Which antiretroviral drug is contraindicated in patients with liver function derangement?

Antiretroviral Drugs Contraindicated in Liver Function Derangement

Nevirapine is the antiretroviral drug most strongly contraindicated in patients with liver function derangement due to its high risk of severe hepatotoxicity, which can progress to fulminant liver failure and death. 1

Nevirapine-Associated Hepatotoxicity

• Nevirapine has been associated with a 12.5% incidence of hepatotoxicity, with clinical hepatitis diagnosed in 1.1% of patients 1
• In comparative studies, 9.4% of nevirapine-treated patients experienced grade 4 liver enzyme elevation compared with none of the efavirenz-treated patients 1
• Fatal cases of hepatic necrosis have been reported with nevirapine use 1
• Female patients have twice the risk of hepatotoxicity compared to males (12% versus 6%) 1
• Approximately two-thirds of nevirapine-associated clinical hepatitis cases occur within the first 12 weeks of treatment 1

Clinical Presentation of Nevirapine Hepatotoxicity

• May present as part of a hypersensitivity syndrome with skin rash, fever, and eosinophilia 1
• Patients may experience nonspecific gastrointestinal and flu-like symptoms with or without liver enzyme abnormalities 1
• Can progress rapidly to hepatomegaly, jaundice, and hepatic failure within days 1
• Liver biopsy typically shows heavy mixed inflammatory cell infiltrate with eosinophils 2

Risk Factors for Antiretroviral-Associated Hepatotoxicity

• Baseline elevated liver enzymes (>2.5× upper limit of normal) increase risk (RR = 4.3) 3
• Co-infection with hepatitis B (RR = 2.3) or hepatitis C (RR = 5.2) significantly increases risk 3
• For nevirapine specifically, men with CD4 counts ≥400 cells/mm³ have increased risk of hepatotoxicity 3
• Alcohol abuse is an independent risk factor for developing liver toxicity 4

Other Antiretrovirals and Hepatotoxicity

• Protease inhibitors (PIs) can also cause liver enzyme abnormalities, but these typically occur later in the treatment course 1
• Ritonavir and ritonavir/saquinavir-containing regimens cause more severe hepatotoxicity than indinavir, nelfinavir, or saquinavir 1
• Efavirenz is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) 5
• Efavirenz-associated hepatotoxicity is less common than with nevirapine (4% vs 12%) but can still occur 4

Monitoring and Management Recommendations

• Patients who experience severe clinical hepatotoxicity while receiving nevirapine should not receive nevirapine therapy in the future 1
• Close monitoring of liver enzymes and clinical symptoms is advised after nevirapine initiation (every 2 weeks for the first month, then monthly for first 12 weeks) 1
• For patients with underlying liver disease, consider antiretrovirals that don't require dose adjustment in hepatic impairment, such as tenofovir, lamivudine, and raltegravir 1
• Integrase strand transfer inhibitors (InSTIs) should be used with caution in severe hepatic impairment (Child-Pugh C), but no dose adjustment is required for mild to moderate impairment 1

Alternative Antiretroviral Options for Patients with Liver Disease

• Tenofovir, lamivudine, raltegravir, and rilpivirine do not require dose adjustment in patients with severe hepatic impairment 1
• When selecting an antiretroviral regimen for patients with liver disease, drugs that are metabolized independently of the CYP450 pathway (e.g., raltegravir, dolutegravir, or bictegravir-based regimens) are recommended to minimize drug-drug interactions 1

In summary, nevirapine should be avoided in patients with liver function derangement due to its high risk of severe and potentially fatal hepatotoxicity. Alternative antiretroviral options with better hepatic safety profiles should be considered for these patients.