Genetic test can help predict who will develop hyperbilirubinaemia

Some individuals have a genetic predisposition to develop hyperbilirubinaemia, a potential side-effect of treatment with the protease inhibitors atazanavir (Reyataz) and indinavir (Crixivan), according to a study to be published in the October 15^th edition of the Journal of Infectious Diseases. The study investigators, from the Swiss HIV Cohort, calculated that screening for the gene could reduce the incidence of hyperbilirubinaemia in patients taking antiretroviral therapy by up to 75%.

Gilbert syndrome occurs in between 3% - 10% of the population and is recognised as the most common cause of hyperbilirubinaemia. The influence of the genetic polymorphism UGT1A1*28 on the development of Gilbert syndrome and the development of hyperbilirubinaemia has been extensively investigated.

Treatment with protease inhibitors can also cause hyperbilirubinaemia and earlier research suggested that the underlying reason, as in patients with Gilbert syndrome, is induction of the UGT1A1 enzyme.

Hyperbilirubinaemia causes yellowing of the skin and the eyes and although it is not a dangerous side-effect of antiretroviral therapy, it can be stigmatising.

Swiss investigators designed a longitudinal study involving 96 individuals who were followed for a median of six years. The aims of the study were to quantify the degree of elevation in bilirubin levels associated with individual protease inhibitors; to assess the interaction between the presence of UGT1A1*28 and antiretroviral therapy; and, to identify individuals at risk of developing jaundice after starting treatment with a protease inhibitor.

A total of 1386 bilirubin level measurements were obtained during the study. The investigators estimated that the average bilirubin level was 0.51mg/dl and that antiretroviral therapy containing atazanavir increased this level by an estimated 0.89mg/dl (p

Two bilirubin measurements above the threshold for jaundice (2.5mg/dl) were recorded in 27 (28%) patients. However, the investigators observed that six of the nine (67%) patients who had the UGT1A1*28 polymorphism, and received treatment with atazanavir or indinavir, had bilirubin within the jaundice range, compared to only 7% (four of 54 patients) with the polymorphism who did not receive treatment with either of these protease inhibitors.

The investigators then modelled the theoretical impact that testing for UGT1A1*28 before the initiation of antiretroviral therapy would have on the incidence of jaundice. They calculated that universal provision of antiretroviral treatment including either atazanavir or indinavir would involve a 22% incidence of hyperbilirubinaemia, however HIV therapy guided by genetic testing could reduce this incidence to 6%.

“The most relevant finding of this study is the identification of a gene-antiretroviral therapy-association that could lead to severe hyperbilirubinaemia”, comment the investigators. They conclude that their findings have the potential for clinical use in the future.