Acute Hepatic Cytolysis Associated with Atazanavir: A Case Report

No liver-related adverse events  have been attributed to atazanavir so far. The following excerpts from a case report published in AIDS (July 23, 2004) represent the first observation of acute hepatic cytolysis * associated with atazanavir.

A 56-year-old woman was admitted to the infectious diseases clinic at the Hôpital Saint-Antoine in Paris, France on 27 February 2003 with a 5-day history of subclinical jaundice and fatigue. She had been diagnosed HIV positive in 1998 and had been on highly active antiretroviral therapy didanosine (ddI; Videx), efavirenz (Sustiva) and abacavir (Ziagen) since September 1999, with a switch to stavudine (Zerit), didanosine and nelfinavir (Viracept) in July 2000 because of genotypic resistance to efavirenz and abacavir.

In March 2001, she developed moderate lipodystrophy. In July 2001, nelfinavir was replaced by the lopinavir-ritonavir combination (with stavudine and didanosine) because of recurrent diarrhea.

The diarrhea improved gradually, but lipodystrophy worsened and dyslipidemia occurred (total cholesterol 8.18 mmol/l, HDL-cholesterol 0.76 mmol/l, LDL-cholesterol 6.63 mmol/l, triglycerides 3.18 mmol/l). Because of the increased cardiovascular risk associated with this type IIb dyslipidemia, lopinavir-ritonavir was replaced by atazanavir on 11 July 2002, in combination with tenofovir (introduced in April 2002 to replace stavudine) and didanosine.

At the time of treatment switch, transaminase activity was normal [aspartate aminotransferase (AST) 24 IU/ml and alanine aminotransferase (ALT) 25 IU/ml], and was similar to values recorded in December 2001 (AST 19 IU/l, ALT 27 IU/l).

The lipid status improved markedly and the dyslipidemia disappeared (total cholesterol 6.07 mmol/l, LDL-cholesterol 4.34 mmol/l, HDL-cholesterol 1.24 mmol/l, triglycerides 1.34 mmol/l).

In contrast, transaminase activity gradually increased after the introduction of atazanavir, with a marked increase between weeks 8 and 30 (up to 10 times the normal value: AST 236 IU/ml, ALT 405 IU/ml.

In the light of these clinical, biochemical and histological findings, and the chronology of events, the responsibility of atazanavir in the onset of hepatic cytolysis was classified as 'probable.’

Antiretroviral treatment was discontinued on 28 July 2003 (AST 236 IU/ml, ALT 405 IU/ml). Transaminase activity almost normalized after 8 weeks (AST 51 IU/ml, ALT 48 IU/ml). The patient was subsequently prescribed a combination of didanosine, tenofovir (Viread) and nelfinavir, and liver enzyme activity remained normal.

Several cases of acute cytolytic hepatitis have been reported in patients receiving protease inhibitors. Two mechanisms have been described: mitochondrial toxicity, and liver inflammation as a result of the reactivation of viral hepatitis B or C after immune reconstitution. The rare cases of elevated transaminase activity reported in patients taking atazanavir were all associated with hepatitis B or hepatitis C virus co-infection. No viral co-infection was found in this patient.

Three elements point to the probable responsibility of atazanavir in the onset of hepatic cytolysis in this patient:

·         The concomitance of atazanavir administration and the onset of cytolysis;

·         The greater than 50% fall in transaminase activity within 30 days after atazanavir withdrawal; and

·         The fact that didanosine and tenofovir had been prescribed, respectively, 4 years and 3 months before the introduction of atazanavir and had been well tolerated. 

In addition, re-challenge with these two nucleoside inhibitors, in combination with nelfinavir, did not lead to an increased hepatic transaminase activity. Thorough etiological investigations ruled out other causes of acute hepatic cytolysis. In this patient, pre-existing hepatic steatosis may have increased the risk of drug-induced hepatitis.

The authors conclude, “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 (non-alcoholic steatohepatitis, chronic hepatitis B or C, large alcohol intake).”

* hepatic cytolysis = destruction of liver cells.

Service de Maladies Infectieuses, Service d'Hépatologie, and Service d'Anatomie Pathologique, Hôpital Saint-Antoine, Paris, France.

09/08/04

Reference
S P Eholié and others. Acute hepatic cytolysis in an HIV-infected patient taking atazanavir. AIDS 18(11): 1610-1611. July 23, 2004.