An identification of the novel combination therapy for hepatitis C virus 1b infection by using a replicon system and human induced pluripotent stem cells
Authors: Hisashi Moriguchi, Raymond T. Chung, Chifumi Sato
Journal: Hepatology (2009)

Emanuele summarized the issues about the antiviral effects and safeties of statins for hepatitis C virus (HCV).1 Therefore, according to our replicon system,2 we evaluated the risk-benefit for the combinations of pitavastatin plus acyclic retinoid (AR) or pitavastatin, AR, and interferon alfa for HCV-1b infection in vitro. As a result, the HCV replication was significantly and dose-dependently suppressed by both combination therapies. Dose-effect analyses showed that the inhibitory concentration for 90% (IC90) value of pitavastatin plus AR was 0.45 μM and 10 μM, respectively. Furthermore, the IC90 value of pitavastatin, AR, and interferon alfa was 0.25 μM, 10 μM, and 1.0 IU/mL, respectively. These data demonstrated 90% inhibition of HCV RNA replication. Moreover, the combination of pitavastatin, AR, and interferon alfa was overwhelmingly more effective, compared with the previous results for the combination treatment of interferon alfa with ribavirin3 or the combination treatment of interferon alfa plus fluvastatin.4 In particular, we could decrease the doses of interferon alfa and statin in order to get an IC90 value by the combination of pitavastatin, AR, and interferon alfa, that is comparable with the results of the combination treatment of interferon alfa plus fluvastatin.4 For example, in the former combination, pitavastatin and interferon alfa was 0.25 μM and 1.0 IU/mL, respectively. On the other hand, in the latter combination, interferon alfa and fluvastatin was 4.0 IU/mL and 6.7 μmol/L, respectively.4 This would be meaningful in order to avoid the adverse effects of drugs. Next, we also generated human hepatocyte-like cells from human induced pluripotent stem cells (iPSCs),5 and we tried to investigate the hepatotoxicities for the combination of pitavastatin (0.25 μM), AR (10 μM), and interferon alfa (1.0 IU/mL) by using the normal human hepatocyte-like cells.5 As a result, we found the activities of glutamic oxaloacetic transaminase and lactate dehydrogenase (LDH) in the culture medium of the normal human hepatocyte-like cells were not significantly different between the combination of pitavastatin (0.25 μM), AR (10 μM), and interferon alfa (1.0 IU/mL) and the combination of interferon alfa (4.0 IU/mL) plus ribavirin (25 μM). Therefore, considering the abovementioned observations, the antiviral effects and safeties for the combination therapy of pitavastatin (0.25 μM), AR (10 μM), and interferon alfa (1.0 IU/mL) could be confirmed. However, by using the patient-specific hepatocyte-like cells differentiated from human iPSCs of patients with hepatitis C virus 1b (HCV-1b) infection, the efficacies and toxicities of the abovementioned combination therapy for the individual patients with HCV-1b infection should be more precisely evaluated in the near future. In conclusion, we found a novel combination therapy for HCV-1b infection by using our replicon system2 and human iPSCs. We are grateful to members of our laboratories for technical support. Furthermore, we are also grateful to Ms. Satoko Iioka for helpful discussions. Hisashi Moriguchi* , Raymond T. Chung , Chifumi Sato , * Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan, Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, Department of Analytical Health Science, Graduate School of Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan.