HIV and Bilirubin Elevation
HIV infection itself does not directly increase bilirubin levels, but antiretroviral medications used to treat HIV—particularly protease inhibitors like atazanavir and indinavir—commonly cause unconjugated hyperbilirubinemia through inhibition of bilirubin metabolism. 1, 2, 3
Mechanism of Antiretroviral-Induced Hyperbilirubinemia
The elevation in bilirubin associated with HIV treatment occurs through specific drug mechanisms rather than the virus itself:
- Atazanavir and indinavir inhibit UDP-glucuronosyltransferase (UGT1A1), the enzyme responsible for bilirubin conjugation, leading to accumulation of unconjugated (indirect) bilirubin 4, 5
- These protease inhibitors also inhibit bilirubin transporters OATP1B1 and OATP1B3, further contributing to hyperbilirubinemia 1, 2
- This manifests as isolated unconjugated hyperbilirubinemia without ALT elevations, distinguishing it from hepatocellular injury 1
Clinical Significance and Frequency
The hyperbilirubinemia from protease inhibitors is common but generally benign:
- Atazanavir causes Grade 3-4 total bilirubin elevation (≥2.6× ULN) in 35-47% of treatment-naive patients, compared to <1-3% with other regimens 3
- Jaundice/scleral icterus occurs in 5-9% of patients on atazanavir-containing regimens 3
- This is not associated with hepatocellular damage and does not represent true liver toxicity 2
Genetic Predisposition
Individuals with Gilbert syndrome are at substantially higher risk:
- Patients homozygous for the UGT1A1*28 polymorphism (Gilbert syndrome, ~10% of population) experience significantly greater bilirubin elevations when taking indinavir or atazanavir 4, 5
- 67% of UGT1A1*28 homozygotes receiving atazanavir or indinavir had ≥2 episodes of jaundice-range hyperbilirubinemia (>43 μmol/L or >2.5 mg/dL), versus only 7% of those with the common allele not receiving these drugs 5
Drug-Specific Effects
Different antiretrovirals have varying impacts on bilirubin:
- Atazanavir increases bilirubin by an average of 15 μmol/L (0.87 mg/dL) 5
- Indinavir increases bilirubin by an average of 8 μmol/L (0.46 mg/dL) 5
- Ritonavir, lopinavir, saquinavir, and nelfinavir have minimal or no effect on bilirubin levels 5
- Ritonavir-boosting of indinavir can cause severe symptomatic hyperbilirubinemia through metabolic inhibition leading to higher indinavir concentrations 6
Coinfection Considerations
Hepatitis C coinfection creates additional complexity:
- HIV/HCV coinfected patients on atazanavir who initiate pegylated interferon and ribavirin therapy experience marked increases in hyperbilirubinemia, with Grade 3-4 hyperbilirubinemia rising from 9% to 45% 7
- Ribavirin causes hemolysis, which contributes to indirect hyperbilirubinemia and compounds the effect of atazanavir 8, 7
- HCV coinfection is associated with a 2-10-fold increased risk of elevated transaminases during HAART, though this represents hepatocellular injury rather than isolated hyperbilirubinemia 9
Monitoring Recommendations
For patients on protease inhibitors known to affect bilirubin:
- Monitor liver function tests (including total bilirubin) at baseline and at Weeks 2,4, and 8 when initiating therapy 10
- Determine whether hyperbilirubinemia is predominantly unconjugated or conjugated to distinguish protease inhibitor effect from hepatocellular injury 8
- HIV/HCV coinfected patients should have monthly liver function tests during HAART 9
Clinical Management
The benign nature of protease inhibitor-induced hyperbilirubinemia guides management:
- Isolated unconjugated hyperbilirubinemia without transaminase elevation does not require discontinuation of atazanavir or indinavir 2, 4
- HAART should not be routinely withheld from HIV/HCV coinfected patients despite increased risk of liver enzyme abnormalities 10
- Symptomatic jaundice may warrant switching to an alternative protease inhibitor that does not inhibit UGT1A1, such as lopinavir or darunavir 6, 5