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

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 aWHO-recommended TDF-containing first-line regimen. However, the full spectrumof 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-naive individuals. To identify TRAMs specifically associatedwith TDF-selection pressure, we compared the proportion of each TRAMto 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 -weremore common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMswill be important formonitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen. (C) 2017 The Authors. Published by Elsevier B. V.