Portland, OR—How effective have oral antivirals actually been in preventing short- and long-term COVID-19-related outcomes? A new study examined that issue during Omicron variant (B.1.1.529) transmission and with limited COVID-19 vaccinations.

The article in Annals of Internal Medicine included results from three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir.

The participants were nonhospitalized patients being treated by the Veterans' Health Administration (VHA) who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 from January 2022 through July 2022. The researchers from the Veterans Affairs Portland, Oregon Health Care System, and the Oregon Health & Science University and colleagues focused on intervention with nirmatrelvir-ritonavir, marketed as Paxlovid, or molnupiravir pharmacotherapy.

The study team tracked any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. Most of the participants (87%) were male with a median age of 66 years; 18% were unvaccinated.

The results indicated that compared with matched, untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had a lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1,000 participants; risk difference [RD], –8.25 [95% CI, –12.27 to –4.23] per 1,000 participants) and death (1.25 vs. 5.47 per 1,000 participants; RD, –4.22 [95% CI, –5.45 to –3.00] per 1,000 participants).

"Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02])," the researchers advised. "Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1,000 participants at 30 days; RD, –10.42 [CI, –13.49 to –7.35] per 1,000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization."

The authors added that a difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. They also pointed out that a study limitation was that the date of COVID-19 symptom onset was unknown for most of the veterans.

"Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death," the study concluded. "Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals."

The authors pointed out that effectiveness studies of nirmatrelvir-ritonavir and molnupiravir are necessary because early clinical trials were conducted among unvaccinated participants before the emergence of the Omicron variant and subsequent sublineages.

"Randomized, controlled trials did not directly compare efficacy of antiviral agents, nor did they evaluate outcomes beyond 29 days after symptomatic infection," the authors wrote. "Early observational studies of nirmatrelvir-ritonavir and molnupiravir have shown varying degrees of reduced risk for short-term hospitalization and death."

The VHA provided a good setting, they added, because it is "the largest integrated healthcare system in the United States, providing care to more than 9 million veterans, the majority of whom are older and have a high burden of underlying medical conditions."

Overall, the recent studies suggested lower effectiveness than previous research. "Although the combined hospitalization and mortality benefit associated with nirmatrelvir-ritonavir was also observed in EPIC-HR [Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients]," the researchers noted, "our estimated risk reduction was smaller despite similar event rates among untreated groups in EPIC-HR and our study. EPIC-HR showed an 89% relative reduction and a 6Ðpercentage point absolute reduction in 28-day COVID-19Ðrelated hospitalization or death, whereas we observed a 33% lower risk for 30-day hospitalization or death, corresponding to a reduction of 1 percentage point (11 per 1000 persons)."

The reasons for the difference could include predominant circulating variants, differences in vaccination levels, age, and comorbidities, they added.

"Consistent with EPIC-HR, we observed benefit in veterans aged 65 years or older as well as those aged 18 to 64 years; however, we did not find a lower risk for hospitalization or death in the older group compared with the younger group," the authors explained.

As for molnupiravir, the short-term benefit was limited to an absolute risk reduction of one percentage point for 30-day mortality.

"In conclusion, nirmatrelvir-ritonavir seems to be an effective treatment for eligible persons with COVID-19 to reduce risk for short-term outcomes of severe COVID-19," the researchers concluded. "The benefit of molnupiravir may be more limited. Further studies are needed to clarify the long-term effectiveness of oral antivirals with regard to incident post–COVID-19 conditions."

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