Severe hepatotoxicity associated with asunaprevir and daclatasvir in chronic hepatitis C
Authors: Soichiro Shibata, Takeji Umemura, Michiharu Komatsu, Eiji Tanaka
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We read the article by Fujii et al.1 with great interest because we present a case of severe hepatic injury caused by asunaprevir, a second‐generation hepatitis C virus NS3/4A protease inhibitor, and daclatasvir, an NS5A inhibitor combination therapy. A 57‐year‐old Japanese woman with genotype 1b liver cirrhosis C was prescribed asunaprevir (100 mg twice daily) and daclatasvir (60 mg once daily) combination therapy. She had no history of drug or other allergies or hepatic encephalopathy. Prior to treatment, her white blood cell count was 4000/µL, eosinophils 5.8%, serum alanine aminotransferase 34 IU/L, alkaline phosphatase 528 IU/L, albumin 2.8 g/dL, bilirubin 1.6 mg/dL, prothrombin index 71%, and hepatitis C virus RNA 5.7 log IU/mL. Abdominal ultrasonography showed no ascites, and her Child‐Pugh classification was A (score 6). Eleven days later, the patient chose to discontinue therapy due to fever (39°C), malaise, nausea, and vomiting. She presented to a nearby hospital with dark urine and jaundice 3 days afterward. She was alert on admission and had a body temperature of 39.0°C. Her bilirubin level was 6.6 mg/dL, white blood cell count 10,100/µL, eosinophils 19.8%, alanine aminotransferase 114 IU/L, alkaline phosphatase 253 IU/L, prothrombin index 33%, and immunoglobulin E 892 IU/mL. Screening for viral hepatitis (hepatitis A, B, and E viruses; cytomegalovirus; and Epstein‐Barr virus) and autoimmune markers (antinuclear antibodies and antimitochondrial antibodies) was negative apart from influenza A virus positivity. Abdominal computed tomography demonstrated ascites with no evidence of biliary obstruction. She received laninamivir for her influenza infection, and her fever resolved in 6 days. As she had suffered from a rapid decline in liver function (maximum elevation of serum bilirubin 19.3 mg/dL, prothrombin index 30%), she was given intravenous fresh frozen plasma for 8 days and glycyrrhizin for 30 days. Her eosinophilia and liver function tests normalized 1 and 3 months later, respectively. Meanwhile, hepatitis C virus RNA became undetectable 2 weeks after stopping the combination therapy, and she had achieved a sustained virological response at 12 weeks. Lymphocyte stimulation test results, which are useful for diagnosing drug‐induced immunoallergic liver injury,2 were positive (normal <181%) for both asunaprevir (186%) and daclatasvir (264%). The exact mechanism of the hepatotoxicity in our patient is unknown. However, the presence of fever (possibly due to influenza viral infection), eosinophilia, and elevated immunoglobulin E strongly indicated an immunoallergic reaction as a contributing factor. Although we examined the patient weekly as indicated in treatment guidelines, she rapidly developed hepatic failure with ascites, jaundice, and a low prothrombin index. Fortunately, she recovered without the need for orthotopic liver transplantation. Accordingly, clinicians need to be aware of this possibility when prescribing combination therapy and to pay special attention to liver function during early follow‐up.