Affiliation:
1. Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA
Abstract
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.
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)
Reference19 articles.
1. Clinical targeting of HIV capsid protein with a long-acting small molecule;Link;Nature,2020
2. GS-6207, A Potent and Selective First-in-Class Long-Acting HIV-1 Capsid Inhibitor;Yant
3. ACTIVITY AND RESISTANCE CHARACTERIZATION OF THE HIV CAPSID INHIBITOR LENACAPAVIR;VanderVeen
4. Absence of lenacapavir (GS-6207) phenotypic resistance in HIV gag cleavage site mutants and in isolates with resistance to existing drug classes;Margot;Antimicrob Agents Chemother,2021
5. In Vitro Resistance Profile of GS-6207, a First-in-Class Picomolar HIV Capsid Inhibitor in Clinical Development as a Novel Long-Acting Antiretroviral Agent;Yant
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