Eighth International Congress on Drug Therapy in HIV Infection Glasgow, UK - 12-16 November 2006

Int Cong Drug Therapy HIV 2006 Nov 12-16;8:Abstract No. PL5.3

Ulrike Moebius, T O Lankisch, M Wehmeier, G M Behrens, M P Manns, R E Schmidt, C P Strassburg
Charité Universitätsmedizin Berlin, Berlin, Germany; Hannover Medical School, Hannover, Germany

PURPOSE OF THE STUDY: Atazanavir (ATV) has been shown to cause severe jaundice in individual patients, particularly those with Gilbert’s disease (GD). GD is characterized by a TATA box polymorphism in the bilirubin-UGT gene (UGT1A1*28). Based on the hypothesis of genetically determined metabolic risk factors we performed a UGT1A gene haplotype analysis in ATV-treated HIV-positive patients including UGT1A1*28 and UGT1A3-66, UGT1A7 129/131 and UGT1A7-57 to test the involvement of these functional single nucleotide polymorphisms (SNP) in ATV toxicity.

METHODS: SNP-detection of UGT1A1*28, UGT1A3-66, UGT1A7 129/131 and UGT1A7-57 was performed by DNA sequencing and Taqman 5´-nuclease assays in 106 ATV-treated patients and 104 healthy blood donors. Statistical analyses were performed by using two-tailed fisher exact test and chi-square-test.

SUMMARY OF RESULTS: Homozygous allelic variants of UGT1A3 and UGT1A7 were significantly higher in the ATV group compared to healthy blood donors (p=0.0006 and p=0.02, respectively). 76% of all patients with allelic variants of UGT1A1, UGT1A3 and UGT1A7 showed grade 3 or 4 hyperbilirubinemia. In addition, all patients with grade 4 hyperbilirubinemia (n=6) simultaneously carried the homozygous allelic variants of UGT1A1, UGT1A3 and UGT1A7.

CONCLUSIONS: GD-associated jaundice in ATV-treated patients is a phenotype associated with a novel UGT1A gene haplotype encompassing four genetic variants with altered glucuronidation activity of the affected genes. In normal individuals these variants do not occur in linkage dysequilibrium. The detection of variants at the UGT1A gene locus is a potentially powerful pharmacogenetic tool contributing to prediction and identification of drug-associated toxicity and disease susceptibility.

Plenary Session: Oral Papers

2006-11-12
PL5.3

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