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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'abstract': '<jats:p>Background: Information about the effectiveness of oral antivirals in preventing '
'short- and long-term 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 long-term 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, RD -11.71, 95% CI -16.07 to -7.35). '
'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, RD -27.10, 95% CI -50.63 to -3.58). 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.</jats:p>',
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