Résumé
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.
•We determined the spectrum of tenofovir-selected mutations associated with first-line tenofovir-containing regimens.•Several of these mutations should be added to the list of mutations used for drug-resistance surveillance.•Several of these mutations require further evaluation to determine their effects on tenofovir susceptibility.
Tenofovir disoproxil fumarate (TDF) plus a cytosine analog is the universally recommended NRTI backbone for first-line antiretroviral (ARV) therapy and for pre-exposure prophylaxis. TDF is also frequently recommended for second-line therapy provided it retains activity against viruses that emerge following virological failure (VF) on a first-line ARV treatment regimen. The expanded spectrum of TDF-selected mutations identified in this study will be important for monitoring TDF-associated drug-resistance. Their clinical significance requires phenotypic and clinical studies to characterize their effects on the continued activity of TDF and the newly developed prodrug tenofovir alafenamide in individuals with VF on a TDF-containing regimen.