Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes.

Background: Limited data are available regarding the susceptibility of the reverse transcriptase V106 polymorphism to doravirine.
Methods: Doravirine susceptibility was measured in site-directed mutants (SDMs) containing V106I, V106A, V106M, and Y188L mutations in subtype B (NL4-3, HXB2) and CRF02_AG background and in recombinant viruses with RT harboring V106I alone derived from 50 people with HIV.
Results: HIV-1 B subtype was detected in 1523 of 2705 cases. Prevalence of V106I was 3.2% in B and 2.5% in non-B subtypes, and was higher in subtype F (8.1%) and D (14.3%). Fold-changes (FC) in susceptibility for SDMs were below doravirine biological cutoff (3.0) for V106I, but not for V106A, V106M, and Y188L. Clinically derived viruses tested included 22 B (median FC, 1.2; interquartile range [IQR], 0.9-1.6) and 28 non-B subtypes (median FC, 1.8; IQR, 0.9-3.0). Nine (18%) viruses showed FC values equal or higher than the doravirine biological FC cutoff.
Conclusions: The prevalence of the HIV-1 RT V106I polymorphism in MeditRes HIV consortium remains low, but significantly more prevalent in subtypes D and F. V106I minimally decreased the susceptibility to doravirine in SDMs and most clinical isolates. Reduced susceptibility seems to occur at increased frequency in subtype F1; however, the clinical impact remains to be investigated.
Clinical Trials Registration: NCT04894357.
Competing Interests: Potential conflicts of interest. E. T. has received funds for attending meetings and/or travel from Moderna. C. C. has received funds for attending symposia, speaking, organizing educational activities, and travel grants from Gilead Sciences, ViiV Healthcare, and Merck Sharp and Dohme. A. A. has received funds for attending symposia, speaking, organizing educational activities, and travel grants from Gilead Sciences, Roche, Vircell, and Abbvie. R. D. has served as a speaker, a consultant, and an advisory board member for GSK, Gilead, Merck Sharp and Dohme, Hologic, and ViiV Healthcare. S. L.-N. has received funds for attending symposia, speaking, organizing educational activities, and travel grants from Gilead Sciences, Merck Sharp and Dohme, and ViiV Healthcare. P. G. has received funds for attending symposia, speaking, and travel grants from Gilead Sciences, Merck Sharp and Dohme, and ViiV Healthcare. D. P. has received funds for attending meetings and/or travel from Moderna. M. M. S. has received funds for attending symposia, speaking, and organizing educational activities from ViiV Healthcare, Janssen-Cilag, MSD, and Theratechnologies. F. C.-S. has received funds for attending symposia, speaking, organizing educational activities, travel grants, advisory/consulting, and/or research grants from Abbvie, Gilead Sciences, Janssen-Cilag, Merck Sharp and Dohme, Theratechnologies, and ViiV Healthcare. A.-G. M. has received funds for attending symposia, speaking, and research grants from VIIV Healthcare, Gilead Sciences, and Merck Sharp and Dohme. M. Z. reports research grants from MSD, Theratechnologies, and ViiV Healthcare; consulting fees for advisory boards from MSD, Gilead Sciences, Theratechnologies, and ViiV Healthcare; support for attending meetings from Gilead Sciences and Theratechnologies; and receipt of drug for in vitro studies from Theratechnologies and MSD, outside the submitted work. F. G. has received funds for attending symposia, speaking, and research grants from Abbvie, Gilead, Merck/MSD, Roche, Hologic, Thera, Vircell, and Seegene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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