EBioMedicine. 2017 Apr;18:225-235. doi: 10.1016/j.ebiom.2017.03.024. Epub 2017 Mar 19.

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.

Rhee SY¹, Varghese V², Holmes SP³, Van Zyl GU⁴, Steegen K⁵, Boyd MA⁶, Cooper DA⁶, Nsanzimana S⁷, Saravanan S⁸, Charpentier C⁹, de Oliveira T¹⁰, Etiebet MA¹¹, Garcia F¹², Goedhals D¹³, Gomes P¹⁴, Günthard HF¹⁵, Hamers RL¹⁶, Hoffmann CJ¹⁷, Hunt G¹⁸, Jiamsakul A⁶, Kaleebu P¹⁹, Kanki P²⁰, Kantor R²¹, Kerschberger B²², Marconi VC²³, D'amour Ndahimana J⁷, Ndembi N²⁴, Ngo-Giang-Huong N²⁵, Rokx C²⁶, Santoro MM²⁷, Schapiro JM²⁸, Schmidt D²⁹, Seu L³⁰, Sigaloff KCE¹⁶, Sirivichayakul S³¹, Skhosana L⁵, Sunpath H³², Tang M², Yang C³³, Carmona S⁵, Gupta RK³⁴, Shafer RW².

Author information

1: Department of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: syrhee@stanford.edu.
2: Department of Medicine, Stanford University, Stanford, CA 94305, USA.
3: Department of Statistics, Stanford University, Stanford, CA 94305, USA.
4: Division of Medical Virology, Stellenbosch University, National Health Laboratory Service, Tygerberg 7505, South Africa.
5: Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, WITS 2050, South Africa.
6: The Kirby Institute, UNSW, Sydney, NSW 2052, Australia.
7: HIV/AIDS Division, Rwanda Biomedical Center, Kigali, P.O. Box 87, Rwanda.
8: Y.R. Gaitonde Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India.
9: 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.
10: College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.
11: Institute of Human Virology, University of Maryland School of Medicine, MD 21201, USA.
12: Hospital Universitario San Cecilio, 18012 Granada, Spain.
13: Department of Medical Microbiology and Virology, National Health Laboratory Service/University of the Free State, Bloemfontein 9301,South Africa.
14: Laboratorio de Virologia, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon 1449-005, Portugal.
15: University Hospital Zurich, Institute of Medical Virology, University of Zurich, 8091 Zurich, Switzerland.
16: Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, P.O. Box 22700, The Netherlands.
17: Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
18: National Institute for Communicable Diseases, Sandringham, Johannesburg 2131, South Africa.
19: Uganda Virus Research Institute, Entebbe, P.O. Box 49, Uganda.
20: Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
21: Division of Infectious Diseases, Alpert Medical School, Brown University, Providence, RI 02903, USA.
22: Médecins sans Frontières, Mbabane, H100, Swaziland.
23: Emory University School of Medicine, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
24: Institute of Human Virology Nigeria, Abuja, Federal Capital Territory, P.O. Box 9396, Nigeria.
25: Institut de Recherche pour le Developpement (IRD), UMI 174 - PHPT, 13572 Marseilles, France.
26: Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
27: University of Rome Tor Vergata, 00173 Rome, Italy.
28: National Hemophilia Center, Sheba Medical Center, Tel Aviv 5262000, Israel.
29: Department of Infectious Disease Epidemiology, HIV/AIDS, STI and Blood Born Infections, Robert Koch-Institute, 13353 Berlin, Germany.
30: School of Medicine, University of Alabama at Birmingham, AL 35210, USA.
31: Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
32: School of Clinical Sciences, University of KwaZulu- Natal, Durban 4041, South Africa.
33: Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Port-au-Prince, Haiti.
34: UCL, Department of Infection, London WC1E 6BT, UK.

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.