학술논문
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.
Document Type
Academic Journal
Author
Rhee SY; Department of Medicine, Stanford University, Stanford, California, United States of America. Leuven—University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.; Blanco JL; Hospital Clinic Universitari-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.; Jordan MR; Tufts University School of Medicine, Boston, Massachusetts, United States of America.; Taylor J; Department of Statistics, Stanford University, Stanford, California, United States of America.; Lemey P; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.; Varghese V; Department of Medicine, Stanford University, Stanford, California, United States of America.; Hamers RL; 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.; Bertagnolio S; World Health Organization, Geneva, Switzerland.; Rinke de Wit TF; 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.; Aghokeng AF; Virology Laboratory CREMER-IMPM, Yaoundé, Cameroon.; Albert J; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.; Avi R; Department of Microbiology, University of Tartu, Tartu, Estonia.; Avila-Rios S; National Institute of Respiratory Diseases, Centre for Research in Infectious Diseases, Mexico City, Mexico.; Bessong PO; HIV/AIDS & Global Health Research Programme, Department of Microbiology, University of Venda, Thohoyandou, South Africa.; Brooks JI; National HIV and Retrovirology Laboratories, Public Health Agency of Canada, Ottawa, Ontario, Canada.; Boucher CA; Department of Viroscience, Erasmus Medical Centre, Erasmus University, Rotterdam, Netherlands.; Brumme ZL; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.; Busch MP; Blood Systems Research Institute, San Francisco, California, United States of America.; Bussmann H; Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.; Chaix ML; Laboratoire de Virologie, Hôpital Saint Louis, Université Paris Diderot, INSERM U941, Paris, France.; Chin BS; Center for Infectious Diseases, National Medical Center, Seoul, Republic of Korea.; D'Aquin TT; CIRBA-Programme PACCI, Abidjan, Côte d'Ivoire.; De Gascun CF; UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland.; Derache A; Department of Virology, Pitie-Salpetriere Hospital, Paris, France.; Descamps D; Laboratoire de Virologie, Assistance Publique-Hôpitaux de Paris Hôpital Bichat-Claude Bernard, INSERM UMR 1137, Université Paris Diderot, Paris, France.; Deshpande AK; Department of Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Mumbai, India.; Djoko CF; Global Viral Cameroon, Intendance Round About, EMAT/CRESAR, Yaoundé, Cameroon.; Eshleman SH; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Fleury H; Laboratoire de Virologie, Centre Hospitalier Universitaire de Bordeaux, CNRS UMR 5234, Université de Bordeaux, Bordeaux, France.; Frange P; Microbiology Department, Hôpital Necker-Enfants Malades, Paris, France.; Fujisaki S; Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.; Harrigan PR; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.; Hattori J; National Hospital Organization Nagoya Medical Center, Nagoya, Japan.; Holguin A; Department of Microbiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.; Hunt GM; Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.; Ichimura H; Department of Viral Infection and International Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.; Kaleebu P; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.; Katzenstein D; Department of Medicine, Stanford University, Stanford, California, United States of America.; Kiertiburanakul S; Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.; Kim JH; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.; Kim SS; Division of AIDS, Korea National Institute of Health, Osong, Chungcheongbuk-do, Republic of Korea.; Li Y; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.; Lutsar I; Department of Microbiology, University of Tartu, Tartu, Estonia.; Morris L; Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.; Ndembi N; Institute of Human Virology, Abuja, Nigeria.; Ng KP; Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; Paranjape RS; National AIDS Research Institute, Indian Council of Medical Research, Pune, India.; Peeters M; Unité Mixte Internationale 233, Institut de Recherche pour le Développement, INSERM U1175, and University of Montpellier, 34394 Montpellier, France; Computational Biology Institute, Montpellier, France.; Poljak M; Institute of Microbiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.; Price MA; Department of Medical Affairs, International AIDS Vaccine Initiative, New York, New York, United States of America; Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America.; Ragonnet-Cronin ML; University of Edinburgh, Edinburgh, Scotland, United Kingdom.; Reyes-Terán G; National Institute of Respiratory Diseases, Centre for Research in Infectious Diseases, Mexico City, Mexico.; Rolland M; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.; Sirivichayakul S; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.; Smith DM; University of California San Diego, La Jolla, California, United States of America.; Soares MA; Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.; Soriano VV; Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.; Ssemwanga D; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.; Stanojevic M; Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.; Stefani MA; Federal University of Goias, Goias, Brazil.; Sugiura W; National Hospital Organization Nagoya Medical Center, Nagoya, Japan.; Sungkanuparph S; Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.; Tanuri A; Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.; Tee KK; Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; Truong HM; Department of Medicine, University of California, San Francisco, California, United States of America.; van de Vijver DA; Department of Viroscience, Erasmus Medical Centre, Erasmus University, Rotterdam, Netherlands.; Vidal N; Institut de Recherche pour le Développement, University of Montpellier 1, Montpellier, France.; Yang C; International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.; Yang R; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.; Yebra G; Department of Microbiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.; Ioannidis JP; Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, California, United States of America; Meta-Research Innovation Center at Stanford, Stanford University, Stanford, California, United States of America.; Vandamme AM; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium; Global Health and Tropical Medicine, Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal.; Shafer RW; Department of Medicine, Stanford University, Stanford, California, United States of America.
Source
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101231360 Publication Model: eCollection Cited Medium: Internet ISSN: 1549-1676 (Electronic) Linking ISSN: 15491277 NLM ISO Abbreviation: PLoS Med Subsets: MEDLINE
Subject
Language
English
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.
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.