Efficacy of interferon-based antiviral therapy on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: Further evidence in decompensation cirrhosis
Authors: Fanpu Ji, Shu Zhang, Hong Deng, Zongfang Li
Journal: Journal of Hepatology (2013)

Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: A prospective, multicenter studyJournal of HepatologyVol. 58Issue 3PreviewThe effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV. Full-Text PDF We read with great interest the paper by Eiichi Ogawa and colleagues [[1]Ogawa E. Furusyo N. Kajiwara E. Takahashi K. Nomura H. Maruyama T. et al.Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective, multicenter study.J Hepatol. 2013; 58: 495-501Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar], accepted for publication in the Journal of Hepatology. The authors performed a large-scale, multicenter, prospective study and presented important data regarding the observation that sustained virological response (SVR) and transient virological response (TVR: defined as relapse or breakthrough) were associated with a lower risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C, with or without cirrhosis, when compared with non-virological response (NVR). However, cirrhotic patients with advanced disease, namely decompensated cirrhosis, have been excluded from their study. No study to date has provided evidence that virus suppression and elimination after interferon (IFN)-based antiviral therapy reduce the risk of HCC in this difficult-to-treat population. We performed a prospective pilot trial to investigate the safety and efficacy of pegylated/standard IFN-α combined with ribavirin for decompensated cirrhosis patients with HCV infection. From January 2008 to January 2011, 50 consecutive, IFN-naïve HCV decompensated cirrhotic patients were treated with PegIFN-α-2b at 1.0–1.5 μg/kg/week or standard IFN-α-2b, 3MU, thrice weekly, plus ribavirin at 800–1000 mg/day for 48 weeks, with a low accelerating dosage regimen. The diagnosis of decompensated liver cirrhosis was made when a patient had experienced one or more of the following clinical symptoms: ascites, variceal bleeding, spontaneous bacterial peritonitis (SBP), and encephalopathy, which referred to Iacobellis’ and our previous studies [2Iacobellis A. Siciliano M. Perri F. Annicchiarico B.E. Leandro G. Caruso N. et al.Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study.J Hepatol. 2007; 46: 206-212Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 3Ji F.P. Li Z.X. Cai Z.F. Tian C.Y. Xue H.A. Pan G.Y. et al.Short-term efficacy and safety of standard interferon with a low accelerating dosage regimen in HCV-related decompensated cirrhosis.Zhonghua Gan Zang Bing Za Zhi. 2010; 18: 946-948PubMed Google Scholar]. Patients with HCC, chronic renal failure, unstable cardiovascular disease, severe chronic obstructive lung disease, co-infection with immunodeficiency or hepatitis B viruses, current alcohol abuse, platelets <35,000/μl, neutrophils <1000/μl, haemoglobin <100 g/L, or Child-Pugh class C were excluded [2Iacobellis A. Siciliano M. Perri F. Annicchiarico B.E. Leandro G. Caruso N. et al.Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study.J Hepatol. 2007; 46: 206-212Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 3Ji F.P. Li Z.X. Cai Z.F. Tian C.Y. Xue H.A. Pan G.Y. et al.Short-term efficacy and safety of standard interferon with a low accelerating dosage regimen in HCV-related decompensated cirrhosis.Zhonghua Gan Zang Bing Za Zhi. 2010; 18: 946-948PubMed Google Scholar]. Patients were routinely monitored for SVR, TVR, and NVR according to the accepted guidelines and Ogawa’s study [1Ogawa E. Furusyo N. Kajiwara E. Takahashi K. Nomura H. Maruyama T. et al.Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective, multicenter study.J Hepatol. 2013; 58: 495-501Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 4European Association for the Study of the Liver EASL clinical practice guidelines: management of hepatitis C virus infection.J Hepatol. 2011; 55: 245-264Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar]. The primary end point of our study was the assessment of HCC development after treatment; the length of the follow-up period was calculated from the end of the antiviral therapy to the diagnosis of HCC or the last follow-up visit. The secondary end point was to investigate further events of decompensation after treatment. The baseline characteristics and clinical prognosis of the 50 studied patients as classified by treatment outcome, are shown in Table 1. There was no HCC development during antiviral treatment. Of all patients, 9 (18%) required premature treatment withdrawal because of adverse effects and/or poor virological response. Of the studied patients, 21 achieved SVR (42.0%), 15 were TVR (30.0%), and 14 (28.0%) were NVR. Median follow-up off-therapy was 29 (range 8–45) months, seven (14%) patients developed HCC, including 2/21 with SVRs (9.5%), 1/15 with TVRs (6.7%) and 4 of 14 with NVRs (28.6%), respectively. During the follow-up period, 4/21 patients with SVRs (19.0%), 5/15 (33.3%) with TVRs and 13 out of 14 without virological response (92.9%) experienced further events of decompensation (p <0.001).Table 1Pretreatment characteristics and clinical prognosis of 50 patients with decompensated cirrhosis classified by the treatment outcome.Data are expressed as number (%) or mean and interquartile range.∗Statistical analysis was performed using the Chi-square, Fisher’s exact test or one-way ANOVA following confirmation of normal distribution of data; the comparison is among the three groups.SVR, sustained virological response; TVR, transient virological response; NVR, non-virological response; PTA, prothrombin time activity; HCV, hepatitis C virus. Open table in a new tab Data are expressed as number (%) or mean and interquartile range. ∗Statistical analysis was performed using the Chi-square, Fisher’s exact test or one-way ANOVA following confirmation of normal distribution of data; the comparison is among the three groups. SVR, sustained virological response; TVR, transient virological response; NVR, non-virological response; PTA, prothrombin time activity; HCV, hepatitis C virus. In patients with HCV compensated cirrhosis, a significant reduction in the annual incidence of HCC has been reported after SVR [5Shiratori Y. Ito Y. Yokosuka O. Imazeki F. Nakata R. Tanaka N. et al.Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival.Ann Intern Med. 2005; 142: 105-114Crossref PubMed Scopus (249) Google Scholar, 6Morgan T.R. Ghany M.G. Kim H.Y. Snow K.K. Shiffman M.L. De Santo J.L. et al.Outcome of sustained virological responders with histologically advanced chronic hepatitis C.Hepatology. 2010; 52: 833-844Crossref PubMed Scopus (401) Google Scholar]; and Ogawa and colleagues found that compensation cirrhotic patients with TVR also have a lower incidence rate of HCC compared with patients with NVR. For decompensation cirrhotic patients in our study, although a low number of patients developed HCC and the observation period was short, the Kaplan–Meier curves for the end point of HCC showed a noticeable separation of both patients with SVR and TVR from those with NVR, at approximately 16 months of post-treatment follow-up (overall: p = 0.048, SVR vs. TVR: p = 0.887, SVR vs. NVR: p = 0.045, and TVR vs. NVR: p = 0.089 by Log-rank test) (Supplementary Fig. 1). It is inconsistent with the results of the study showing that HCC developed at comparable rates in decompensation cirrhotic patients with and without SVR during a 5-year follow-up, upon completion of the combination therapy [[7]Iacobellis A. Perri F. Valvano M.R. Caruso N. Niro G.A. Andriulli A. Long-term outcome after antiviral therapy of patients with hepatitis C virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2011; 9: 249-253Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. One possible explanation for the discrepant results may be that the efficacy of TVR on the risk of HCC was included in no SVR group, in their study [[7]Iacobellis A. Perri F. Valvano M.R. Caruso N. Niro G.A. Andriulli A. Long-term outcome after antiviral therapy of patients with hepatitis C virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2011; 9: 249-253Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. An intriguing finding from our study is that 72% (36/50) of decompensation cirrhotic patients, compared with 68% (102/150) of compensation cirrhotic patients in Ogawa and colleagues’ study, had an undetectable HCV RNA at the end of treatment. Asians have a significantly higher probability of viral response to IFN-based antiviral therapy has been attributed to genetic variants in the interleukin (IL)-28B gene [8Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar, 9Huang C.F. Huang J.F. Yang J.F. Hsieh M.Y. Lin Z.Y. Chen S.C. et al.Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients responding to 24 weeks peginterferon/ribavirin.J Hepatol. 2012; 56: 34-40Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 10Yu M.L. Huang C.F. Huang J.F. Chang N.C. Yang J.F. Lin Z.Y. et al.Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients.Hepatology. 2011; 53: 7-13Crossref PubMed Scopus (171) Google Scholar]. None of our patients underwent IL28B genotyping analysis; whether IL28B genotyping contributed to the high viral response in our study needs further clarification. However, the fact is that more cirrhotic patients may benefit from antiviral treatment in East Asia. In summary, our data indicate that complete viral suppression during antiviral treatment may play an important role in preventing the development of HCC in patients with HCV decompensated cirrhosis, and add further evidence for virus suppression and elimination after IFN-based antiviral therapy reduce the risk of HCC in patients with chronic hepatitis C by Ogawa et al. However, results from large and well-designed long-term studies are awaited. Since cirrhosis is an independent risk factor for HCC and the considerable risk of developing HCC remains even after HCV eradication, a vigilant monitoring of HCC development in patients with HCV-related compensated and decompensated cirrhosis should be mandatory, irrespective of SVR. This work was supported by a grant from Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: 1171) and Health Research Foundation of Shaanxi Province (No. 2010H31). The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.