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Epidemiology of HIV-1 transmitted drug resistance

April 07, 2015

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."
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


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


Soo-Yon Rhee
Stanford University
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