Severe hepatotoxicity associated with the combination of enfuvirtide and tipranavir/ritonavir: case report

Abstract

Tipranavir (TPV), a new non-peptidic protease inhibitor (PI) was approved in summer 2005 after demonstration of its efficacy in patients with multiple-PI resistant virus [1]. In particular TPV worked much better in reducing HIV viral load in highly treatment experienced patients when combined with the fusion inhibitor enfuvirtide (T-20) [2]. Recently it was shown that the co-administration of TPV/ritonavir (RTV) with T-20 potentially affected volume of distribution and elimination half-life of TPV and RTV resulting in higher nadir levels of TPV and RTV [3]. This, together with the results of the RESIST 1 and 2 trials in which 10% of participants taking TPV developed new grade 3 or 4 alanine aminotrasferase (ALT) or aspartate aminotransferase (AST) elevations (compared to 3% taking a comparison boosted PI) suggests that potential hepatotoxic effects could result because of the higher TPV levels under co-administration with T-20 [4]. Case report We here report a 52-year-old white male (Centers for Disease Control and Prevention stage C3) with a 20-year history of multidrug-resistant HIV. In February 2005 he was started on an antiretroviral regimen with TPV and RTV (500/200 mg twice daily), continuing the existing regimen of zidovudine/lamivudine (300/150 mg twice daily) and T-20 (90 mg twice daily), which was started 12 months before without hepatic disorders. Initial laboratory values were CD4 count 312 cells/μl, viral load 86 × 106 copies/ml, with normal liver function tests (LFT). The patient was known to have chronic hepatitis B virus (HBV) infection with no evidence of delta virus infection. Two weeks after the initiation of the TPV containing regimen, the patient developed elevated liver enzymes with AST, ALT and gamma-glutamyltransferases (G-GT) up to 261, 538 and 238 U/l respectively. Abdominal ultrasonography showed normal bile ducts; HBV DNA viral load was low with 20 000 copies/ml, autoimmune markers for hepatitis and cirrhosis were negative, excessive alcohol consumption was denied. Percutaneous liver biopsy showed a mild, non-active hepatitis with moderate lymphocyte infiltration in the portal areas and no intrahepatic steatosis. Following the patient's wish to interrupt the T-20 treatment because of severe local skin reactions, and under the assumption of a hepatotoxic effect of the antiretroviral regimen T-20 was discontinued for 6 weeks. Shortly after, liver function improved with a 50% decrease in LFT values. Due to a weight loss of 10 kg and an elevation of the viral load treatment with T-20 was recommenced and 2 weeks later after an increase of the G-GT TPV/RTV was discontinued. The liver function tests returned to normal within 4 weeks. The patient's CD4 cell count is currently stable but the viral load has increased to 17 000 copies/ml. No further deterioration in the liver function tests has been observed. Discussion Hepatotoxicity as a result of TPV containing therapy is well documented, although the mechanism for this toxicity remains unknown. In contrast to TPV, a strong inducer of CYP3A4, and RTV, a strong inhibitor of CYP3A4, T-20 does not affect the P450 cytochrome system. Our patient developed grade 4 levels of LFT under the co-administration of TPV/RTV and T-20 and recovered clearly after T-20 was discontinued. It is hypothesized that the hepatotoxicity was induced by TPV/TPV aggravated by the usage of T-20 causing higher TPV/RTV serum levels. Unfortunately no drug level tests were performed in our patient. Further studies are needed concerning the metabolic pathways and interactions of this potentially fatal drug combination. Physicians who treat patients with HIV need to be aware of the potential additive effect regarding hepatotoxicity when administering TPV/RTV and T-20. Close monitoring of TPV serum levels and dosage adaption could help to avoid hepatotoxicity. Furthermore, a reduction or even discontinuation of RTV should be considered when TPV is combined with T-20 due to its potential boosting effect.