Molnupiravir cuts hospitalization, death in COVID-19 patients at high risk of progression

An emulation of a randomized target trial suggests that molnupiravir may reduce hospital admission or death in adults who have tested positive for COVID-19 during the predominance of Omicron who were at high risk of progression to severe disease.

Compared with no treatment, molnupiravir use was associated with a reduction in hospital admission or death at 30 days (relative risk [RR], 0.72). Event rate was lower in the molnupiravir vs the no-treatment arm (2.7 percent vs 3.8 percent), yielding an absolute risk reduction of 1.1 percent with the former vs the latter regimen.

Evaluation of the individual elements of the composite outcome suggested that molnupiravir was effective in reducing hospital admission (RR, 0.80) and death (RR, 0.35).

“Overall, evidence supporting the effectiveness of molnupiravir is limited. Whether any benefit from the drug can be maintained in people of varying vaccination status is not known,” said the researchers. “[It is also] unclear whether molnupiravir could have provided protection during periods when the Omicron subvariants BA.1 or BA.2 and BA.5 were predominant or in [those who were re-infected] with SARS-CoV-2.”

Using electronic health records from the US Department of Veterans Affairs databases, the team sought to evaluate adults who contracted SARS-CoV-2 infection between 5 January and 30 September 2022 and had at least one risk factor for progression to severe disease. Of the 85,998 eligible participants (mean age 67.3 years, 89.5 percent male), 7,818 received oral molnupiravir within 5 days of COVID-19 diagnosis. The rest received no treatment. [BMJ 2023;380:e072705]

Molnupiravir seemed effective among the unvaccinated (RR, 0.83) and those who had one or two vaccine doses (RR, 0.69) and a booster dose (RR, 0.71). Same goes for those who have been infected during the predominance of the Omicron subvariant BA.1 or BA.2 (RR, 0.72) and BA.5 (RR, 0.75), and those with (RR, 0.75) and without history of SARS-CoV-2 infection (RR, 0.72).

Extends evidence base

The only randomized trial to evaluate the efficacy of molnupiravir was MOVe-OUT, which included unvaccinated participants in the pre-Omicron era. [N Engl J Med 2022;386:509-520] Although the findings aligned with the current analysis, MOVe-OUT did not represent vaccinated* individuals and those with exposure to an Omicron subvariant.

“Our study extends this evidence base to the eras when three [Omicron subvariants (BA.1, BA.2, and BA.5)] predominated in the US … The results suggest that molnupiravir was effective [against these subvariants] and that the magnitude of effectiveness was similar,” the researchers said.

Conversely, the PANORAMIC trial demonstrated no reduction in the risk of hospitalization or death following molnupiravir use. [Lancet 2023;401:281-293] While it did include participants at risk of progression to severe disease, it excluded those at the highest risk category. “The difference between our results and those of PANORAMIC could be explained by variations in study setting, recruitment strategy, and definition of the intervention,” they explained.

More beneficial for those at highest risk of progression?

“Taken together, the results from MOVe-OUT, PANORAMIC, and our analysis suggest the possibility of graded erosion in effectiveness of molnupiravir as the baseline risk (risk in the control arm) of the target population decreases – suggesting that those at the highest risk of progression to severe COVID-19 are likely to derive most benefit,” they said.

However, adverse events were not assessed. “[Also, as] the COVID-19 pandemic is still evolving dynamically … the effectiveness of therapeutics may change as the virus mutates and as other characteristics of the pandemic develop over time,” said the researchers.

“We also did not evaluate risk of post-acute outcomes. [This is] an area of intense interest that should be investigated in future research,” they added.