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

Abstract

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.

Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 community, highly vaccinated patients with high risk for severe disease: Evidence that both antivirals reduce the risk for disease progression and death

“…In the same study, nirmatrelvir/ritonavir recipients had a reduced risk for death (HR:0.34) and hospitalization (HR: 0.76), with mortality risks to be consistently lower among elderly patients with early antiviral use [20]. In a study conducted among U.S. veterans, molnupiravir use reduced the 30-day risk for hospitalization or death among people older than 65 years (RR:0.67) [23]. Similarly, nirmatrelvir-ritonavir recipients had reduced risk for hospitalization or death (RR: 0.53), which was observed mainly in people aged older than 65 years (RR: 0.46) [23].…”

“…In a study conducted among U.S. veterans, molnupiravir use reduced the 30-day risk for hospitalization or death among people older than 65 years (RR:0.67) [23]. Similarly, nirmatrelvir-ritonavir recipients had reduced risk for hospitalization or death (RR: 0.53), which was observed mainly in people aged older than 65 years (RR: 0.46) [23]. Notably, no difference was found in the relative risk for hospitalization and death between molnupiravir- and nirmatrelvir/ritonavir-treated patients, but a significant reduction in the absolute risk for death was found for nirmatrelvir/ritonavir recipients versus those with molnupiravir use [23].…”

“…Similarly, nirmatrelvir-ritonavir recipients had reduced risk for hospitalization or death (RR: 0.53), which was observed mainly in people aged older than 65 years (RR: 0.46) [23]. Notably, no difference was found in the relative risk for hospitalization and death between molnupiravir- and nirmatrelvir/ritonavir-treated patients, but a significant reduction in the absolute risk for death was found for nirmatrelvir/ritonavir recipients versus those with molnupiravir use [23]. In the study by Wai et al , both antivirals were associated with reduced risk for hospital admissions [22], and all cause-mortality, with no significant difference to be observed between the two drugs, whereas nirmatrelvir/ritonavir was associated with a stronger effect in hospital admission [22].…”

“…Nirmatrelvir/ritonavir subsequently received EU approval for use in January 2022, with the same indication as in the UK [16]. Molnupiravir and nirmatrelvir/ritonavir outpatient use in COVID-19 patients with a high risk for disease progression has shown evidence for a significant reduction in the risk for hospitalization and death in real-world studies, however, more real-world data is necessary [17][18][19][20][21][22][23].…”

Target Trial Emulation Using Hospital-Based Observational Data: Demonstration and Application in COVID-19

“…This design framework can be applied to mimic a hypothetical trial or contribute to existing knowledge, especially when data from randomised controlled trials are unavailable [ 17 ]. During the COVID-19 pandemic, this framework was used in a wide range of evaluations, i.e., drug therapies [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ], extracorporeal membrane oxygenation [ 25 , 26 ], vaccine effectiveness [ 27 , 28 ], non-pharmaceutical interventions, and policy evaluations [ 29 ]. To emulate a trial, there are two common methods: the cloning approach and the sequential trial approach [ 17 , 30 ].…”