Drug‐induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir
Authors: Yohei Fujii, Yoshihito Uchida, Satoshi Mochida
Journal: Hepatology (2014)

Observations in Hepatotoxicity aims to highlight cases of drug or dietary supplement–induced liver injury that are illustrative of new presentations of injury or novel insights into the mechanisms thereof. The case described by Drs. Mochida, Fujii, and Uchida illustrates injury resulting from daclatasvir and asunaprevir. The combination of asunaprevir, a second-generation hepatitis C virus (HCV) NS3/4A protease inhibitor, and daclatasvir, an NS5A inhibitor, was approved in July 2014 in Japan as oral therapy for chronic hepatitis C due to HCV genotype 1. A phase-III clinical trial showed a sustained virological response rate of 85% after 24 weeks of therapy.1 One patient enrolled in this trial developed fever, eosinophilia and liver injury suggestive of immunoallergic hepatitis. A 57-year-old man with chronic hepatitis C (genotype 1b) was started on a planned 24-week course of daclatasvir (60 mg once daily) and asunaprevir (100 mg twice daily). He was a nonresponder to a previous course of peginterferon and ribavirin. He had no history of allergic conditions or drug allergies. Before starting therapy, serum alanine aminotransferase was 94 U/L (ALT: normal <40), alkaline phosphatase 208 U/L (Alk P: normal 96-284), bilirubin 1.1 mg/dL, total white count 3,620/mm3 (eosinophils 109/mm3), C-reactive protein <0.1 mg/dL (CRP: normal <0.25), and HCV RNA 12.6 million IU/mL. When seen on day 15, the patient reported fever, but denied rash, dark urine, or jaundice. ALT levels were normal and serum HCV-RNA levels had decreased to 50 IU/mL while the eosinophil count had increased to 467 mm3 and serum CRP to 1.7 mg/dL (Fig. 1). Asunaprevir and daclatasvir were continued. The fever fluctuated (peak 38.4°C) and when seen on day 29 he had fever but no rash, facial edema, or lymphadenopathy. Liver tests had worsened, with ALT 609 U/L, Alk P 320 U/L, and bilirubin 3.3 mg/dL accompanied by a further increase in eosinophils to 2,876 mm3 and CRP to 4.4 mg/dL. White blood cell differential counts showed a lymphocytosis. Serum ANA was negative and IgG and IgM levels were normal, while IgA (631 mg/dL) and IgE (670 IU/dL) were elevated. Abdominal ultrasonography revealed splenomegaly, which was not present before the therapy. There was no evidence of biliary obstruction. Both daclatasvir and asunaprevir were stopped on day 29. Fever resolved within 5 days but serum enzymes and eosinophilia persisted. A liver biopsy performed on day 36 revealed a focal lobular necrosis accompanied by inflammatory infiltrates of eosinophils, lymphocytes, and plasma cells in the hepatic lobules and portal areas. There was also interface hepatitis and bridging fibrosis (Fig. 2). Molecular analysis showed Epstein-Barr virus (EBV), human herpesvirus (HHV)−6, HHV-7, and HHV-8 DNA in the serum. Prednisolone (30 mg daily) was started on the following day, which was followed by prompt resolution of eosinophilia and improvement in serum ALT and CRP levels. Prednisolone was continued for 24 days with dose reduction by 5 or 10 mg every 5 or 7 days. Thereafter, liver tests and eosinophil counts remained normal but HCV RNA was again detected in serum 4 weeks later. Direct sequencing and cycling-probe analysis revealed Y93H mutation in the NS5A region of circulating HCV RNA in a pretreatment sample and de novo appearance of D168E mutations in the NS3 and L31M mutations in the NS5A regions after relapse. Clinical course of a patient with immunoallergic liver injury during therapy with daclatasvir and asunaprevir. Light-microscopic features of the liver in a patient with immunoallergic hepatitis due to antiviral therapy with daclatasvir and asunaprevir. In an open-label trial of oral antiviral therapy conducted in Japan, ALT elevations occurred in 16% and were above 5 times the upper limit of normal in 7% of patients treated with the combination of asunaprevir and daclatasvir. In two patients, serum enzyme elevations were accompanied by fever and eosinophilia.1 In all patients except the present case, the liver enzyme elevations resolved promptly upon discontinuation of the therapy and patients achieved a sustained virological response. The present case suffered a hypersensitivity reaction accompanied by liver injury and jaundice that persisted for a week after stopping the antiviral agents and led to use of corticosteroids. The overall clinical syndrome was typical of drug fever or drug-hypersensitivity syndrome2 rather than the typical syndrome of drug rash with eosinophilia and systemic signs (DRESS). Stopping therapy was followed by a resolution of fever, but continued evidence of liver injury, which is typical of hypersensitivity reactions. Whether asunaprevir or daclatasvir was responsible for the hypersensitivity reaction could not be formally assessed. While rechallenge with one or the other agent might clarify the issue, this was considered inadvisable because of the possibility of inducing further drug-resistant mutations. Interestingly, this syndrome as well as ALT elevations and fever appear to be more frequent in Japanese1 than U.S. or European studies of these agents,3, 4 suggesting a genetic basis for the reaction. We thank Professor Hajime Takikwa (Teikyo University) for useful suggestions regarding the patient. We also express appreciation to Dr. Takaya Ichimura (Department of Pathology, Saitama Medical University) for contributions to pathological readings.