학술논문
Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration
Document Type
article
Author
Soo-Yon Rhee; Vici Varghese; Susan P. Holmes; Gert U. Van Zyl; Kim Steegen; Mark A. Boyd; David A. Cooper; Sabin Nsanzimana; Shanmugam Saravanan; Charlotte Charpentier; Tulio de Oliveira; Mary-Ann A. Etiebet; Federico Garcia; Dominique Goedhals; Perpetua Gomes; Huldrych F. Günthard; Raph L. Hamers; Christopher J Hoffmann; Gillian Hunt; Awachana Jiamsakul; Pontiano Kaleebu; Phyllis Kanki; Rami Kantor; Bernhard Kerschberger; Vincent C. Marconi; Jean D'amour Ndahimana; Nicaise Ndembi; Nicole Ngo-Giang-Huong; Casper Rokx; Maria M. Santoro; Jonathan M. Schapiro; Daniel Schmidt; Lillian Seu; Kim C.E. Sigaloff; Sunee Sirivichayakul; Lindiwe Skhosana; Henry Sunpath; Michele Tang; Chunfu Yang; Sergio Carmona; Ravindra K. Gupta; Robert W. Shafer
Source
EBioMedicine, Vol 18, Iss C, Pp 225-235 (2017)
Subject
Language
English
ISSN
2352-3964
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.