SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants

Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and...

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Published in:Antimicrobial agents and chemotherapy 2024-12, p.e0123824
Main Authors: Rodriguez, Lauren, Lee, Hery W, Li, Jiani, Martin, Ross, Han, Dong, Xu, Simin, Moshiri, Jasmine, Peinovich, Nadine, Camus, Gregory, Perry, Jason K, Hyland, Robert H, Porter, Danielle P, Abdelghany, Mazin, Götte, Matthias, Hedskog, Charlotte
Format: Article
Language:English
Subjects:
Antiviral Agents
Clinical Microbiology
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Summary:Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and 14) were eligible for analysis if their viral load was above the lower limit of quantification for the RT-qPCR assay (2228 copies/mL). The SARS-CoV-2 genome was sequenced for all remdesivir participants and 50% of placebo participants (baseline, Days 3, 7, and 14) and for participants who progressed to COVID-19-related hospitalization or all-cause death (all time points). Emergent substitutions in Nsp12 and other replication complex proteins were phenotyped using site-directed mutagenesis in a SARS-CoV-2 subgenomic replicon system. Overall, emergent Nsp12 substitutions were detected in 8/115 (7.0%) remdesivir participants and 7/129 (5.4%) placebo participants (1 substitution overlap between groups). Based on a structural analysis, none of the emergent Nsp12 substitutions were in direct contact with the incoming nucleoside triphosphate substrate, the RNA, or the RNA template 5' overhang. One substitution (A376V) showed reduced susceptibility to remdesivir (12.6-fold change in remdesivir half-maximal concentration [EC ]); it also showed reduced fitness when introduced in the SARS-CoV-2 replicon and virus . Other substitutions had
ISSN:0066-4804
1098-6596
1098-6596
DOI:10.1128/aac.01238-24