Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

Bajema et al., medRxiv, doi:10.1101/2022.12.05.22283134

Dec 2022

Retrospective 112,380 high-risk patients in the USA, showing significantly higher acute or long-term care admission at 180 days with molnupiravir treatment, and no significant difference for other outcomes. The title and headers of Table S14 are conflicting but the data appears to match be title.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Chamod, Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zhou, Zibat. Multiple analyses have identified variants potentially created by molnupiravir Fountain-Jones, Kosakovsky Pond, Sanderson, twitter.com.

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2. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

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5. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

6. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

7. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

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Important missing comments or errors? Let us know.

Study covers paxlovid and molnupiravir.

risk of death, 18.0% lower, HR 0.82, p = 0.40, treatment 24 of 897 (2.7%), control 29.0 of 897 (3.2%), NNT 179, cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of death, 49.3% lower, RR 0.51, p = 0.19, treatment 7 of 897 (0.8%), control 13.8 of 897 (1.5%), NNT 132, propensity score matching, day 30.

risk of mechanical ventilation, 16.7% lower, RR 0.83, p = 1.00, treatment 3 of 897 (0.3%), control 3.6 of 897 (0.4%), NNT 1495, propensity score matching, day 30.

risk of ICU admission, 1.0% lower, RR 0.99, p = 1.00, treatment 10 of 897 (1.1%), control 10.1 of 897 (1.1%), NNT 8970, propensity score matching, day 30.

risk of hospitalization, 30.0% higher, HR 1.30, p = 0.04, treatment 162 of 897 (18.1%), control 124.3 of 897 (13.9%), cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of hospitalization, 8.6% lower, RR 0.91, p = 0.73, treatment 37 of 897 (4.1%), control 40.5 of 897 (4.5%), NNT 256, propensity score matching, day 30.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Bajema et al., 6 Dec 2022, retrospective, USA, preprint, median age 67.0, 18 authors, study period 1 January, 2022 - 28 February, 2022.

This Paper Molnupiravir All

Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

MD, MSc Kristina L Bajema, PhD Kristin Berry, PhD Elani Streja, PhD Nallakkandi Rajeevan, MS Yuli Li, PhD Lei Yan, PharmD Francesca Cunningham, MPH Denise M Hynes, MPH Mazhgan Rowneki, PhD, MHS Amy Bohnert, Edward J Boyko, MD, PhD Theodore J Iwashyna, PhD Matthew L Maciejewski, Thomas F Osborne, MD, MPH, MSc Elizabeth M Viglianti, PhD Mihaela Aslan, MPH, PhD Grant D Huang, BMBCh George N Ioannou

doi:10.1101/2022.12.05.22283134

Background: Information about the effectiveness of oral antivirals in preventing short-and longterm COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or longterm care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, ). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, . A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir-or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral. for use under a CC0 license.

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