Molnupiravir and risk of post-acute sequelae of covid-19: cohort study

Abstract

Objective: To examine whether treatment with the antiviral agent molnupiravir during the first five days of SARS-CoV-2 infection is associated with reduced risk of post-acute adverse health outcomes.

Design: Cohort study.

Setting: US Department of Veterans Affairs.

Participants: 229 286 participants who tested positive for SARS-CoV-2 between 5 January 2022 and 15 January 2023, had at least one risk factor for progression to severe covid-19, and survived the first 30 days after testing positive were enrolled. 11 472 participants received a prescription for molnupiravir within five days of the positive test result and 217 814 received no covid-19 antiviral or antibody treatment (no treatment group).

Main outcome measures: Risks of post-acute sequelae of SARS-CoV-2 (PASC, defined based on a prespecified set of 13 post-acute sequelae), post-acute death, post-acute hospital admission, and each individual post-acute sequela between the molnupiravir group and no treatment group were examined after application of inverse probability weighting to balance the treatment and no treatment groups. Post-acute outcomes were ascertained from 30 days after the first SARS-CoV-2 positive test result until end of follow-up. Risks on the relative scale (relative risk or hazard ratio) and absolute scale (absolute risk reduction at 180 days) were estimated.

Results: Compared with no treatment, molnupiravir use within five days of a positive SARS-CoV-2 test result was associated with reduced risk of PASC (relative risk 0.86 (95% confidence interval 0.83 to 0.89); absolute risk reduction at 180 days 2.97% (95% confidence interval 2.31% to 3.60%)), post-acute death (hazard ratio 0.62 (0.52 to 0.74); 0.87% (0.62% to 1.13%)), and post-acute hospital admission (0.86 (0.80 to 0.93); 1.32% (0.72% to 1.92%)). Molnupiravir was associated with reduced risk of eight of the 13 post-acute sequelae: dysrhythmia, pulmonary embolism, deep vein thrombosis, fatigue and malaise, liver disease, acute kidney injury, muscle pain, and neurocognitive impairment. Molnupiravir was also associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received at one or two vaccine doses, and had received a booster dose, and in people with primary SARS-CoV-2 infection and reinfection.

Conclusions: In people with SARS-CoV-2 infection and at least one risk factor for progression to severe covid-19, compared with no treatment, molnupiravir use within five days of infection was associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received one or two vaccine doses, and had received a booster dose, and in those with primary SARS-CoV-2 infection and reinfection. Among people at high risk of progression to severe covid-19, molnupiravir use within five days of SARS-CoV-2 infection may be a viable approach to reduce the risk of PASC.

Fig 1

Relative and absolute risk reduction of molnupiravir on post-acute sequelae of SARS-CoV-2 (PASC), post-acute death, post-acute hospital admission, and composite outcome of post-acute death or hospital admission compared with no treatment. Post-acute outcomes were ascertained 30 days after a first SARS-CoV-2 positive test result between 5 January 2022 and 15 January 2023 until end of follow-up. Adjusted relative risk or hazard ratios and 95% confidence intervals are presented. Length of shaded area represents risk reduction per 100 people at 180 days. Whiskers represent 95% confidence intervals (CIs)

Fig 2

Event rates of post-acute sequelae in molnupiravir group (n=11 472) and no treatment group (n=217 814). Post-acute outcomes were ascertained 30 days after a first SARS-CoV-2 positive test result between 5 January 2022 and 15 January 2023 until end of follow-up. Event rates were estimated based on inverse probability weighting method. Shading represents 95% confidence intervals (CIs)

Fig 3

Hazard ratio and absolute risk reduction of molnupiravir compared with no treatment on individual post-acute sequelae. Post-acute outcomes were ascertained 30 days after a first SARS-CoV-2 positive test result between 5 January 2022 and 15 January 2023 until end of follow-up. Length of shaded area represents risk reduction per 100 people at 180 days, Whiskers represent 95% confidence intervals (CIs)

Fig 4

Relative risk of molnupiravir compared with no treatment on post-acute sequelae of covid-19 according to vaccination status and primary SARS-CoV-2 infection or reinfection. Outcomes were ascertained 30 days after a first SARS-CoV-2 positive test result between 5 January 2022 and 15 January 2023 until end of follow-up. CI=confidence interval

Fig 5

Relative risk of molnupiravir on post-acute sequelae of covid-19 compared with no treatment in subgroups by personal characteristics and comorbidities. Post-acute outcomes were ascertained 30 days after a first positive SARS-CoV-2 test result between 5 January 2022 and 15 January 2023 until end of follow-up. CI=confidence interval