Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen: an international collaboration. EBioMedicine
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 on a WHO-recommended TDF-containing first-line regimen. Rhee et al. aimed to identify TDF regimen-associated mutations (TRAMs) by comparing the proportion of each reverse transcriptase mutation in 2’873 individuals with virological failure on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50’803 antiretroviral-naïve individuals.
The authors identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen: A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F.
In conclusion, the study shows that the spectrum of TDF-selected mutations extends beyond K65R/N and K70E/G/Q. Several of the additional TDF-selected mutations are non-polymorphic mutations that are currently not considered surveillance drug resistance mutations yet may be important for monitoring TDF associated transmitted drug-resistance. Additionally, the clinical significance of several mutations that occurred commonly in combination with K65R including A62V, S68G/N/D, L74I, V75L and Y115F requires further phenotypic and clinical studies to better understand their effects on both TDF and the newly developed prodrug tenofovir alafenamide (TAF).