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

Details

• Alternative Title:
  EBioMedicine
• Personal Author:
  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 ; Günthard, Huldrych F. ; Hamers, Raph L. ; Hoffmann, Christopher J ; Hunt, Gillian ; Jiamsakul, Awachana ; Kaleebu, Pontiano ; Kanki, Phyllis ; Kantor, Rami ; Kerschberger, Bernhard ; Marconi, Vincent C. ; D'amour Ndahimana, Jean ; 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.
• Description:
  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.
• Subjects:
  Antiretroviral Therapy Drug Resistance HIV-1 Research Paper Reverse Transcriptase Tenofovir WHO-recommended First-line
• Source:
  EBioMedicine. 2017; 18:225-235.
• Pubmed ID:
  28365230
• Pubmed Central ID:
  PMC5405160
• Document Type:
  Journal Article
• Funding:
  R24 TW007988/TW/FIC NIH HHS/United States
• Volume:
  18
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d6fa2a42f668b33894e5190344c772c77eac9d026d0b11d394a10cdeae4d6339
• Download URL:
  https://stacks.cdc.gov/view/cdc/45741/cdc_45741_DS1.pdf
• File Type:
  [PDF - 727.61 KB ]