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

Soo-Yon Rhee¹, Vici Varghese², Susan P Holmes³, Gert U Van Zyl⁴, Kim Steegen⁵, Mark A Boyd⁶, David A Cooper⁶, Sabin Nsanzimana⁷, Shanmugam Saravanan⁸, Charlotte Charpentier⁹, Tulio de Oliveira¹⁰, Mary-Ann A Etiebet¹¹, Federico Garcia¹², Dominique Goedhals¹³, Perpetua Gomes¹⁴, Huldrych F Günthard¹⁵, Raph L Hamers¹⁶, Christopher J Hoffmann¹⁷, Gillian Hunt¹⁸, Awachana Jiamsakul⁶, Pontiano Kaleebu¹⁹, Phyllis Kanki²⁰, Rami Kantor²¹, Bernhard Kerschberger²², Vincent C Marconi²³, Jean D'amour Ndahimana⁷, Nicaise Ndembi²⁴, Nicole Ngo-Giang-Huong²⁵, Casper Rokx²⁶, Maria M Santoro²⁷, Jonathan M Schapiro²⁸, Daniel Schmidt²⁹, Lillian Seu³⁰, Kim C E Sigaloff¹⁶, Sunee Sirivichayakul³¹, Lindiwe Skhosana⁵, Henry Sunpath³², Michele Tang², Chunfu Yang³³, Sergio Carmona⁵, Ravindra K Gupta³⁴, Robert W Shafer²

Affiliations

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.

PMID: 28365230
PMCID: PMC5405160
DOI: 10.1016/j.ebiom.2017.03.024

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

Soo-Yon Rhee et al. EBioMedicine. 2017 Apr.

. 2017 Apr:18:225-235.

doi: 10.1016/j.ebiom.2017.03.024. Epub 2017 Mar 19.

Authors

Affiliations

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.

PMID: 28365230
PMCID: PMC5405160
DOI: 10.1016/j.ebiom.2017.03.024

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: Antiretroviral therapy; Drug resistance; HIV-1; Reverse transcriptase; Tenofovir; WHO-recommended first-line.

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Figures

**Fig. 1**
Prevalence of nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in 2,873 individuals with virological failure (VF) on a TDF-containing 1st-line regimen (a); in 5,805 individuals with VF on a thymidine analog-containing 1st-line regimen (b); and in 50,803 antiretroviral (ARV)-naive individuals (c). NRTI TRAMs that were significantly more common in individuals receiving a TDF-containing regimen compared to in individuals receiving a thymidine analog-containing regimen are shown in blue. NRTI TRAMs that were significantly more common in individuals receiving a thymidine analog-containing regimen compared to in individuals receiving a TDF-containing regimen are shown in brown.

**Fig. 2**
Prevalence of non-nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in 2,873 individuals with virological failure (VF) on a TDF-containing 1st-line regimen (a); in 5,805 individuals with VF on a thymidine analog-containing 1st-line regimen (b); and in 50,803 antiretroviral (ARV)-naive individuals (c). NNRTI TRAMs that were significantly more common in individuals receiving a TDF-containing regimen compared to in individuals receiving a thymidine analog-containing regimen are shown in blue. NNRTI TRAMs that were significantly more common in individuals receiving a thymidine analog-containing regimen compared to in individuals receiving a TDF-containing regimen are shown in brown.

**Fig. 3**
Covariation patterns of nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in a network created from the adjacency matrix of phi correlation coefficients for each pair of NRTI TRAMs. Each edge in the network represents a strongly significant correlation (phi ≥ 0.1 and an adjusted p < 0.05) and the thickness of the edge is proportional to the strength of the correlation (phi) of a pair. Shown in orange are the NRTI TRAMs that were strongly associated with K65R: A62V, S68G/N/D, T69deletion, K70T, V75M and Y115F.

See this image and copyright information in PMC

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

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

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