title: Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.
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.
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: syrhee@stanford.edu.
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Vici
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authors.lastname: Varghese
authors.affiliation: Department of Statistics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Susan P
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authors.lastname: Holmes
authors.affiliation: Division of Medical Virology, Stellenbosch University, National Health Laboratory Service, Tygerberg 7505, South Africa.
authors.forename: Gert U
authors.initials: GU
authors.lastname: Van Zyl
authors.affiliation: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa.
authors.forename: Kim
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authors.lastname: Steegen
authors.affiliation: The Kirby Institute, UNSW, Sydney, NSW 2052, Australia.
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authors.affiliation: The Kirby Institute, UNSW, Sydney, NSW 2052, Australia.
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authors.initials: DA
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authors.affiliation: Y.R. Gaitonde Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India.
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authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, IAME, UMR 1137, INSERM, F-75018 Paris, France; AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, F-75018 Paris, France.
authors.forename: Charlotte
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authors.lastname: Charpentier
authors.affiliation: College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.
authors.forename: Tulio
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authors.lastname: de Oliveira
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, MD 21201, USA.
authors.forename: Mary-Ann A
authors.initials: MA
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authors.affiliation: Hospital Universitario San Cecilio, 18012 Granada, Spain.
authors.forename: Federico
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authors.affiliation: Department of Medical Microbiology and Virology, National Health Laboratory Service/University of the Free State, Bloemfontein 9301,South Africa.
authors.forename: Dominique
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authors.lastname: Goedhals
authors.affiliation: Laboratorio de Virologia, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon 1449-005, Portugal.
authors.forename: Perpetua
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authors.lastname: Gomes
authors.affiliation: University Hospital Zurich, Institute of Medical Virology, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Huldrych F
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authors.affiliation: Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, P.O. Box 22700, The Netherlands.
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authors.initials: RL
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authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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authors.affiliation: National Institute for Communicable Diseases, Sandringham, Johannesburg 2131, South Africa.
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authors.affiliation: The Kirby Institute, UNSW, Sydney, NSW 2052, Australia.
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authors.affiliation: Uganda Virus Research Institute, Entebbe, P.O. Box 49, Uganda.
authors.forename: Pontiano
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authors.affiliation: Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Phyllis
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authors.affiliation: Division of Infectious Diseases, Alpert Medical School, Brown University, Providence, RI 02903, USA.
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authors.forename: Bernhard
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authors.lastname: D'amour Ndahimana
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authors.forename: Nicaise
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authors.affiliation: Institut de Recherche pour le Developpement (IRD), UMI 174 - PHPT, 13572 Marseilles, France.
authors.forename: Nicole
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authors.affiliation: Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
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authors.affiliation: University of Rome Tor Vergata, 00173 Rome, Italy.
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authors.initials: MM
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authors.affiliation: Department of Infectious Disease Epidemiology, HIV/AIDS, STI and Blood Born Infections, Robert Koch-Institute, 13353 Berlin, Germany.
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authors.forename: Lillian
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authors.affiliation: Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, P.O. Box 22700, The Netherlands.
authors.forename: Kim C E
authors.initials: KCE
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authors.affiliation: Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sunee
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authors.lastname: Sirivichayakul
authors.affiliation: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa.
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authors.lastname: Skhosana
authors.affiliation: School of Clinical Sciences, University of KwaZulu- Natal, Durban 4041, South Africa.
authors.forename: Henry
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authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA.
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authors.forename: Chunfu
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authors.affiliation: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa.
authors.forename: Sergio
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authors.lastname: Carmona
authors.affiliation: UCL, Department of Infection, London WC1E 6BT, UK.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA.
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mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D009154:Mutation; D015995:Prevalence; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000068698:Tenofovir / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load; D014944:World Health Organization
chemical_list: D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Antiretroviral therapy; Drug resistance; HIV-1; Reverse transcriptase; Tenofovir; WHO-recommended first-line