Drug-induced Liver Injury With Ritonavir-Boosted Nirmatrelvir: Evidence From Coronavirus Disease 2019 Emergency Use Authorization Adverse Event Reporting System

Dear Editors:

Little is known about the risks of drug-induced liver injury potentially associated with the use of molnupiravir or ritonavir-boosted nirmatrelvir in a real-world setting until the recently reported work by Wong et al.¹ In their study, they analyzed retrospectively the data from 13,041 molnupiravir users and 4408 ritonavir-boosted nirmatrelvir users vs 165,592 molnupiravir and nirmatrelvir nonusers in Hong Kong, China between January 1, 2022 and March 31, 2022 and concluded subsequently that both molnupiravir and ritonavir-boosted nirmatrelvir were not associated with a significantly higher risk of drug-induced liver injury as compared with nonusers. Of note, only data from the first quarter of 2022 were collected, and the sample size of ritonavir-boosted nirmatrelvir users was much smaller than that of molnupiravir users in their study. Moreover, as acknowledged,¹ their study shared limitations similar to other retrospective studies. Further studies using real-world data are warranted, particularly for ritonavir-boosted nirmatrelvir.

We therefore explored whether there is a safety signal of drug-induced liver injury associated with ritonavir-boosted nirmatrelvir using data from the US Food and Drug Administration Adverse Event Reporting System for coronavirus disease 2019 (COVID-19) Emergency Use Authorization (EUA) products.² This reporting system updates weekly adverse event reports submitted to the US Food and Drug Administration for medications used under the EUA for severe acute respiratory syndrome coronavirus 2 infection. A total of 25,551 adverse event reports of ritonavir-boosted nirmatrelvir was submitted to the COVID-19 EUA Adverse Event Reporting System between January 1, 2022 and January 13, 2023. Among these adverse event reports, only 0.023% (6/25,551) of ritonavir-boosted nirmatrelvir users were documented to have drug-induced liver injury, which is much lower than that reported by Wong et al.¹ The median age of the 6 patients identified was 66.0 years (interquartile range, 46.5–68.8), and 4 cases involved female patients. All 6 cases with drug-induced liver injury relating to ritonavir-boosted nirmatrelvir were recorded to have serious outcomes, but none was documented to have died, which is in agreement with the observations of Wong et al.¹

To assess quantitatively putative associations of ritonavir-boosted nirmatrelvir with drug-induced liver injury using these pharmacovigilance data, a case–noncase (disproportionality) analysis were performed through the Bayesian neural network method,³ which was considered to be a significant pharmacovigilance signal if the lower limit of the 95% credible interval of the information component (IC₀₂₅), the most robust risk measure in disproportionality analyses,⁴ was greater than 0. Based on the disproportionality analysis, no significant pharmacovigilance signal of drug-induced liver injury was observed for ritonavir-boosted nirmatrelvir (IC₀₂₅ = –0.80) (Supplementary Figure 1) as compared with other drugs used under the EUA for COVID-19, suggesting a lack of any association of ritonavir-boosted nirmatrelvir with drug-induced liver injury. Sensitivity analyses by restricting the data to those reported by healthcare professionals only showed very similar results with an IC₀₂₅ of –0.88 (Supplementary Figure 1), ensuring no potential associations between ritonavir-boosted nirmatrelvir and drug-induced liver injury existed.

To the best of our knowledge, this is the first disproportionality analysis of drug-induced liver injury with ritonavir-boosted nirmatrelvir using large-scale and timely pharmacovigilance data, showing consistent observations with those by Wong et al.¹ Together with a previous randomized control trial⁵ and the retrospective cohort study by Wong et al,¹ our disproportionality analysis using real-world pharmacovigilance data strongly support the lack of a meaningful safety signal of drug-induced liver injury with ritonavir-boosted nirmatrelvir, recommending the use of ritonavir-boosted nirmatrelvir in clinical practice without fear of adverse events in terms of drug-induced liver injury.