Atazanavir: genetic predictors for hyperbilirubinemia found

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Genetic factors that put people taking the protease inhibitor atazanavir (Reyataz)at risk of severe hyperbilirubinaemia have been identified by Spanish researchers.

Raised levels of bilirubin in the blood- hyperbilirubinaemia- is a common side effect of atazanavir treatment and it is directly linked with the plasma concentrations of the drug. The effect is reversible and usually causes no significant problems- although around eight per cent of people will develop severe symptoms such as jaundice which make them stop taking the drug.

The researchers looked at two genes in the DNA of 118 HIV-infected Caucasian people taking atazanavir 300mg daily boosted with ritonavir 100mg daily.

Glossary

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

bilirubin

A substance produced during the normal breakdown of red blood cells. Bilirubin passes through the liver and is excreted in faeces. Elevated levels of bilirubin (jaundice) may indicate liver damage or disease.

CAT scan

A computerised axial tomography (CAT) or computed tomography (CT) scan is a type of specialised X-ray that gives a view of a 'slice' through the body, and is used to help detect tumours, infections and other changes in anatomy.

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

enzyme

A protein which speeds up a chemical reaction.

The first was the MDR1 gene which encodes a protein involved in pumping foreign molecules such as protease inhibitors from cells. Some variants of the gene are known to increase the blood levels of some drugs.

The second gene, UGT1A1, encodes the enzyme uridine-glucuronosyl transferase (UGT) which is crucial in the excretion of bilirubin. But this enzyme is known to be inhibited by high levels of atazanavir, leading to a build up of bilirubin in the blood.

They found that people with a particular DNA sequence, or polymorphism, at position 3435 of the MDR1 gene had higher blood levels of atazanavir therefore putting them at greater risk of hyperbilirubinaemia.

Thirty-two per cent of people had two cytosine nucleotides at position 3435 (the CC genotype), while 47% had one cytosine and one thymine (CT) leaving 21% of people with the TT genotype.

CC patients had much higher plasma concentrations of atazanavir, an average minimum concentration of 939ng/ml compared to 376ng/ml for patients with the CT or TT genotype (p=0.001).

But they also discovered that a particular form of the UGT1A1 gene- termed UGT1A1-TA7 put patients at almost three times higher risk of developing severe hyperbilirubinaemia (odds ratio 2.96; 95% confidence interval 1.29 to 6.78, p=0.01).

Eighty per cent of people with two copies of the UGT1A1-TA7 gene had grade three or four hyperbilirubinaemia, compared to 29% of people with one copy of the TA7 gene and one of the TA6 gene and just 18% of those with two UGT1A1-TA6 genes.

The researchers claim that having both TA7 versions of the UGT1A1 gene so strongly predicts the development of severe hyperbilirubinaemia that it could be used to pre-screen people considering taking atazanavir. But they concede that its usefulness might be restricted to Caucasians as this was the only ethnic group studied here.

The conclude that these results need to be validated in larger, more ethnically diverse populations. This could clarify the complex interactions between the genetic factors which increase the levels of atazanavir and those which put patients at particular risk of hyperbilirubinaemia.

References

Rodríguez-Nóvoa S et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS 2007;21:41-46.