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.

Additional Metadata
Keywords Antiretroviral therapy, Drug resistance, HIV-1, Reverse transcriptase, Tenofovir, WHO-recommended first-line
Persistent URL dx.doi.org/10.1016/j.ebiom.2017.03.024, hdl.handle.net/1765/99000
Journal EBioMedicine
Citation
Rhee, S.Y, Varghese, V, Holmes, S.P. (Susan P.), Van Zyl, G.U. (Gert U.), Steegen, K. (Kim), Boyd, M.A. (Mark A.), … Shafer, R.W. (2017). Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen: An international collaboration. EBioMedicine. doi:10.1016/j.ebiom.2017.03.024