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


ABSTRACT: 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.

SUBMITTER: Rhee SY 

PROVIDER: S-EPMC5405160 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Rhee Soo-Yon SY   Varghese Vici V   Holmes Susan P SP   Van Zyl Gert U GU   Steegen Kim K   Boyd Mark A MA   Cooper David A DA   Nsanzimana Sabin S   Saravanan Shanmugam S   Charpentier Charlotte C   de Oliveira Tulio T   Etiebet Mary-Ann A MA   Garcia Federico F   Goedhals Dominique D   Gomes Perpetua P   Günthard Huldrych F HF   Hamers Raph L RL   Hoffmann Christopher J CJ   Hunt Gillian G   Jiamsakul Awachana A   Kaleebu Pontiano P   Kanki Phyllis P   Kantor Rami R   Kerschberger Bernhard B   Marconi Vincent C VC   D'amour Ndahimana Jean J   Ndembi Nicaise N   Ngo-Giang-Huong Nicole N   Rokx Casper C   Santoro Maria M MM   Schapiro Jonathan M JM   Schmidt Daniel D   Seu Lillian L   Sigaloff Kim C E KCE   Sirivichayakul Sunee S   Skhosana Lindiwe L   Sunpath Henry H   Tang Michele M   Yang Chunfu C   Carmona Sergio S   Gupta Ravindra K RK   Shafer Robert W RW  

EBioMedicine 20170319


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-  ...[more]

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