Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen: An international collaboration

• Type of Material: Article
• Authors: Soo-Yoon Rhee, Stanford University; Vici Varghese, Stanford University; Susan P. Holmes, Stanford University; Gert U. Van Zyl, Stellenbosch University; Kim Steegen, University of the Witwatersrand; Mary-Ann A. Boyd, University of New South Wales; David A. Cooper, University of New South Wales; Sabin Nsanzimana, Rwanda Biomedical Center; Shanmugam Saravanan, YR Gaitonde Centre for AIDS Research and Education; Charlotte Charpentier, Universite Paris - Denis Diderot; Tulio de Oliveira, University of KwaZulu-Natal; Mary-Ann A. Etiebet, University of Maryland School of Medicine; Federico Garcia, Hospital Universitario San Cecilio; Dominique Goedhals, National Health Laboratory Service/University of the Free State; Perpetua Gomes, Centro Hospitalar de Lisboa Ocidental; Huldrych F. Günthard, University of Zurich; Raph L. Hamers, University of Amsterdam; Christopher J. Hoffmann, Johns Hopkins University School of Medicine; Gillian Hunt, National Institute for Communicable Diseases; Awachana Jiamsakul, University of New South Wales; Pontiano Kaleebu, Uganda Virus Research Institute; Phyllis Kanki, Harvard T. H. Chan School of Public Health; Rami Kantor, Brown University; Bernhard Kerschberger, Médecins sans Frontières; Vincent Marconi, Emory University; Jean D'amour Ndahimana, Rwanda Biomedical Center; Nicaise Ndembi, Institute of Human Virology Nigeria; Nicole Ngo-Giang-Huong, Institut de Recherche pour le Developpement; Casper Rokx, Erasmus University Medical Center; Maria M. Santoro, University of Rome Tor Vergata; Jonathan M.Chaim Sheba Medical Center Israel Schapiro, Sheba Medical Center; Daniel Schmidt, Robert Koch-Institute; Lillian Seu, University of Alabama at Birmingham; Kim C.E. Sigaloff, University of Amsterdam; Sunee Sirivichayakul, Chulalongkorn University; Lindiwe Skhosana, University of the Witwatersrand; Henry Sunpath, University of KwaZulu-Natal; Michele Tang, Stanford University; Chunfu Yang, Centers for Disease Control and Prevention; Sergio Carmona, University of the Witwatersrand; Ravindra K. Gupta, University of California, Los Angeles; Robert W. Shafer, Stanford University
• Language: English
• Date: 2017-01-26
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2017.03.024
• Title of Journal or Parent Work: EBioMedicine
• ISSN: 2352-3964
• Volume: 18
• Start Page: 225
• End Page: 235
• Grant/Funding Information: This study was funded in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number NIAID AI068581.
• Keywords: Reverse transcriptase; Antiretroviral therapy; HIV-1; Tenofovir; Drug resistance; WHO-recommended first-line
• Research Categories: Health Sciences, Epidemiology; Biology, Virology

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.