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

J Infect Dis. 2024 Jun 14;229(6):1796-1802. doi: 10.1093/infdis/jiae010.

Abstract

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.

Keywords: HIV; V106I; doravirine; resistance.

MeSH terms

  • Adult
  • Anti-HIV Agents* / pharmacology
  • Drug Resistance, Viral* / genetics
  • Female
  • Genotype
  • HIV Infections* / epidemiology
  • HIV Infections* / virology
  • HIV Reverse Transcriptase* / genetics
  • HIV-1* / classification
  • HIV-1* / drug effects
  • HIV-1* / enzymology
  • HIV-1* / genetics
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic
  • Prevalence
  • Pyridones* / pharmacology
  • Reverse Transcriptase Inhibitors / pharmacology
  • Triazoles* / pharmacology

Substances

  • HIV Reverse Transcriptase
  • doravirine
  • Pyridones
  • reverse transcriptase, Human immunodeficiency virus 1
  • Anti-HIV Agents
  • Triazoles
  • Reverse Transcriptase Inhibitors

Associated data

  • ClinicalTrials.gov/NCT04894357