Only a limited number of surveillance drug-resistance mutations (SDRMs) are responsible for most instances of non-nucleoside reverse transcriptase inhibitor (NNRTI)- and nucleoside reverse transcriptase inhibitor (NRTI)-associated resistance, and most strains of HIV-1 transmitted drug resistance (TDR) in sub-Saharan Africa (SSA) and south/southeast Asia (SSEA) arose independently, according to a study published this week in PLOS Medicine. The study, led by Soo-Yon Rhee of Stanford University, and colleagues, came to these conclusions after analyzing individual virus sequences from 287 published studies.
These findings have implications for TDR surveillance and control. The small number of NNRTI-resistance mutations responsible for a high percentage of high-level resistance suggests that screening for these specific high-prevalence mutations could identify most patients with TDR before they initiate therapy. The finding that most TDR strains arose independently rather than resulting from endemic strains that spread suggests that reducing the generation of new resistant strains by using antiretroviral (ARV) regimens with a high genetic barrier to resistance and improving patient adherence could have an impact on TDR prevalence.
This study is most relevant to the low- and middle-income countries of SSA and SSEA - the regions in which most of the 15 million individuals receiving ARV therapy live. Although national treatment programs in these regions have grown dramatically since 2000, the prevalence of TDR has not increased as much as once feared.
The researchers came to these conclusions after studying individual virus sequences from 50,870 HIV-positive individuals from 111 countries. By analyzing each virus sequence for the presence of 93 SDRMs previously shown to be specific indicators of TDR, the researchers found that the overall prevalence of TDR ranged from 2.8% in SSA to 11.5% in North America. The odds of TDR increased in SSA by 1.09-fold per year following national ARV scale-up, due to increased NNRTI- and NRTI-resistance, but remained unchanged in LMICs in SSEA following ARV scale-up. The odds of NNRTI but not NRTI resistance increased in Latin America/Caribbean, North America, Europe, and upper-income Asian countries since 1995. Just four NNRTI- and 16 NRTI-SDRMs accounted for most NNRTI- and NRTI-TDR, and 89% of NNRTI-SDRMs were associated with high-level resistance to nevirapine or efavirenz. In SSA and SSEA, only 5% of transmitted drug-resistant viruses were closely related to one another, suggesting that most TDR strains in these regions arose independently.
The authors say: "This study demonstrates that sequence analysis is an important component of TDR surveillance because it yields insights into the molecular epidemiology of TDR and the specific drug-resistance mutations responsible for TDR."
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Research Article
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.
Competing Interests: 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 (BristolMyers 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.
Citation: Rhee S-Y, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, et al. (2015) Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and SequenceLevel Meta-Analysis. PLoS Med 12(4): e1001810. doi:10.1371/journal.pmed.1001810
Author Affiliations:
Stanford University, UNITED STATES
University of Barcelona, SPAIN
Tufts University School of Medicine, UNITED STATES
University of Leuven, BELGIUM
Academic Medical Center of the University of Amsterdam, THE NETHERLANDS
World Health Organization, SWITZERLAND
Virology Laboratory CREMER-IMPM, CAMEROON
Karolinska Institutet, SWEDEN
University of Tartu, ESTONIA
National Institute of Respiratory Diseases, MEXICO
University of Venda, SOUTH AFRICA
Public Health Agency of Canada, CANADA
Simon Fraser University, CANADA
Blood Systems Research Institute, UNITED STATES
Botswana-Harvard AIDS Institute Partnership, BOTSWANA
Universite Paris Diderot, INSERM U941, FRANCE
National Medical Center, REPUBLIC OF KOREA
CIRBA-Programme PACCI, COTE D'IVOIRE
University College Dublin, IRELAND
Pitie-Salpetriere Hospital, FRANCE
Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, INDIA
Global Viral Cameroon, CAMEROON
Johns Hopkins University School of Medicine, UNITED STATES
Universite de Bordeaux, FRANCE
Hôpital Necker-Enfants Malades, FRANCE
National Institute of Infectious Diseases, JAPAN
National Hospital Organization Nagoya Medical Center, JAPAN
Instituto Ramón y Cajal de Investigación Sanitaria, SPAIN
National Institute for Communicable Diseases, SOUTH AFRICA
Kanazawa University, JAPAN
MRC/UVRI Uganda Research Unit on AIDS, UGANDA
Mahidol University, THAILAND
Walter Reed Army Institute of Research, UNITED STATES
Korea National Institute of Health, REPUBLIC OF KOREA
Chinese Academy of Sciences, CHINA
Institute of Human Virology, NIGERIA
University of Malaya, MALAYSIA
Indian Council of Medical Research, INDIA
Institut de Recherche pour le Développement, FRANCE
University of Montpellier, FRANCE
Computational Biology Institute, FRANCE
University of Ljubljana, SLOVENIA
International AIDS Vaccine Initiative, UNITED STATES
University of California, San Francisco, School of Medicine, UNITED STATES
University of Edinburgh, SCOTLAND
Chulalongkorn University, THAILAND
University of California San Diego, UNITED STATES
Universidade Federal do Rio de Janeiro, BRAZIL
Hospital Carlos III, SPAIN
University of Belgrade, SERBIA
Federal University of Goias, BRAZIL
Centers for Diseases Control and Prevention, UNITED STATES
Universidade Nova de Lisboa, PORTUGAL
Contact:
Soo-Yon Rhee
Stanford University
UNITED STATES
+1 (650) 736-0911
syrhee@stanford.edu; sooyonrhee@gmail.com
Journal
PLoS Medicine