Is dolutegravir (Integrase inhibitor) hepatotoxic?

Dolutegravir and Hepatotoxicity

Dolutegravir has a low risk of hepatotoxicity compared to other antiretroviral drugs, but it can cause liver injury in rare cases, particularly in patients with underlying liver disease. While generally well-tolerated, monitoring for hepatotoxicity is recommended, especially in patients with hepatitis B or C coinfection.

Hepatotoxicity Profile of Dolutegravir

• Dolutegravir (an integrase strand transfer inhibitor) has been associated with hepatic adverse events, though these are relatively uncommon 1
• Cases of hepatic toxicity, including elevated liver enzymes, hepatitis, and acute liver failure have been reported in patients receiving dolutegravir-containing regimens, even without pre-existing liver disease 1
• Drug-induced liver injury leading to liver transplantation has been reported with dolutegravir-containing regimens such as TRIUMEQ (abacavir, dolutegravir, and lamivudine) 1, 2
• Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction including liver injury have been reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials 1

Risk Factors for Dolutegravir-Associated Hepatotoxicity

• Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with dolutegravir use 1
• In some cases, elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly when anti-hepatitis therapy was withdrawn 1
• Hepatitis-coinfected patients are at 2.7-fold increased hazard of developing liver enzyme elevations on integrase inhibitors compared to HIV-monoinfected patients 3
• Severe liver enzyme elevations typically occur within the first 6 months after starting integrase inhibitors like dolutegravir 3

Comparison with Other Antiretrovirals

• Dolutegravir has a better hepatic safety profile compared to nevirapine, which is strongly contraindicated in patients with liver function derangement 4
• Nevirapine has been associated with a 12.5% incidence of hepatotoxicity, with clinical hepatitis diagnosed in 1.1% of patients, and can progress to fulminant liver failure and death 4
• Unlike nevirapine, which causes early-onset hepatotoxicity often within the first 12 weeks, dolutegravir-associated liver injury can occur at any time during treatment 4, 5
• Integrase inhibitors like dolutegravir are generally considered safer from a hepatotoxicity perspective compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) 6, 4

Monitoring and Management Recommendations

• The FDA recommends monitoring for hepatotoxicity in patients receiving dolutegravir 1
• Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated if signs of hypersensitivity develop 1
• No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh Score 7-9) 7
• Although the unbound fraction of dolutegravir is increased in patients with moderate hepatic impairment, this is not considered clinically significant 7
• Discontinue dolutegravir immediately if signs or symptoms of hypersensitivity reactions develop, including hepatitis 1

Pharmacological Considerations

• Dolutegravir is primarily metabolized by UGT1A1 and to a lesser extent by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems 8
• It has a very low potential for drug interactions and can be administered in routine doses with most drugs 8
• Dose adjustment is not required in patients with mild or moderate liver failure 8
• Dolutegravir can cause isolated creatinine elevations through inhibition of renal tubular secretion, but this is not a toxicity 6

Conclusion

While dolutegravir can cause hepatotoxicity in rare cases, it has a favorable hepatic safety profile compared to many other antiretroviral medications, particularly nevirapine. Close monitoring of liver function is still recommended, especially in patients with pre-existing liver disease or hepatitis coinfection.