Molnupiravir and nirmatrelvir/ritonavir show favourable hepatic safety in COVID-19 patients in HK

A territory-wide cohort study in Hong Kong shows favourable hepatic safety profile with the oral antivirals, molnupiravir and nirmatrelvir/ritonavir, in COVID-19 patients, including those at risk of drug-induced liver injury (DILI).

Among COVID-19 patients, molnupiravir and nirmatrelvir/ritonavir users are not at higher risk of elevated liver enzymes or DILI compared with oral antiviral nonusers. Furthermore, a similarly low incidence of significant DILI was found between oral antiviral users and nonusers. [Gastroenterology 2022;doi:10.1053/j.gastro.2022.09.008]

Molnupiravir and nirmatrelvir/ritonavir are novel oral antivirals for mild-to-moderate COVID-19 in adult patients at high risk of progressing to severe COVID-19. In preregistration clinical trials, these COVID-19 antivirals demonstrated no clinically apparent liver injury events. [https://bit.ly/3UDHEoV; https://bit.ly/3xTLJfc] “However, the risk of liver injury associated with COVID-19 antivirals is unclear in the real world,” the researchers stated.

To evaluate the hepatic safety profile of molnupiravir and nirmatrelvir/ritonavir, the researchers collected data from 183,041 COVID-19 patients who accessed public clinical services in Hong Kong between 1 January and 31 March 2022. Most patients had normal liver biochemistry patterns at baseline. The oral antivirals were initiated at a median of 0 days after COVID-19 diagnosis, and >95 percent of patients received treatment for 5 days. The primary endpoint was elevation of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST).

During this Omicron-dominant period, 20,797 patients underwent serial liver biochemistry tests. Of these patients, 19,103 were oral antiviral nonusers, 1,391 were molnupiravir users, and 303 were nirmatrelvir/ritonavir users. Up to 30-day follow-up, ALT was elevated in 23.6 percent of molnupiravir users, 27.4 percent of nirmatrelvir/ritonavir users, and 23.8 percent of oral antiviral nonusers. The corresponding rates of peak ALT ≥2x upper limit of normal (ULN) were 8.4 percent, 8.3 percent and 7.7 percent respectively, and rates of peak ALT ≥5x ULN were 2.2 percent, 2.6 percent and 1.8 percent, respectively.

Peak total bilirubin >1x ULN was more frequent with molnupiravir use than nonuse of oral antivirals (12.9 percent vs 9.7 percent; p=0.003). However, elevated peak total bilirubin occurred at similar rates between nirmatrelvir/ritonavir users and oral antiviral nonusers (9.2 percent vs 9.7 percent; p=0.97).

DILI occurred in 9.17 percent of molnupiravir users, 7.60 percent of nirmatrelvir/ritonavir users and 5.14 percent of oral antiviral nonusers, most of whom experienced category 1 events (8.8 percent, 7.6 percent and 4.9 percent, respectively). No category 4 DILI, liver-related deaths and liver transplantation were reported.

In univariate analysis, molnupiravir or nirmatrelvir/ritonavir use was associated with a lower risk of ALT and/or AST ≥2x ULN. After adjusting for significant confounding factors in multivariable analysis, molnupiravir use (adjusted odds ratio [aOR], 0.36; 95 percent confidence interval [CI], 0.28–0.47; p<0.001) and nirmatrelvir/ritonavir use (aOR, 0.16; 95 percent CI, 0.08–0.34; p<0.001) were found to be independent factors protective of liver injury.

“This territory-wide, real-world study confirms the favourable hepatic safety profile of molnupiravir and nirmatrelvir/ritonavir,” the researchers concluded. “We are able to reassure healthcare practitioners and patients of the minimal risk of DILI with these COVID-19 antivirals [in this population]. At-risk COVID-19 patients should use these antivirals to reduce adverse clinical outcomes.”