Retransplantation for Acute Liver Failure Due to Combined Antiviral Agents in an HIV-HCV Coinfected Liver Transplant Recipient

Abstract

We report the case of a human immunodeficiency virus (HIV)-hepatitis C virus (HCV) coinfected patient retransplanted 22 weeks after a first orthotopic liver transplantation (OLT) because of drug-induced acute liver failure. A cytomegalovirus (CMV)-negative patient with severe hemophilia A was diagnosed with HIV-HCV (genotype 1b) coinfection that was thought to be acquired before 1985. Since 1996, he had been receiving didanosine, stavudine, and saquinavir. In February 1998, interferon-α2b (IFN-α2b) was introduced for chronic HCV, associated with a 2-month course of ribavirin stopped because of severe thrombocytopenia, and stavudine was discontinued and switched to efavirenz. At the end of 2000, the patient presented severe HCV-related cirrhosis (Child-Pugh score C11) and refractory ascites. Plasma HIV-RNA was undetectable. On January 2001 (D0), this 34-year-old patient underwent a cadaveric OLT with a CMV negative donor and antiretroviral therapy was stopped. Immunosuppressive treatment was based on tacrolimus (targeted trough blood concentrations 12-17 ng/ml) and prednisone (20 mg/day, tapered to 5 mg/day at 3 months). Acute rejection (D13) was treated by a transient increase of the tacrolimus dose. Stavudine (40 mg bid), didanosine (400 mg daily) and efavirenz (200 mg tid) were reintroduced on D53 for sustained HIV replication (plasma viral load=251 000 copies/ml). On D82 a liver biopsy showed mild hepatitis C recurrence (METAVIR score A2F0) and insignificant steatosis. A second liver biopsy performed on D146 because of elevated transaminases (ALT=8N) and low prothrombin index (40%), was assessed as A2F1 and also showed marked steatosis. On D150, IFN-α2b (3MUI) and ribavirin (600 mg daily) were restarted. The following day, the patient developed 200-fold increase of AST and ALT over normal values, 6% prothrombin index (Fig. 1), blood lactate level to 8.6 mmol/L, encephalopathy and acute renal failure requiring hemodialysis. Nucleoside reverse transcriptase inhibitors (NRTIs) liver toxicity was suspected and any antiviral therapy was discontinued. Treatment with levocarnitine was ineffective and the patient was retransplanted seven days later (D158). The explanted graft showed major microvacuolar steatosis involving more than 40% hepatocytes, associated with massive centro- and mediolobular necrosis. In contrast inflammation was mild-to-moderate. After the second OLT, mild acute rejection was documented on D276 without HCV recurrence. Antiretroviral therapy without NRTIs using efavirenz and lopinavir-ritonavir was reintroduced later (D409) and tacrolimus was reduced to 0.5 mg once a week. At 4-year follow-up, the patient is perfectly well.FIGURE 1.: Evolution of alanine aminotransferase (ALT) and prothrombin index (PI) from the first liver transplantation over 4 years in our patient.Because HCV infection has a more rapid progression in HIV-coinfected patients, antiviral therapy with IFN-α plus ribavirin has been proposed. The toxicity of NRTIs, particularly didanosine and stavudine, is due to inhibition of DNA polymerase-γ, which causes mitochondrial dysfunction (1) and ribavirin increases didanosine toxicity (2). Although IFN-α-induced liver toxicity has been reported (3), marked microvacuolar steatosis associated with hyperlactatemia is consistent with NRTIs toxicity enhanced by ribavirin in our patient (4, 5). HIV-HCV coinfected patients receiving nucleoside analogues, ribavirin and IFN-α, may develop severe liver toxicity, whether or not they are transplanted, especially if didanosine is used. Even though liver transplantation is not common for such patients, it should be considered as the best therapeutic option in selected situations. Elisabeth Polard Christophe Camus Anne-Yvonne Abault Bruno Turlin Cédric Arvieux Michel Messner Hervé Allain Karim Boudjema Centre Régional de Pharmacovigilance, Service des Maladies Infectieuses et Réanimation Médicale, Hôpital Pontchaillou, Rennes, France