Can Human Immunodeficiency Virus (HIV) treatment increase bilirubin levels?

Yes, HIV Treatment Can Increase Bilirubin Levels

Certain HIV antiretroviral medications, particularly protease inhibitors like atazanavir and indinavir, commonly cause elevations in unconjugated (indirect) bilirubin through inhibition of bilirubin metabolism. This is a well-established, class-specific effect that is generally benign but can lead to visible jaundice in some patients.

Mechanism of Bilirubin Elevation

HIV protease inhibitors increase bilirubin through direct inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1), the enzyme responsible for bilirubin conjugation 1, 2. This results in:

• Unconjugated (indirect) hyperbilirubinemia without associated liver toxicity 3, 4
• Competitive inhibition of UGT enzymatic activity, with indinavir showing a K(I) of 183 μM 2
• The effect is dose-dependent and related to therapeutic drug concentrations 1, 2

Specific Antiretroviral Agents That Increase Bilirubin

Atazanavir (Most Significant Effect)

• Increases bilirubin by approximately 15 μmol/L (0.87 mg/dL) on average 1
• Grade 3-4 total bilirubin elevations (≥2.6 × ULN) occur in 44% of patients receiving atazanavir with ritonavir 3
• Jaundice/scleral icterus reported in 5-9% of patients 3
• Unboosted atazanavir (400 mg) causes Grade 3-4 bilirubin elevations in 35-47% of patients 3

Indinavir (Moderate Effect)

• Increases bilirubin by approximately 8 μmol/L (0.46 mg/dL) 1
• Unconjugated hyperbilirubinemia develops in up to 25% of patients 2
• Bilirubin increases occur in approximately 14% of patients 4
• When combined with ritonavir, can cause severe symptomatic hyperbilirubinemia due to metabolic inhibition 5

Other Protease Inhibitors (Minimal to No Effect)

• Ritonavir, lopinavir, saquinavir, and nelfinavir have minimal or no effect on bilirubin levels 1
• Saquinavir inhibits UGT activity but has a higher K(I) (360 μM) and lower therapeutic levels, making clinical hyperbilirubinemia unlikely 2

Paritaprevir (Used in HCV/HIV Coinfection)

• Inhibits bilirubin transporters OATP1B1 and OATP1B3, causing transient increases in indirect bilirubin 6, 7
• Greater frequency of total bilirubin increases observed in patients with cirrhosis 6, 7

Genetic Predisposition: UGT1A1*28 Polymorphism

Patients with Gilbert syndrome (UGT1A1*28 polymorphism) are at substantially higher risk for clinically significant hyperbilirubinemia:

• Homozygous UGT1A1*28 increases baseline bilirubin by 5.2 μmol/L (0.3 mg/dL) 1
• 67% of individuals homozygous for UGT1A1*28 receiving atazanavir or indinavir had ≥2 episodes of hyperbilirubinemia in the jaundice range (>43 μmol/L or >2.5 mg/dL), versus only 7% of those with the common allele not receiving these drugs 1
• Mean bilirubin increase of 1.45 mg/dL in patients with UGT1A1*28 polymorphism versus 0.34 mg/dL in those without 2
• Genotyping for UGT1A1*28 before initiating therapy can identify patients at risk and decrease jaundice episodes 1, 8

Clinical Management Strategies

For Patients Developing Hyperbilirubinemia on Atazanavir/Ritonavir:

• Switching from boosted to unboosted atazanavir (400 mg) in UGT1A1*28 carriers reduces total bilirubin from 4.09 to 1.82 mg/dL without compromising virologic efficacy 8
• This switch also reduces triglycerides and total cholesterol 8
• Therapeutic drug monitoring confirms adequate atazanavir concentrations after unboosting 8

Protective Effect of Efavirenz:

• Efavirenz results in decreased bilirubin levels, consistent with induction of UGT1A1 1
• This contrasts with the bilirubin-elevating effects of protease inhibitors 1

Important Clinical Caveats

• Bilirubin elevations from HIV protease inhibitors are typically unconjugated and not associated with hepatotoxicity 3, 4, 2
• The hyperbilirubinemia is generally benign and does not necessitate drug discontinuation unless symptomatic jaundice develops 4, 5
• Distinguish protease inhibitor-induced hyperbilirubinemia from other causes: it manifests as isolated unconjugated hyperbilirubinemia without ALT elevations 7, 3
• When ribavirin is co-administered (in HCV/HIV coinfection), hemolysis contributes additional indirect hyperbilirubinemia 7
• Monitor liver function tests regularly when starting medications known to affect bilirubin 7