title: 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.
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.
  
  
  RESULTS
  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.
authors: 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.
authors: Soo-Yon
authors: SY
authors: Rhee
authors: Hospital Clinic Universitari-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors: Jose Luis
authors: JL
authors: Blanco
authors: Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Michael R
authors: MR
authors: Jordan
authors: Department of Statistics, Stanford University, Stanford, California, United States of America.
authors: Jonathan
authors: J
authors: Taylor
authors: KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.
authors: Philippe
authors: P
authors: Lemey
authors: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors: Vici
authors: V
authors: Varghese
authors: 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.
authors: Raph L
authors: RL
authors: Hamers
authors: World Health Organization, Geneva, Switzerland.
authors: Silvia
authors: S
authors: Bertagnolio
authors: 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.
authors: Tobias F
authors: TF
authors: Rinke de Wit
authors: Virology Laboratory CREMER-IMPM, Yaoundé, Cameroon.
authors: Avelin F
authors: AF
authors: Aghokeng
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
authors: Jan
authors: J
authors: Albert
authors: Department of Microbiology, University of Tartu, Tartu, Estonia.
authors: Radko
authors: R
authors: Avi
authors: National Institute of Respiratory Diseases, Centre for Research in Infectious Diseases, Mexico City, Mexico.
authors: Santiago
authors: S
authors: Avila-Rios
authors: HIV/AIDS & Global Health Research Programme, Department of Microbiology, University of Venda, Thohoyandou, South Africa.
authors: Pascal O
authors: PO
authors: Bessong
authors: National HIV and Retrovirology Laboratories, Public Health Agency of Canada, Ottawa, Ontario, Canada.
authors: James I
authors: JI
authors: Brooks
authors: Department of Viroscience, Erasmus Medical Centre, Erasmus University, Rotterdam, Netherlands.
authors: Charles A B
authors: CA
authors: Boucher
authors: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Zabrina L
authors: ZL
authors: Brumme
authors: Blood Systems Research Institute, San Francisco, California, United States of America.
authors: Michael P
authors: MP
authors: Busch
authors: Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
authors: Hermann
authors: H
authors: Bussmann
authors: Laboratoire de Virologie, Hôpital Saint Louis, Université Paris Diderot, INSERM U941, Paris, France.
authors: Marie-Laure
authors: ML
authors: Chaix
authors: Center for Infectious Diseases, National Medical Center, Seoul, Republic of Korea.
authors: Bum Sik
authors: BS
authors: Chin
authors: CIRBA-Programme PACCI, Abidjan, Côte d'Ivoire.
authors: Toni T
authors: TT
authors: D'Aquin
authors: UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland.
authors: Cillian F
authors: CF
authors: De Gascun
authors: Department of Virology, Pitie-Salpetriere Hospital, Paris, France.
authors: Anne
authors: A
authors: Derache
authors: Laboratoire de Virologie, Assistance Publique-Hôpitaux de Paris Hôpital Bichat-Claude Bernard, INSERM UMR 1137, Université Paris Diderot, Paris, France.
authors: Diane
authors: D
authors: Descamps
authors: Department of Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Mumbai, India.
authors: Alaka K
authors: AK
authors: Deshpande
authors: Global Viral Cameroon, Intendance Round About, EMAT/CRESAR, Yaoundé, Cameroon.
authors: Cyrille F
authors: CF
authors: Djoko
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Susan H
authors: SH
authors: Eshleman
authors: Laboratoire de Virologie, Centre Hospitalier Universitaire de Bordeaux, CNRS UMR 5234, Université de Bordeaux, Bordeaux, France.
authors: Herve
authors: H
authors: Fleury
authors: Microbiology Department, Hôpital Necker-Enfants Malades, Paris, France.
authors: Pierre
authors: P
authors: Frange
authors: Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Seiichiro
authors: S
authors: Fujisaki
authors: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
authors: P Richard
authors: PR
authors: Harrigan
authors: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors: Junko
authors: J
authors: Hattori
authors: Department of Microbiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: Africa
authors: A
authors: Holguin
authors: Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.
authors: Gillian M
authors: GM
authors: Hunt
authors: Department of Viral Infection and International Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Hiroshi
authors: H
authors: Ichimura
authors: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors: Pontiano
authors: P
authors: Kaleebu
authors: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors: David
authors: D
authors: Katzenstein
authors: Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors: Sasisopin
authors: S
authors: Kiertiburanakul
authors: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors: Jerome H
authors: JH
authors: Kim
authors: Division of AIDS, Korea National Institute of Health, Osong, Chungcheongbuk-do, Republic of Korea.
authors: Sung Soon
authors: SS
authors: Kim
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors: Yanpeng
authors: Y
authors: Li
authors: Department of Microbiology, University of Tartu, Tartu, Estonia.
authors: Irja
authors: I
authors: Lutsar
authors: Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.
authors: Lynn
authors: L
authors: Morris
authors: Institute of Human Virology, Abuja, Nigeria.
authors: Nicaise
authors: N
authors: Ndembi
authors: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Kee Peng
authors: KP
authors: Ng
authors: National AIDS Research Institute, Indian Council of Medical Research, Pune, India.
authors: Ramesh S
authors: RS
authors: Paranjape
authors: Unité Mixte Internationale 233, Institut de Recherche pour le Développement, INSERM U1175, and University of Montpellier, 34394 Montpellier, France; Computational Biology Institute, Montpellier, France.
authors: Martine
authors: M
authors: Peeters
authors: Institute of Microbiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors: Mario
authors: M
authors: Poljak
authors: 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.
authors: Matt A
authors: MA
authors: Price
authors: University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: Manon L
authors: ML
authors: Ragonnet-Cronin
authors: National Institute of Respiratory Diseases, Centre for Research in Infectious Diseases, Mexico City, Mexico.
authors: Gustavo
authors: G
authors: Reyes-Terán
authors: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors: Morgane
authors: M
authors: Rolland
authors: Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Sunee
authors: S
authors: Sirivichayakul
authors: University of California San Diego, La Jolla, California, United States of America.
authors: Davey M
authors: DM
authors: Smith
authors: Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Marcelo A
authors: MA
authors: Soares
authors: Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
authors: Vincent V
authors: VV
authors: Soriano
authors: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors: Deogratius
authors: D
authors: Ssemwanga
authors: Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors: Maja
authors: M
authors: Stanojevic
authors: Federal University of Goias, Goias, Brazil.
authors: Mariane A
authors: MA
authors: Stefani
authors: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors: Wataru
authors: W
authors: Sugiura
authors: Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors: Somnuek
authors: S
authors: Sungkanuparph
authors: Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Amilcar
authors: A
authors: Tanuri
authors: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Kok Keng
authors: KK
authors: Tee
authors: Department of Medicine, University of California, San Francisco, California, United States of America.
authors: Hong-Ha M
authors: HM
authors: Truong
authors: Department of Viroscience, Erasmus Medical Centre, Erasmus University, Rotterdam, Netherlands.
authors: David A M C
authors: DA
authors: van de Vijver
authors: Institut de Recherche pour le Développement, University of Montpellier 1, Montpellier, France.
authors: Nicole
authors: N
authors: Vidal
authors: International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors: Chunfu
authors: C
authors: Yang
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors: Rongge
authors: R
authors: Yang
authors: Department of Microbiology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: Gonzalo
authors: G
authors: Yebra
authors: 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.
authors: John P A
authors: JP
authors: Ioannidis
authors: 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.
authors: Anne-Mieke
authors: AM
authors: Vandamme
authors: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors: Robert W
authors: RW
authors: Shafer
mesh_terms: D000349:Africa; D000569:Americas; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001208:Asia; D001483:Base Sequence; D024882:Drug Resistance, Viral; D005060:Europe; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D017720:Molecular Epidemiology; D009154:Mutation; D010802:Phylogeny
chemical_list: D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase