SARS-CoV-2 viral dynamics in a placebo-controlled phase 2 study of patients infected with the SARS-CoV-2 Omicron variant and treated with pomotrelvir

• Published in: Microbiology spectrum 2024-02, Vol.12 (2), p.e0298023-e0298023
• Main Authors: Borroto-Esoda, Katyna, Wilfret, David, Tong, Xiao, Plummer, Andrew, Kearney, Brian, Kwong, Ann D
• Format: Article
• Language: English
• Subjects: Adult; Antimicrobial Chemotherapy; COVID-19; Double-Blind Method; Humans; infectious virus assay; Omicron; qRT-PCR; rapid antigen test; Research Article; SARS-CoV-2; Time Factors; viral dynamics
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.02980-23

Current guidelines recommend that individuals with moderate COVID-19 disease isolate for 5 days after the first appearance of symptoms or a positive SARS-CoV-2 test. It would be useful to understand the time course of infectious virus production and its correlation with virus detection using a rapid antigen test (RAT) or quantitative reverse transcriptase (qRT)-PCR. In a phase 2 study, 242 vaccinated patients with COVID-19 and at low risk for progression to severe disease initiated 5 days of treatment with pomotrelvir (PBI-0451, a SARS-CoV-2 main protease inhibitor) or placebo within 5 days after symptom onset. The primary endpoint, the proportion of subjects with SARS-CoV-2 viral titers below the limit of detection on Day 3 of treatment in the pomotrelvir versus placebo groups, was not met. No between-group differences in SARS-CoV-2 clearance or symptom resolution or alleviation were observed. Additional analyses evaluated the dynamics of SARS-CoV-2 replication in mid-turbinate nasal swabs and saliva samples using infectious virus assay (IVA), RAT, and qRT-PCR. SARS-CoV-2 cleared rapidly, with negative results first determined by IVA (TCID below the limit of detection), followed by the RAT (negative for SARS-CoV-2 N antigen), and qRT-PCR (RNA below the limit of detection), which suggests that delayed initiation of treatment (up to 5 days after symptom onset) may have contributed to the lack of treatment response. Symptom resolution lagged behind viral clearance assessed by IVA and RAT. These data support reliance on a negative RAT to determine when an individual is no longer producing infectious virus and may end isolation.IMPORTANCEA phase 2 double-blind, placebo-controlled study was performed evaluating pomotrelvir, a SARS-CoV-2 Mpro inhibitor, compared with placebo in 242 non-hospitalized, vaccinated, symptomatic adults with COVID-19 (Omicron). No improvement in the decrease of viral replication or relief of symptoms was observed between the two groups when treatment was initiated ≥3 days after symptom onset. These results suggest that future COVID-19 antiviral studies using a similar patient population may need to initiate treatment earlier, like influenza studies. This is the first study to prospectively evaluate SARS-CoV-2 viral dynamics and the time to viral clearance in a significant number of patients using concurrently obtained results from an infectious virus assay, a rapid antigen test (RAT), and a qRT-PCR assay over a 15-day time course. Thes