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 JiamsakulPontiano 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)225-235
Number of pages11
JournalEBioMedicine
Volume18
DOIs
StatePublished - Apr 2017

Keywords

  • Antiretroviral therapy
  • Drug resistance
  • HIV-1
  • Reverse transcriptase
  • Tenofovir
  • WHO-recommended first-line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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