How effective were oral antivirals during HK’s Omicron BA.2 wave?

A real-world study during Hong Kong’s Omicron BA.2 wave showed that both molnupiravir and nirmatrelvir/ritonavir effectively lowered the risks of disease progression and all-cause mortality in hospitalized COVID-19 patients not requiring oxygen supplementation on admission. However, mortality risk reduction was larger with nirmatrelvir/ritonavir vs molnupiravir.

“This is probably the world’s first study on real-world effectiveness of inpatient use of these novel antivirals,” said Professor Gabriel Leung of the LKS Faculty of Medicine, University of Hong Kong (HKU), who presented the findings at Advances in Medicine 2022. “Our results show that both antivirals work, but nirmatrelvir/ritonavir works even better.” [medRxiv 2022;doi:10.1101/2022.05.19.22275291]

The territory-wide retrospective cohort study included 40,776 patients with confirmed SARS-CoV-2 infection hospitalized between 26 February and 26 April 2022. After propensity score (PS) matching, the analysis included 2,116 molnupiravir users (with 8,396 matched controls) and 991 nirmatrelvir/ritonavir users (with 3,952 matched controls), who received the oral antivirals at a median of 2 days from symptom onset.

Over a mean follow-up of 41.3 days, use of the oral antivirals was associated with a significantly lower risk of the composite outcome of disease progression (ie, all-cause mortality, initiation of invasive mechanical ventilation [IMV], or intensive care unit admission) vs control (molnupiravir: hazard ratio [HR], 0.53; 95 percent confidence interval [CI], 0.46–0.62; p<0.001) (nirmatrelvir/ritonavir: HR, 0.33; 95 percent CI, 0.24–0.46; p<0.001). Results were similar for all-cause mortality (molnupiravir: HR, 0.55; 95 percent CI, 0.47–0.63; p<0.001) (nirmatrelvir/ritonavir: HR, 0.32; 95 percent CI, 0.23–0.45; p<0.001).

 Molnupiravir users had a significantly lower risk of IMV vs controls (HR, 0.31; 95 percent CI, 0.16–0.61; p<0.001). Time to achieving lower viral load (ie, cycle threshold [Ct] value ≥30) was significantly shorter for users of either antiviral (molnupiravir: HR, 1.21; 95 percent CI, 1.07–1.37; p=0.002) (nirmatrelvir/ritonavir: HR, 1.25; 95 percent CI, 1.04–1.50; p=0.015) vs controls.

Among survivors, hospital length of stay was significantly shorter for nirmatrelvir/ritonavir users vs controls (-0.70 days; p=0.039).

Head-to-head comparison of the two antivirals showed that molnupiravir users had a significantly higher risk of all-cause mortality (HR, 1.53; 95 percent CI, 1.01–2.31; p=0.047), a numerically higher risk of disease progression (HR, 1.44; 95 percent CI, 0.96–2.18; p=0.078), numerically slower viral load reduction to Ct ≥30 (HR, 0.88; 95 percent CI, 0.69–1.11; p=0.281), and significantly longer hospital length of stay (+0.83 days; p=0.032) vs nirmatrelvir/ritonavir users.

“For both antivirals, we found significant interaction of clinical benefit with age [for the composite disease progression outcome; p_interaction=0.003 for molnupiravir, p_interaction<0.001 for nirmatrelvir/ritonavir],” said Leung. “There is an amazing effect in patients aged >65 years [molnupiravir: HR, 0.50; 95 percent CI, 0.43–0.58; p<0.001] [nirmatrelvir/ritonavir: HR, 0.27; 95 percent CI, 0.19–0.38; p<0.001]. If you are ≤65 years of age, these antivirals probably don’t do anything for you [molnupiravir: HR, 1.24; 95 percent CI, 0.70–2.21; p=0.462] [nirmatrelvir/ritonavir: HR, 1.97; 95 percent CI, 0.86–4.53; p=0.111].”

In outpatients with COVID-19, an analysis in 4,875 molnupiravir users (with 48,409 PS-matched controls) and 5,366 nirmatrelvir/ritonavir users (with 53,289 PS-matched controls) showed that both antivirals were effective in reducing the risks of all-cause mortality (molnupiravir: HR, 0.61; 95 percent CI, 0.46–0.82; p<0.001) (nirmatrelvir/ritonavir: HR, 0.25; 95 percent CI, 0.13–0.47; p<0.001) and in-hospital disease progression (molnupiravir: HR, 0.64; 95 percent CI, 0.50–0.83; p<0.001) (nirmatrelvir/ritonavir: HR, 0.47; 95 percent CI, 0.31–0.71; p<0.001). However, the risk of hospitalization was significantly reduced with nirmatrelvir/ritonavir only (HR, 0.69; 95 percent CI, 0.60–0.79; p<0.001).

“Subgroup analysis showed consistent effects of nirmatrelvir/ritonavir across vaccination status and age. For molnupiravir, however, the effects were less consistent,” said Leung. “The benefits of these antivirals may be larger in patients who have not been fully vaccinated and in elderly patients.”