Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia.
BACKGROUND
Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice.


METHODS
We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years.


RESULTS
The estimated average bilirubin level was 8.8 micromol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 mu mol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 micromol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 micromol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had > or =2 episodes of hyperbilirubinemia in the jaundice range (>43 micromol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1.


CONCLUSIONS
Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.
Rotger
Margalida
M
Institute of Microbiology and Service of Infectious Diseases, University of Lausanne, Lausanne, Switzerland.
Taffe
Patrick
P
Bleiber
Gabriela
G
Gunthard
Huldrych F
HF
Furrer
Hansjakob
H
Vernazza
Pietro
P
Drechsler
Henning
H
Bernasconi
Enos
E
Rickenbach
Martin
M
Telenti
Amalio
A
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D005878:Gilbert Disease / Q000150:complications*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000150:complications; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme