Real-world data during HK’s Omicron wave: Molnupiravir and nirmatrelvir/ritonavir effective in community-dwelling outpatients with COVID-19

In a real-world, territory-wide, propensity score (PS)–matched study during Hong Kong’s Omicron BA.2.2 wave, early initiation of molnupiravir or nirmatrelvir/ritonavir is shown to reduce the risks of mortality and in-hospital outcomes among community-dwelling outpatients with COVID-19. However, the risk of hospitalization is lowered with nirmatrelvir/ritonavir but not molnupiravir.

The different clinical outcomes between molnupiravir and nirmatrelvir/ritonavir users may be related to differences in baseline characteristics, such as age, pre-existing comorbidities and vaccination status. The risk of drug-drug interactions with and the later availability of nirmatrelvir/ritonavir in Hong Kong also need to be taken into account. [Lancet 2022;400:1213-1222]

In this study, the PS-matched cohorts included 4,983 molnupiravir users with 49,234 matched nonusers, and 5,542 nirmatrelvir/ritonavir users with 54,672 matched nonusers. The oral antivirals were initiated at a median of 2 days since symptom onset, and ≥99.7 percent of patients completed the 5-day course of treatment.

Molnupiravir users were generally older (>60 years, 88.7 percent vs 85.2 percent), and had more pre-existing comorbidities (Charlson Comorbidity Index score ≥5, 10.2 percent vs 4.5 percent) and lower rate of complete COVID-19 vaccination (≥2 doses of BNT162b2 or ≥3 doses of CZ02, 16.1 percent vs 33.4 percent) than nirmatrelvir/ritonavir users. Median follow-up was 103 days for molnupiravir users and 99 days for nirmatrelvir/ritonavir users.

Both molnupiravir and nirmatrelvir/ritonavir use significantly reduced the risk of all-cause mortality (molnupiravir: hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.61–0.95; p=0.013) (nirmatrelvir/ritonavir: HR, 0.34; 95 percent CI, 0.22–0.52; p<0.0001) and the composite outcome of in-hospital disease progression (molnupiravir: HR, 0.57; 95 percent CI, 0.43–0.76; p=0.0001) (nirmatrelvir/ritonavir: HR, 0.57; 95 percent CI, 0.38–0.87; p=0.0083) vs nonuse of the oral antivirals. Nirmatrelvir/ritonavir use also significantly decreased hospitalization (HR, 0.76; 95 percent CI, 0.67–0.86; p<0.0001) vs nonuse.

Notably, for the composite outcome of in-hospital disease progression, molnupiravir use was associated with risk reductions in both in-hospital mortality (HR, 0.53; 95 percent CI, 0.38–0.75; p=0.0002) and initiation of invasive mechanical ventilation (HR, 0.40; 95 percent CI, 0.19–0.84; p=0.016), but not intensive care unit admission (HR, 0.74; 95 percent CI, 0.45–1.21; p=0.24). In contrast, risk reduction in in-hospital disease progression with nirmatrelvir/ritonavir was mainly driven by in-hospital mortality (HR, 0.25; 95 percent CI, 0.12–0.50; p=0.0001).

Subgroup analyses further demonstrated the beneficial effects of these oral antivirals among older patients in the community setting. Molnupiravir users aged >60 years had significantly lower risks of all-cause mortality (HR, 0.75; 95 percent CI, 0.60–0.93; p=0.0076), hospitalization (HR, 0.89; 95 percent CI, 0.81–0.97; p=0.0067), and in-hospital disease progression (HR, 0.55; 95 percent CI, 0.42–0.73; p<0.0001) vs nonusers. In this age group, nirmatrelvir/ritonavir use also significantly reduced the risks of all-cause mortality (HR, 0.48; 95 percent CI, 0.32–0.74; p=0.00069) and hospitalization (HR, 0.80; 95 percent CI, 0.69–0.91; p=0.0011) vs nonuse.

“This is one of the first real-world studies exploring the clinical use of oral antivirals during the pandemic wave dominated by the Omicron variant [ie, Omicron BA.2.2]. These data extend the evidence from clinical trials in patients infected with the Delta variant and at risk of severe COVID-19 from being overweight,” the researchers concluded.