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PLoS Med. 2015 Apr 7;12(4):e1001810. doi: 10.1371/journal.pmed.1001810. eCollection 2015 Apr.

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.

Author information

1
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.
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 Medicine, Stanford University, Stanford, California, United States of America.
7
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.
8
World Health Organization, Geneva, Switzerland.
9
Virology Laboratory CREMER-IMPM, Yaoundé, Cameroon.
10
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; 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; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
17
Blood Systems Research Institute, San Francisco, California, United States of America.
18
Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
19
Laboratoire de Virologie, Hôpital Saint Louis, Université Paris Diderot, INSERM U941, Paris, France.
20
Center for Infectious Diseases, National Medical Center, Seoul, Republic of Korea.
21
CIRBA-Programme PACCI, Abidjan, Côte d'Ivoire.
22
UCD National Virus Reference Laboratory, University College Dublin, Dublin, Ireland.
23
Department of Virology, Pitie-Salpetriere Hospital, Paris, France.
24
Laboratoire de Virologie, Assistance Publique-Hôpitaux de Paris Hôpital Bichat-Claude Bernard, INSERM UMR 1137, Université Paris Diderot, Paris, France.
25
Department of Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Mumbai, India.
26
Global Viral Cameroon, Intendance Round About, EMAT/CRESAR, Yaoundé, Cameroon.
27
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
28
Laboratoire de Virologie, Centre Hospitalier Universitaire de Bordeaux, CNRS UMR 5234, Université de Bordeaux, Bordeaux, France.
29
Microbiology Department, Hôpital Necker-Enfants Malades, Paris, France.
30
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
31
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
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; Computational Biology Institute, Montpellier, France.
45
Institute of Microbiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
46
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.
47
University of Edinburgh, Edinburgh, Scotland, United Kingdom.
48
Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
49
University of California San Diego, La Jolla, California, United States of America.
50
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
51
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
52
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
53
Federal University of Goias, Goias, Brazil.
54
Department of Medicine, University of California, San Francisco, California, United States of America.
55
Institut de Recherche pour le Développement, University of Montpellier 1, Montpellier, France.
56
International Laboratory Branch, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
57
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.
58
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.

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.

PMID:
25849352
PMCID:
PMC4388826
DOI:
10.1371/journal.pmed.1001810
[Indexed for MEDLINE]
Free PMC Article

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