Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen : an international collaboration

Rhee, Soo-Yon ; Varghese, Vici ; Holmes, Susan P. ; Van Zyl, Gert U. ; Steegen, Kim ; Boyd, Mark A. ; Cooper, David A. ; Nsanzimana, Sabin ; Saravanan, Shanmugam ; Charpentier, Charlotte ; De Oliveira, Tulio ; Etiebet, Mary-Ann A. ; Garcia, Federico ; Goedhals, Dominique ; Gomes, Perpetua ; Gunthard, Huldrych F. ; Hamers, Raph L. ; Hoffmann, Christopher J. ; Hunt, Gillian ; Jiamsakul, Awachana ; Kaleebu, Pontiano ; Kanki, Phyllis ; Kantor, Rami ; Kerschberger, Bernhard ; Marconi, Vincent C. ; Ndahimana, Jean D'amour ; Ndembi, Nicaise ; Ngo-Giang-Huong, Nicole ; Rokx, Casper ; Santoro, Maria M. ; Schapiro, Jonathan M. ; Schmidt, Daniel ; Seu, Lillian ; Sigaloff, Kim C. E. ; Sirivichayakul, Sunee ; Skhosana, Lindiwe ; Sunpath, Henry ; Tang, Michele ; Yang, Chunfu ; Carmona, Sergio ; Gupta, Ravindra K. ; Shafer, Robert W. (2017)

CITATION: Rhee, S. Y., et al. 2017. Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen : an international collaboration. EBioMedicine, 18: 225-235, doi:10.1016/j.ebiom.2017.03.024.

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Article

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.

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