Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency.
BACKGROUND
High prevalence of severe atazanavir-associated hyperbilirubinemia in Asians with low prevalence of the UDP-glucuronosyltransferase (UGT)1A1*28 polymorphism suggests the importance of genetic factors other than UGT1A1*28 for atazanavir-associated hyperbilirubinemia in these populations.


METHODS
Serum bilirubin levels were measured in 129 Korean human immunodeficiency virus-infected patients 3 months after initiation of atazanavir (400 mg per day) with good adherence to medication. The multidrug resistance gene 1 (MDR1) C3435T and G2677T/A variations and UGT1A1*6 and *28 were examined by direct sequencing of DNA from peripheral whole blood samples. The associations between genetic polymorphisms and severe (grade 3-4) hyperbilirubinemia were evaluated using multivariate logistic regression analysis including demographic and clinical variables.


RESULTS
The median patient age was 39 years (interquartile range, 34-51 years), and 91% were men. At baseline, the median CD4 cell count was 261 cells/microL (interquartile range, 181-405 cells/microL). Severe hyperbilirubinemia was detected in 27 patients (21%). The independent risk factors for severe hyperbilirubinemia were low baseline CD4 cell count (adjusted odds ratio per 10 cells/microL increase, 0.97; 95% confidence interval, 0.94-0.99), UGT1A1*28 (adjusted odds ratio, 4.15; 95% confidence interval, 1.46-11.84), and MDR1 G2677T/A (adjusted odds ratio, 9.65; 95% confidence interval, 1.09-85.61). Of 19 patients with wild-type alleles for both MDR1 2677 and UGT1A1*28, none developed severe hyperbilirubinemia.


CONCLUSIONS
The MDR1 G2677T/A variation and UGT1A1*28 are independent risk factors for severe atazanavir-associated hyperbilirubinemia in Korean human immunodeficiency virus-infected patients.
Park
Wan Beom
WB
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Choe
Pyoeng Gyun
PG
Song
Kyoung-Ho
KH
Jeon
Jae Hyun
JH
Park
Sang Won
SW
Kim
Hong Bin
HB
Kim
Nam Joong
NJ
Oh
Myoung-Don
MD
Choe
Kang Won
KW
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR; D014453:Glucuronosyltransferase / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D006932:Hyperbilirubinemia / Q000235:genetics*; D007723:Korea; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009842:Oligopeptides / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000009:adverse effects*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D000099148:UGT1A1 Enzyme
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D001663:Bilirubin; D014453:Glucuronosyltransferase; D009842:Oligopeptides; D011725:Pyridines; D000099148:UGT1A1 Enzyme; C513055:ABCB1 protein, human