Atazanavir-treated patients have increased risk of hyperbilirubinaemia after starting therapy for hepatitis C

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Treatment for hepatitis C increases the risk of hyperbilirubinaemia for HIV-positive patients taking atazanavir (Reyataz), investigators report in the November 30th edition of AIDS. The proportion of atazanavir-treated patients with hyperbilirubinaemia increased from 9% to 45% after hepatitis C therapy consisting of pegylated interferon and ribavirin was started.

Atazanavir is a protease inhibitor with a number of attractive features. It can be taken once daily and does not cause the lipid increases associated with many other protease inhibitors. The main side-effect of atazanavir is hyperbilirubinaemia, a build-up of bilirubin, a waste product produced by the liver during the breakdown of old red blood cells. It is not dangerous but can cause jaundice that persists unless treatment with atazanavir is discontinued.

A significant proportion of HIV-positive individuals are also infected with hepatitis C. Current treatment for hepatitis C consists of pegylated interferon with ribavirin. Interactions between ribavirin and anti-HIV drugs from the NRTI class have been reported, but there are no known interactions between ribavirin and atazanavir.

Glossary

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.

jaundice

A yellowing of the skin and whites of the eyes associated with liver or gall bladder problems.

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.

pegylated interferon

Pegylated interferon, also known as peginterferon, is a chemically modified form of the standard interferon, sometimes used to treat hepatitis B and C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the blood much longer. 

serum

Clear, non-cellular portion of the blood, containing antibodies and other proteins and chemicals.

 

However, both drugs can increase bilirubin levels and this could mean that patients treated with atazanavir could have an increased risk of developing hyperbilirubinaemia and jaundice after starting hepatitis C treatment.

Investigators therefore designed a study to monitor changes in bilirubin in 72 HIV- and hepatitis C-co-infected patients who were taking antiretroviral therapy. Half of these patients were taking atazanavir and the investigators compared changes in serum bilirubin in the atazanavir-treated patients and those taking taking other antiretroviral drugs after the initiation of treatment for hepatitis C. Tests were also conducted to see if the gene *28 effected bilirubin levels.

At baseline, median bilirubin level was 1.25 mg/dl. There was a significant increase in both arms of the study four weeks after starting treatment with ribravirin (p = 0.014). This increase was significantly more marked in the atazanavir-treated patients than in the patients taking other antiretroviral drugs (0.80 vs. 0.15 mg/dl, p = 0.003). The researchers calculated that bilirubin increases following the initiation of hepatitis C treatment including ribavirin were 1.9 fold higher in the patients taking atazanavir compared to individuals taking HIV treatment based on an alternative drug.

Furthermore, the investigators found that 45% of patients taking atazanavir experienced an increase in their bilirubin of more than 1 mg/dl compared to only 3% of individuals taking another drug (p = 0.001).

The proportion of atazanavir-treated patients with moderate-to-severe hyperbilirubinaemia increased from 9% at baseline to 45% after the initiation of ribavirin therapy (p = 0.021). None of the patients in the control arm developed hyperbilirubinaemia.

Equal proportions of the patients in the two study arms had the *28 gene. However, there was no evidence that this gene increased the risk of developing increased bilirubin.

In statistical analysis, the only factors that were significantly associated with increases in bilirubin following initiation of hepatitis C therapy including ribavirin were current treatment with atazanavir and (p = 0.005) and falls in haemoglobin (per 1 g/dl, p = 0.008).

“The present study shows that a large number of HIV-infected patients on stable atazanavir therapy may experience an increase in total serum bilirubin levels following the initiation of hepatitis C therapy”, write the investigators.

They conclude, “the normal clearance of bilirubin might be compromised due to inhibitory competition of atazanavir, causing jaundice in HIV patients following initiation of hepatitis C therapy.”

References

Rodriguez-Novoa, S. et al. Increase in serum bilirubin in HIV/hepatitis C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin. AIDS 22: 2535-37, 2008.