Safety of Paxlovid in Patients with Elevated Liver Enzymes
Paxlovid (nirmatrelvir/ritonavir) can be safely used in patients with mild to moderate liver enzyme elevations, but is not recommended for patients with severe hepatic impairment (Child-Pugh Class C). 1
Hepatic Safety Profile of Paxlovid
FDA Recommendations
The FDA label for Paxlovid clearly states that no dosage adjustment is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, Paxlovid is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) due to lack of pharmacokinetic and safety data in this population. 1
Clinical Evidence
Recent research indicates that Paxlovid has a relatively favorable hepatic safety profile:
A 2022 narrative review found that ritonavir-boosted nirmatrelvir is potentially hepatotoxic, but in phase 3 clinical trials, liver enzyme elevations were uncommon, with AST/ALT increases not exceeding 2.4% of patients. 2
A large self-controlled case-series study from 2023 involving 153,853 patients prescribed nirmatrelvir/ritonavir found that only 0.5% developed acute liver injury (ALI). Importantly, compared to the pre-exposure period, the risk of ALI was not increased during the five-day nirmatrelvir/ritonavir treatment period (IRR = 0.54,95% CI = 0.43-0.70). 3
When ALI did occur in Paxlovid users, it was mostly mild and less severe than ALI events in non-Paxlovid users. ALI cases with nirmatrelvir/ritonavir use had lower risk of all-cause death (29.1% vs. 39.1%) and no increase in risk of liver decompensation (1.0% vs. 1.3%) compared to non-users. 3
Management Approach for Patients with Elevated Liver Enzymes
Assessment of Baseline Liver Function
Classify the degree of liver enzyme elevation:
- Mild (<5× ULN)
- Moderate (5-10× ULN)
- Severe (>10× ULN) 4
Determine Child-Pugh classification if chronic liver disease is present
Decision Algorithm
Mild to moderate hepatic impairment (Child-Pugh A or B):
- Proceed with standard Paxlovid dosing
- Monitor liver enzymes during treatment
Severe hepatic impairment (Child-Pugh C):
- Do not use Paxlovid
- Consider alternative COVID-19 treatments such as remdesivir 5
Patients with elevated liver enzymes but without established cirrhosis:
- If elevation is <5× ULN: Proceed with standard Paxlovid dosing
- If elevation is 5-10× ULN: Use with caution and monitor closely
- If elevation is >10× ULN: Consider alternative treatments
Special Considerations and Precautions
Drug Interactions
Ritonavir is a potent CYP3A inhibitor and can increase plasma concentrations of drugs metabolized by this enzyme. This is particularly important for patients taking medications for liver disease that are CYP3A substrates. 6
Monitoring Recommendations
For patients with pre-existing liver enzyme elevations who are prescribed Paxlovid:
- Check baseline liver tests before initiating treatment
- Consider follow-up liver tests after completing the 5-day treatment course
- Monitor for symptoms of liver injury (jaundice, right upper quadrant pain, fatigue)
Contraindications
- Severe hepatic impairment (Child-Pugh Class C)
- Concomitant use of medications highly dependent on CYP3A for clearance where elevated concentrations are associated with serious reactions 7
Conclusion
Based on the available evidence, Paxlovid appears to be safe in patients with mild to moderate liver enzyme elevations. The 2023 self-controlled case-series study provides reassuring data that the risk of acute liver injury is not increased during Paxlovid treatment compared to pre-treatment periods. For patients with severe hepatic impairment, alternative COVID-19 treatments should be considered.