A study today in the Canadian Medical Association Journal suggests that use of the oral antiviral drugs molnupiravir and Paxlovid in patients with mild or moderate COVID-19 lowered the risk of hospitalization and death without raising the risk of adverse events.
McMaster University researchers in Ontario led the systematic review and network meta-analysis of 40 randomized clinical trials that included 17,563 patients comparing the effectiveness of 16 different antiviral drugs or drug combinations, including molnupiravir, nirmatrelvir-ritonavir (Paxlovid), and remdesivir, with standard care or a placebo in adults with non-severe COVID-19 up to Apr 25, 2022.
The researchers noted that most antiviral trials to date have included hospitalized patients with severe or critical disease rather than those with milder illnesses. "Furthermore, although efficacy data from trials of molnupiravir, nirmatrelvir–ritonavir and remdesivir are promising, no head-to-head trials have compared these drugs," they wrote. "This is particularly important as health care systems attempt to prioritize access to effective COVID-19 treatments in the early stages of the disease."
No death reduction with remdesivir
Most trials in the meta-analysis involved unvaccinated patients and were conducted before the emergence of the highly transmissible Omicron variant. Most patients were 36.5 to 65.5 years old, and proportions of men and women were comparable.
A total of 32 trials with 10,837 patients reported 291 deaths over a median follow-up of 29 weeks. The researchers assumed a baseline risk of 13.3 deaths per 1,000 patients based on median risk in the standard-care and placebo groups.
Molnupiravir and Paxlovid each lowered the risk of death beyond standard care or placebo with moderate certainty (10.9 fewer deaths per 1,000 patients; 95% confidence interval [CI], 12.6 to 4.5 fewer for molnupiravir and 11.7 fewer deaths per 1,000; 95% CI, 13.1 fewer to 2.6 more for Paxlovid).
A total of 10 trials with 5,575 patients reported 252 hospitalizations over a median follow-up of 21 weeks. The researchers assumed a baseline risk of 54.4 hospitalizations per 1,000 patients. Paxlovid lowered the risk of hospitalization by 46.2 admissions per 1,000 (95% CI, 50.1 to 38.9 fewer) with high certainty, while molnupiravir likely reduced the risk of hospitalizations by 16.3 per 1,000 (95% CI, 27.2 to 0 fewer) with moderate certainty.
Relative to molnupiravir, Paxlovid likely reduced the risk of hospitalization (27.8 fewer admissions per 1,000 patients; 95% CI, 32.8 to 18.3 fewer) with moderate certainty. Remdesivir, on the other hand, likely had no effect on risk of death but may have lowered hospitalizations (39.1 fewer admissions per 1,000; 95% CI, 48.7 to 13.7 fewer), but that finding had low certainty.
Results may help guide treatment recommendations
A total of 14 trials with 3,972 patients reported that 123 required mechanical ventilation over a median follow-up of 21 weeks. The researchers assumed a baseline risk of 22 mechanical ventilation events per 1,000.
Relative to standard care or placebo, molnupiravir likely reduced the need for mechanical ventilation by 13 events per 1,000 (95% CI, 18.3 to 0 fewer) with moderate certainty, and remdesivir may have lowered the need for mechanical ventilation by 11.8 events per 1,000 (95% CI, 18.9 fewer to 12.1 more), but with low certainty.
The hepatitis C drug combination sofosbuvir-daclatasvir, however, likely raised the risk of needing mechanical ventilation over standard care or placebo by 11.1 events per 1,000 patients (95% CI, 5.9 fewer to 45.9 more) with moderate certainty.
Twenty-two trials including 7,465 participants reported 190 adverse events that led to discontinuation of antiviral therapy over a median follow-up of 29 weeks. The researchers assumed a baseline risk of 20 adverse events per 1,000 patients.
Molnupiravir had similar rates of adverse events leading to drug stoppage as Paxlovid (5.1 more events per 1,000; 95% CI, 3 fewer to 13.2 more) with moderate certainty. Compared with standard care or placebo, molnupiravir was tied to 4.4 fewer adverse events per 1,000 (95% CI, 11 fewer to 2.1 more) with high certainty while, at 9.5 fewer events per 1,000 (95% CI, 14.3 to 4.8 fewer) with high certainty, Paxlovid did not increase adverse events that led to stopping the drug.
"Our findings suggest that nirmatrelvir–ritonavir may be superior to molnupiravir for some outcomes, which has implications for organizations, such as the WHO [World Health Organization], that are in the process of developing recommendations addressing molnupiravir and nirmatrelvir–ritonavir," the researchers wrote. "Health care systems deciding on drug procurement and cost issues need to consider the relative efficacy of nirmatrelvir-ritonavir over molnupiravir."
In a related commentary, Corinne Hohl, MDCM, and Andrew McRae, MD, PhD, both of the University of British Columbia, said that the best methods of rapidly assessing the effectiveness of antiviral drugs against severe COVID-19 in the setting of viral and population dynamic evolution are large observational studies using linked administrative healthcare data and adaptive platform trials.
"These studies can be completed in Canada, but need to be supported by Canadian research funders, health care institutions, data custodians, health care providers and patients," they wrote.