Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study

Abstract Background Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility. Objectives To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resi...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of antimicrobial chemotherapy Vol. 77; no. 4; pp. 989 - 995
Main Authors:	Margot, Nicolas, Vanderveen, Laurie, Naik, Vidula, Ram, Renee, Parvangada, PC, Martin, Ross, Rhee, Martin, Callebaut, Christian
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 31-03-2022
Subjects:	Anti-HIV Agents - pharmacology Anti-HIV Agents - therapeutic use Anti-Retroviral Agents - therapeutic use Drug Resistance, Viral - genetics HIV Infections - drug therapy HIV-1 - genetics Humans Mutation
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Abstract Background Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility. Objectives To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resistance analyses conducted in a Phase 1b study of lenacapavir (Study 4072) in people with HIV (PWH). Methods Mutations were inserted in a proviral DNA clone by site-directed mutagenesis, and viruses (n = 12) were generated by transfection. Sequences were used to generate single-cycle (SC) test vectors that were evaluated in a Gag-Pro assay, and replicative viruses were tested in a multicycle (MC) MT-2 assay to determine lenacapavir susceptibility. Study 4072 was a Phase 1b, double-blinded, placebo-controlled, dose-ranging, randomized study of lenacapavir in untreated PWH. Participants received a single dose of lenacapavir (up to 750 mg) or placebo (10 day monotherapy). CA resistance was characterized using genotypic and/or phenotypic assays. Results Lenacapavir susceptibility in the SC assay showed an inverse relationship between replication capacity and resistance. In Study 4072, all 29 participants receiving lenacapavir showed a robust virological response with no rebound. At baseline, no participant had resistance mutations to lenacapavir, and all had WT susceptibility to lenacapavir. Post-monotherapy analyses revealed the emergence of CA mutation Q67H at Day 10 in two participants. Conclusions In vitro assays confirmed that increased resistance to lenacapavir was associated with decreased replication capacity of mutant viruses. In the clinical study no pre-existing lenacapavir resistance was detected. Emergence of Q67H occurred at exposures below the dose used in current Phase 2/3 studies. These results support development of lenacapavir as an antiretroviral agent.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-News-3 content type line 23
ISSN:	0305-7453 1460-2091
DOI:	10.1093/jac/dkab503