EBioMedicine (Apr 2017)
Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration
- Soo-Yon Rhee,
- Vici Varghese,
- Susan P. Holmes,
- Gert U. Van Zyl,
- Kim Steegen,
- Mark A. Boyd,
- David A. Cooper,
- Sabin Nsanzimana,
- Shanmugam Saravanan,
- Charlotte Charpentier,
- Tulio de Oliveira,
- Mary-Ann A. Etiebet,
- Federico Garcia,
- Dominique Goedhals,
- Perpetua Gomes,
- Huldrych F. Günthard,
- Raph L. Hamers,
- Christopher J Hoffmann,
- Gillian Hunt,
- Awachana Jiamsakul,
- Pontiano Kaleebu,
- Phyllis Kanki,
- Rami Kantor,
- Bernhard Kerschberger,
- Vincent C. Marconi,
- Jean D'amour Ndahimana,
- Nicaise Ndembi,
- Nicole Ngo-Giang-Huong,
- Casper Rokx,
- Maria M. Santoro,
- Jonathan M. Schapiro,
- Daniel Schmidt,
- Lillian Seu,
- Kim C.E. Sigaloff,
- Sunee Sirivichayakul,
- Lindiwe Skhosana,
- Henry Sunpath,
- Michele Tang,
- Chunfu Yang,
- Sergio Carmona,
- Ravindra K. Gupta,
- Robert W. Shafer
Affiliations
- Soo-Yon Rhee
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
- Vici Varghese
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
- Susan P. Holmes
- Department of Statistics, Stanford University, Stanford, CA 94305, USA
- Gert U. Van Zyl
- Division of Medical Virology, Stellenbosch University, National Health Laboratory Service, Tygerberg 7505, South Africa
- Kim Steegen
- Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa
- Mark A. Boyd
- The Kirby Institute, UNSW, Sydney, NSW 2052, Australia
- David A. Cooper
- The Kirby Institute, UNSW, Sydney, NSW 2052, Australia
- Sabin Nsanzimana
- HIV/AIDS Division, Rwanda Biomedical Center, Kigali, P.O. Box 87, Rwanda
- Shanmugam Saravanan
- Y.R. Gaitonde Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India
- Charlotte Charpentier
- Univ Paris Diderot, Sorbonne Paris Cité, IAME, UMR 1137, INSERM, F-75018 Paris, France
- Tulio de Oliveira
- College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
- Mary-Ann A. Etiebet
- Institute of Human Virology, University of Maryland School of Medicine, MD 21201, USA
- Federico Garcia
- Hospital Universitario San Cecilio, 18012 Granada, Spain
- Dominique Goedhals
- Department of Medical Microbiology and Virology, National Health Laboratory Service/University of the Free State, Bloemfontein 9301,South Africa
- Perpetua Gomes
- Laboratorio de Virologia, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon 1449-005, Portugal
- Huldrych F. Günthard
- University Hospital Zurich, Institute of Medical Virology, University of Zurich, 8091 Zurich, Switzerland
- Raph L. Hamers
- Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, P.O. Box 22700, The Netherlands
- Christopher J Hoffmann
- Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Gillian Hunt
- National Institute for Communicable Diseases, Sandringham, Johannesburg 2131, South Africa
- Awachana Jiamsakul
- The Kirby Institute, UNSW, Sydney, NSW 2052, Australia
- Pontiano Kaleebu
- Uganda Virus Research Institute, Entebbe, P.O. Box 49, Uganda
- Phyllis Kanki
- Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
- Rami Kantor
- Division of Infectious Diseases, Alpert Medical School, Brown University, Providence, RI 02903, USA
- Bernhard Kerschberger
- Médecins sans Frontières, Mbabane, H100, Swaziland
- Vincent C. Marconi
- Emory University School of Medicine, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
- Jean D'amour Ndahimana
- HIV/AIDS Division, Rwanda Biomedical Center, Kigali, P.O. Box 87, Rwanda
- Nicaise Ndembi
- Institute of Human Virology Nigeria, Abuja, Federal Capital Territory, P.O. Box 9396, Nigeria
- Nicole Ngo-Giang-Huong
- Institut de Recherche pour le Developpement (IRD), UMI 174 - PHPT, 13572 Marseilles, France
- Casper Rokx
- Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
- Maria M. Santoro
- University of Rome Tor Vergata, 00173 Rome, Italy
- Jonathan M. Schapiro
- National Hemophilia Center, Sheba Medical Center, Tel Aviv 5262000, Israel
- Daniel Schmidt
- Department of Infectious Disease Epidemiology, HIV/AIDS, STI and Blood Born Infections, Robert Koch-Institute, 13353 Berlin, Germany
- Lillian Seu
- School of Medicine, University of Alabama at Birmingham, AL 35210, USA
- Kim C.E. Sigaloff
- Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, P.O. Box 22700, The Netherlands
- Sunee Sirivichayakul
- Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Lindiwe Skhosana
- Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa
- Henry Sunpath
- School of Clinical Sciences, University of KwaZulu- Natal, Durban 4041, South Africa
- Michele Tang
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
- Chunfu Yang
- Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Port-au-Prince, Haiti
- Sergio Carmona
- Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa
- Ravindra K. Gupta
- UCL, Department of Infection, London WC1E 6BT, UK
- Robert W. Shafer
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
- DOI
- https://doi.org/10.1016/j.ebiom.2017.03.024
- Journal volume & issue
-
Vol. 18,
no. C
pp. 225 – 235
Abstract
Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.
Keywords
- HIV-1
- Antiretroviral therapy
- Reverse transcriptase
- Drug resistance
- Tenofovir
- WHO-recommended first-line
