Gilbert's syndrome and hyperbilirubinemia in protease inhibitor therapy--an extended haplotype of genetic variants increases risk in indinavir treatment.
OBJECTIVE
Gilbert's syndrome is a frequent genetic conjugation abnormality associated with adverse drug effects. Genetic UDP glucuronosyltransferase (UGT)1A gene variants can influence gene transcription, inducibility and glucuronidation activity. Protease inhibitors used in human immunodeficiency virus (HIV) infection and chronic viral hepatitis can inhibit UGTs. Indinavir (IDV) can lead to hyperbilirubinemia in Gilbert's syndrome (UGT1A1*28), which does not explain interindividual severity differences and may thus involve additional UGT1A variants.


METHODS
One hundred and twenty-five HIV patients receiving IDV and 427 healthy blood donors were genotyped for the presence of UGT1A1*28, UGT1A3 -66T/C, UGT1A7 -57T/G, UGT1A7(N129K/R131K) using Taqman 5' nuclease assays.


RESULTS
Hyperbilirubinemia was observed in 42%. UGT1A1*28 frequencies did not differ between HIV patients and controls but were significantly higher in hyperbilirubinemic patients. The frequency of homozygous carriers of the 4 UGT1A marker haplotype increased with hyperbilirubinemia affecting all patients with bilirubin levels >85 micromol/l.


CONCLUSIONS
In IDV treatment the risk of severe hyperbilirubinemia is associated with genetic variants of the UGT1A3 and UGT1A7 genes in addition to Gilbert's syndrome (UGT1A1*28). This haplotype is a useful predictor of protease inhibitor-induced side effects.
Lankisch
Tim O
TO
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany.
Behrens
Georg
G
Ehmer
Ursula
U
Möbius
Ulrike
U
Rockstroh
Juergen
J
Wehmeier
Michael
M
Kalthoff
Sandra
S
Freiberg
Nicole
N
Manns
Michael P
MP
Schmidt
Reinhold E
RE
Strassburg
Christian P
CP
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D005878:Gilbert Disease / Q000188:drug therapy* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000453:epidemiology*; D019469:Indinavir / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011480:Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D019469:Indinavir; D011480:Protease Inhibitors; D000099148:UGT1A1 Enzyme; C122075:UDP-glucuronosyltransferase, UGT1A3; C524630:UGT1A7 protein, human