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- Title
Cell culture selections reveal favourable drug resistance profiles for doravirine and islatravir.
- Authors
Brenner, Bluma G; Oliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Routy, Jean-Pierre; Thomas, Réjean
- Abstract
<bold>Background: </bold>The newer generation NNRTIs, including doravirine and rilpivirine, were designed to show high potency and overcome K103N, Y181C and G190A resistance.<bold>Objectives: </bold>To assess emergent resistance to doravirine and rilpivirine, alone and paired with lamivudine or islatravir through in vitro drug selections.<bold>Methods: </bold>Subtype B (n = 3), non-B subtype (n = 3), and pNL4.3 viral isolates were passaged in cord blood mononuclear cells with progressively increasing concentrations of drug(s). Genotypic analysis compared the acquisition and accumulation of drug resistance mutations at weeks 8 and 24 following drug pressure. Cell-based phenotypic assays assessed cross-resistance patterns to NNRTIs by acquired resistance mutations.<bold>Results: </bold>Doravirine pressure resulted in the acquisition of V108I (6/7) and V106A/I/M (5/7) mutations at weeks 8, followed by F227L (4/7), Y318F (4/7), M230L (2/7) or L234I (2/7) by weeks 24. In contrast, rilpivirine resulted in E138K (5/7) followed by L100I (3/7), K101E (1/7), or M230L (1/7). Doravirine resistance pathways retained susceptibility to rilpivirine, whereas rilpivirine resistance conferred intermediate resistance (12-152-fold) to doravirine. Dual selections with islatravir or lamivudine delayed and diminished emergent resistance to doravirine, resulting in V108I (9/15) with fewer or no other changes at weeks 24. There was a lesser delay in emergent resistance to rilpivirine when combined with islatravir or lamivudine. The M184V mutation did not arise in dual selections with islatravir or lamivudine.<bold>Conclusions: </bold>Doravirine showed a more robust resistance profile compared with other NNRTIs. The long intracellular half-life of islatravir and delayed acquisition of resistance in dual selections provide an opportunity for long-acting treatment options.
- Subjects
CELL culture; SOMATIC mutation; LAMIVUDINE; CORD blood; GENOTYPES; DRUG resistance; HIV infections; ANTI-HIV agents; PROTEINS; PYRIDINE; RESEARCH; GENETIC mutation; HETEROCYCLIC compounds; REVERSE transcriptase inhibitors; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RESEARCH funding; ADENOSINES; DRUG resistance in microorganisms; HIV; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2021, Vol 76, Issue 8, p2137
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkab126