How does atazanavir cause hyperbilirubinemia?

Mechanism of Atazanavir-Induced Hyperbilirubinemia

Atazanavir causes hyperbilirubinemia primarily through inhibition of UDP-glucuronosyltransferase (UGT1A1), the enzyme responsible for bilirubin conjugation in the liver, resulting in elevated unconjugated bilirubin levels. 1

Primary Mechanism

• Atazanavir competitively inhibits UGT1A1, the enzyme that catalyzes the conjugation of bilirubin with glucuronic acid, leading to reduced bilirubin clearance and increased unconjugated (indirect) bilirubin levels in the blood 1, 2
• This hyperbilirubinemia is reversible upon discontinuation of atazanavir, confirming the direct relationship between the drug and the effect 1
• The FDA drug label specifically notes that "most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin" 1

Contributing Factors

• Genetic polymorphisms in the UGT1A1 gene significantly influence the severity of atazanavir-induced hyperbilirubinemia 3, 2
• The UGT1A1*28 variant, which is also responsible for Gilbert's syndrome, predisposes patients to more severe hyperbilirubinemia when taking atazanavir 2, 4
• Homozygosity for UGT1A1*28 increases bilirubin levels by approximately 5.2 μmol/L (0.3 mg/dL) at baseline, and this effect is amplified when combined with atazanavir 2
• Additional genetic variants in UGT1A3 and UGT1A7 may form a haplotype with UGT1A1*28, further increasing the risk of severe hyperbilirubinemia 4

Secondary Mechanisms

• Atazanavir may also inhibit bilirubin transporters OATP1B1 and OATP1B3, further contributing to hyperbilirubinemia 5
• Ritonavir, often co-administered with atazanavir as a pharmacokinetic enhancer, may potentiate hyperbilirubinemia by increasing atazanavir plasma concentrations 6, 7
• Studies have shown that switching from boosted to unboosted atazanavir can reduce bilirubin levels while maintaining therapeutic efficacy in patients with UGT1A1*28 polymorphisms 7

Clinical Implications

• Atazanavir-induced hyperbilirubinemia is considered an indirect hyperbilirubinemia and is not associated with hepatocellular damage 5, 1
• The FDA label notes that this is an expected effect and "not a toxicity" 5
• Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies 1
• Alternative antiretroviral therapy may be considered if jaundice or scleral icterus presents cosmetic concerns for patients 1

Risk Factors and Management

• Baseline factors that predict higher peak bilirubin levels include UGT1A1 rs887829 T allele, higher baseline hemoglobin, higher baseline bilirubin, and slower atazanavir clearance 3
• Zinc sulfate supplementation has been shown to decrease total and unconjugated bilirubin levels in patients on atazanavir, potentially through induction of UGT1A1 activity 6
• Genotyping for UGT1A1*28 before initiating atazanavir therapy can identify individuals at higher risk for developing jaundice 2, 7
• Efavirenz has been observed to decrease bilirubin levels, consistent with induction of UGT1A1 activity 2

Understanding the mechanism of atazanavir-induced hyperbilirubinemia is important for clinical management, as it helps differentiate this benign, expected effect from other causes of liver dysfunction that may require intervention.