Report of rare atazanavir-related liver side-effect published

Treatment with the protease inhibitor atazanavir caused hepatic cytolysis (death of liver cells) in an HIV-positive woman with no risk factors for hepatic side-effects, according to a case report in the July 23^rd edition of AIDS. Although atazanavir treatment has been associated with the development of hyperbilirubinemia (elevated levels of bilirubin) in up to a third of recipients, liver toxicity has not been reported in substantial numbers of patients and this is the first case report of hepatic cytolysis linked to the drug.

In early 2003 a 56-year-old HIV-positive woman presented to doctors in Paris with a five day history of jaundice and fatigue. She was diagnosed with HIV in 1998 and had taken numerous HAART regimens. In April 2002 she started a regimen including ddI and tenofovir and Kaletra. In July 2002 she swapped Kaletra for atazanavir because of worsening blood lipids.

Switching to atazanavir achieved a rapid improvement in the woman’s blood lipid levels. At the time when treatment with atazanavir was commenced, the women had normal AST and ALT liver function values.

However, after 30 weeks of treatment with atazanavir the woman’s liver function had deteriorated significantly, with both ALT and AST levels up to ten times the normal value (AST 236 IU/ml, ALT 405 IU/ml).

There were no signs of chronic liver disease or liver failure, and tests for hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus and cytomegalovirus all proved negative. The woman denied taking any potentially toxic drugs, including alcohol, and had taken no medication other than her antiretrovirals.

A liver biopsy showed acute hepatitis without any evidence of fibrosis, although the investigators believe that she may have had preexisting hepatic steatosis (a fatty liver). The woman stopped all antiretroviral therapy and her liver function normalised within eight weeks.

Clinical and laboratory findings and the woman’s treatment history suggested to the investigators that atazanavir was the “probable” cause of the onset of hepatic cytolysis.

There have been several cases of hepatic cytolysis in patients treated with other protease inhibitors. The cause has been attributed to either mitochondrial toxicity or the reactivation of hepatitis B or hepatitis C virus after immune reconstitution. The rare cases of elevated liver enzymes reported in patients taking atazanavir have all involved individuals coinfected with hepatitis. The investigators emphasise that their patient did not have viral hepatitis coinfection.

The investigators believe that three elements point to atazanavir as the cause of hepatic cytolysis in their patient:

• Cytolysis coincided with the commencement of atazanavir therapy.
• The greater than 50% fall in liver enzyme values within 30 days of stopping atazanavir therapy.
• The other two drugs in the woman’s regimen, ddI and tenofovir, had been prescribed to her for a substantial period of time before atazanavir therapy was started and were well tolerated.

The woman subsequently restarted both ddI and tenofovir with nelfinavir and this regimen did not lead to a recurrence of hepatic cytolysis.

“This case suggests that atazanavir can provoke severe acute cytolytic hepatitis during therapeutic use. Liver function should be closely monitored in atazanavir-treated patients with hepatic risk factors,” the investigators conclude.