Why is dolutegravir (Integrase Inhibitor) hepatotoxic?

Dolutegravir and Hepatotoxicity: Mechanism and Clinical Significance

Dolutegravir has a relatively low risk of hepatotoxicity compared to other antiretroviral medications, but cases of liver injury have been reported and require monitoring, particularly in patients with pre-existing liver disease or hepatitis coinfection. 1

Hepatotoxicity Risk Profile

• Dolutegravir has a better hepatic safety profile compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs) like nevirapine, which is strongly contraindicated in patients with liver function derangement 2
• Hepatic adverse events have been reported in patients receiving dolutegravir-containing regimens, particularly in those with underlying hepatitis B or C 1
• Cases of hepatic toxicity, including elevated liver enzymes, hepatitis, and acute liver failure have occurred in patients without pre-existing hepatic disease 1
• Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine) 1, 3
• In the EuroSIDA cohort study, discontinuations due to hepatotoxicity with dolutegravir were very rare (0.18 per 1000 person-years of follow-up) 4

Mechanism of Hepatotoxicity

• Unlike nevirapine, which has a direct hepatotoxic effect with 12.5% incidence of hepatotoxicity 5, dolutegravir's mechanism of hepatotoxicity is less well understood
• Dolutegravir is primarily metabolized by UGT1A1 and to a lesser extent by CYP3A4, which may contribute to its lower hepatotoxicity profile compared to drugs heavily dependent on hepatic metabolism 6
• Some cases of dolutegravir-related hepatotoxicity may be associated with immune reconstitution syndrome, particularly in patients with hepatitis B or C coinfection 1
• Hypersensitivity reactions to dolutegravir can include liver injury as part of a broader systemic reaction 1

Risk Factors for Dolutegravir Hepatotoxicity

• Pre-existing hepatitis B or C infection increases the risk of transaminase elevations 1
• Patients with a history of liver disease may be at higher risk 1
• Concomitant use of other hepatotoxic medications may increase risk 6
• Immune reconstitution after starting antiretroviral therapy may trigger hepatic inflammation 1

Monitoring Recommendations

• Liver function tests should be performed before starting dolutegravir and monitored during treatment 1
• More frequent monitoring is recommended for patients with:
  • Pre-existing liver disease 1
  • Hepatitis B or C coinfection 1
  • Elevated baseline liver enzymes 1
• Clinical signs of hepatotoxicity include jaundice, fatigue, nausea, vomiting, abdominal pain, and dark urine 7

Management of Dolutegravir-Associated Hepatotoxicity

• For mild to moderate elevations in liver enzymes without symptoms, close monitoring may be sufficient 1
• For severe hepatotoxicity or symptomatic liver injury, discontinuation of dolutegravir should be considered 1
• In cases of hypersensitivity reactions with liver involvement, dolutegravir should be immediately discontinued 1
• After discontinuation due to hepatotoxicity, dolutegravir should not be reintroduced 1

Comparison with Other Antiretrovirals

• Nevirapine has the highest risk of hepatotoxicity among antiretrovirals, with 12.5% incidence and potential for fulminant liver failure 5, 8
• Protease inhibitors can cause liver enzyme abnormalities that may occur at any time during treatment 5
• Ritonavir and ritonavir/saquinavir combinations have higher rates of severe hepatotoxicity compared to other protease inhibitors 5
• Integrase strand transfer inhibitors (INSTIs) like dolutegravir generally have lower rates of hepatotoxicity compared to NNRTIs and PIs 2, 9

Special Considerations

• Dolutegravir can cause isolated creatinine elevations through inhibition of renal tubular secretion, but this is not considered a toxicity 2
• No dose adjustment is required for dolutegravir in patients with mild to moderate hepatic impairment 6
• Dolutegravir has fewer drug-drug interactions compared to other antiretrovirals, which may contribute to its better safety profile 6

While dolutegravir has a relatively favorable hepatic safety profile compared to older antiretrovirals, clinicians should remain vigilant for potential hepatotoxicity, particularly in high-risk patients, and implement appropriate monitoring strategies to detect and manage liver injury early.