, United States of America
                [5 ]KU Leuven—University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium
                [6 ]Department of Global Health and Internal Medicine, Academic Medical Center of the University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
                [7 ]World Health Organization, Geneva, Switzerland
                [8 ]Virology Laboratory CREMER-IMPM, Yaoundé, Cameroon
                [9 ]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
                [10 ]Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
                [11 ]Department of Microbiology, University of Tartu, Tartu, Estonia
                [12 ]National Institute of Respiratory Diseases, Centre for Research in Infectious Diseases, Mexico City, Mexico
                [13 ]HIV/AIDS & Global Health Research Programme, Department of Microbiology, University of Venda, Thohoyandou, South Africa
                [14 ]National HIV and Retrovirology Laboratories, Public Health Agency of Canada, Ottawa, Ontario, Canada
                [15 ]Department of Viroscience, Erasmus Medical Centre, Erasmus University, Rotterdam, Netherlands
                [16 ]British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
                [17 ]Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
                [18 ]Blood Systems Research Institute, San Francisco, California, United States of America
                [19 ]Botswana–Harvard AIDS Institute Partnership, Gaborone, Botswana
                [20 ]Laboratoire de Virologie, Hôpital Saint Louis, Université Paris Diderot, INSERM U941, Paris, France
                [21 ]Center for Infectious Diseases, National Medical Center, Seoul, Republic of Korea
                [22 ]CIRBA-Programme PACCI, Abidjan, Côte d’Ivoire
                [23 ]UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
                [24 ]Department of Virology, Pitie-Salpetriere Hospital, Paris, France
                [25 ]Laboratoire de Virologie, Assistance Publique–Hôpitaux de Paris Hôpital Bichat-Claude Bernard, INSERM UMR 1137, Université Paris Diderot, Paris, France
                [26 ]Department of Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Mumbai, India
                [27 ]Global Viral Cameroon, Intendance Round About, EMAT/CRESAR, Yaoundé, Cameroon
                [28 ]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [29 ]Laboratoire de Virologie, Centre Hospitalier Universitaire de Bordeaux, CNRS UMR 5234, Université de Bordeaux, Bordeaux, France
                [30 ]Microbiology Department, Hôpital Necker-Enfants Malades, Paris, France
                [31 ]Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan
                [32 ]National Hospital Organization Nagoya Medical Center, Nagoya, Japan
                [33 ]Department of Microbiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
                [34 ]Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa
                [35 ]Department of Viral Infection and International Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
                [36 ]MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
                [37 ]Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
                [38 ]US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America
                [39 ]Division of AIDS, Korea National Institute of Health, Osong, Chungcheongbuk-do, Republic of Korea
                [40 ]State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
                [41 ]Institute of Human Virology, Abuja, Nigeria
                [42 ]Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
                [43 ]National AIDS Research Institute, Indian Council of Medical Research, Pune, India
                [44 ]Unité Mixte Internationale 233, Institut de Recherche pour le Développement, INSERM U1175, and University of Montpellier, 34394 Montpellier, France
                [45 ]Computational Biology Institute, Montpellier, France
                [46 ]Institute of Microbiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
                [47 ]Department of Medical Affairs, International AIDS Vaccine Initiative, New York, New York, United States of America
                [48 ]Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America
                [49 ]University of Edinburgh, Edinburgh, Scotland, United Kingdom
                [50 ]Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
                [51 ]University of California San Diego, La Jolla, California, United States of America
                [52 ]Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
                [53 ]Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
                [54 ]Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
                [55 ]Federal University of Goias, Goias, Brazil
                [56 ]Department of Medicine, University of California, San Francisco, California, United States of America
                [57 ]Institut de Recherche pour le Développement, University of Montpellier 1, Montpellier, France
                [58 ]International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [59 ]Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, California, United States of America
                [60 ]Meta-Research Innovation Center at Stanford, Stanford University, Stanford, California, United States of America
                [61 ]Global Health and Tropical Medicine, Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal
                St. Vincent's Hospital, AUSTRALIA
                Author notes

                JHK and MR are employees of the Walter Reed Army Institute of Research, however, the views expressed herein are those of the authors and do not represent the official views of the Departments of the Army or Defense. DD has received honoraria and travel grants from Viiv Healthcare, Janssen-Cilag, Gilead-Sciences, MSD and BMS for participation to advisory boards and international conferences. SHE collaborates on research studies with investigators from Abbott Laboratories (distributor of the ViroSeq HIV-1 Genotyping System). Abbott Laboratories has provided reagents and performed testing for some collaborative studies. PF has received paid employment for educational presentation (Bristol-Myers Squibb, Janssen-Cilag), travel grants and honoraria for speaking or participation at meetings (Bristol-Myers Squibb, MSD, Gilead, Astellas). WS has received honoraria for speaking from Viiv, MSD, Janssen and Torii. PRH has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by: Pfizer, Glaxo-Smith Kline, Abbott, Merck, Tobira Therapeutics, Virco and Quest Diagnostics. MAP was supported in part from the United States Agency for International Development (USAID), however, the contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government. SB is a staff member of the World Health Organization and the contents are the responsibility of the authors and do not necessarily reflect the views of the World Health Organization. JPAI is a member of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.

                Conceived and designed the experiments: AMV JLB JPAI MRJ RWS SYR. Performed the experiments: JLB RWS SYR VV. Analyzed the data: JT PL RWS SYR. Contributed reagents/materials/analysis tools: AD AFA AH AKD AT BSC CABB CFD CFDG CY DAMCvdV DD DK DMS DS GMH GRT GY HB HF HHMT HI IL JA JH JHK JIB KKT KPN LM MAP MASo MASt MLC MLRC MPe MPo MPB MR MS NN NV PF PK POB PRH RA RLH RSP RY SAR SF SHE SK SSi SSu SSK TFRdW TTD VVS WS YL ZLB. Wrote the first draft of the manuscript: JLB RWS SYR. Wrote the paper: AH AMV CY DAMCvdV HHMT JA JLB JIB JPAI JT MASo MLRC MR MRJ PL PRH RLH RWS SB SYR. Agree with manuscript results and conclusions: AD AFA AH AKD AT AMV BSC CABB CFD CFDG CY DAMCvdV DD DK DMS DS GMH GRT GY HB HF HHMT HI IL JA JLB JH JHK JIB JPAI JT KKT KPN LM MAP MASo MASt MLC MLRC MPe MPo MPB MR MRJ MS NN NV PF PK PL POB PRH RA RLH RSP RWS RY SAR SB SF SHE SK SSi SSu SSK SYR TFRdW TTD VV VVS WS YL ZLB. All authors have read, and agree that they meet, ICMJE criteria for authorship.

                Article
                PMEDICINE-D-14-02307
                10.1371/journal.pmed.1001810
                4388826
                25849352
                90592f33-5ca4-450a-bf20-0b0110f10f88

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                History
                : 17 July 2014
                : 27 February 2015
                Page count
                Figures: 12, Tables: 3, Pages: 29
                Funding
                SYR, VV, and RWS were supported in part from NIH grant R01 AI068581. SYR and RWS were supported in part from an Bill & Melinda Gates Foundation grant. MRJ is supported by CFAR grant 1P30A142853. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                This is a combined study of previously published studies with sequence data available in GenBank. The studies and the sequence data included can be accessed on the web site: http://hivdb.stanford.edu/surveillance/map/.

                Medicine
                Medicine

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