Treating hepatitis C in patients with cirrhosis: The effort is worth it
Authors: Xavier Forns, Jordi Bruix
Journal: Journal of Hepatology (2010)

Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosisJournal of HepatologyVol. 52Issue 5PreviewHepatocellular carcinoma (HCC) currently represents the major cause of liver-related death in patients with hepatitis C virus (HCV)-related cirrhosis. We assessed the influence of combination therapy on the risk of HCC, liver-related complications (ascites, variceal bleeding), and liver-related death (or liver transplantation). Full-Text PDF The efficacy of antiviral therapy for chronic hepatitis C (CHC) has improved significantly in the last decade. Currently, with the use of pegylated interferon and ribavirin, around 50% of treated patients will achieve a sustained virological response (SVR) [1Fried M.W. Shiffman M. Reddy K.R. Smith C. Marinos G. Gonçales F. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5854) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5866) Google Scholar]. However, there are certain groups of patients in whom treatment is still a challenge. One of these groups is constituted of individuals with advanced fibrosis or cirrhosis. Several reasons explain the difficulty in treating these patients. First, the efficacy of antiviral therapy in this group is significantly lower than in patients with mild disease. The presence of cirrhosis has not always been an independent factor for non-response in most randomized clinical trials, and the explanation for this is most likely due to the small proportion of individuals with bridging fibrosis or cirrhosis included in these studies. Recent data obtained from a large number of individuals included in three randomized international studies [[3]Bruno S. Shiffman M.L. Roberts S.K. Gane E.J. Messinger D. Hadziyannis S.J. et al.Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis.Hepatology. 2010; 51: 388-397Crossref PubMed Scopus (133) Google Scholar] show that SVR rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (p <0.01); the same figures for genotype 2/3 patients were 76%, 61%, and 57%, respectively (p <0.01). Data from the HALT-C study further support that SVR rates are significantly lower in patients with advanced fibrosis and particularly with cirrhosis [[4]Everson G.T. Hoefs J.C. Seeff L.B. Bonkovsky H.L. Naishadham D. Shiffman M.L. et al.Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial.Hepatology. 2006; 44: 1675-1684Crossref PubMed Scopus (143) Google Scholar]. Apart from a decreased efficacy, patients with advanced liver disease are older in comparison to individuals with mild chronic hepatitis and thus, tolerance to therapy is poor. Furthermore, some adverse events (such as neutropenia, anemia or thrombocytopenia) occur more frequently due to the presence of portal hypertension. Importantly, co-morbidities such as diabetes, hypertension or depression are more prevalent in these individuals. Some of these co-morbidities (such as the presence of diabetes) seem to directly influence the rates of viral clearance; other associated diseases decrease treatment adherence or represent relative contraindications that make antiviral therapy particularly difficult. All together, treating physicians are less motivated to indicate antiviral treatment in patients with CHC and advanced liver disease. In the last few years, a significant amount of information derived from retrospective studies supports the fact that HCV clearance after antiviral therapy is associated with improved outcomes in patients with established cirrhosis. Bruno and collaborators [[5]Bruno S. Stroffolini T. Colombo M. Bollani S. Benvegnu L. Mazzella G. et al.Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.Hepatology. 2007; 45: 579-587Crossref PubMed Scopus (551) Google Scholar] analyzed the effect of SVR in a cohort of 920 biopsy-proven cirrhotic patients treated with interferon-alfa and followed for a median of 96 months. Only 124 of them achieved SVR. Multivariate analysis showed that non-SVR was associated with a higher risk of liver-related complications, HCC and liver-related mortality. Similar results were obtained by Veldt and colleagues [[6]Veldt B.J. Heathcote E.J. Wedemeyer H. Reichen J. Hofmann W.P. Zeuzem S. et al.Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.Ann Intern Med. 2007; 147: 677-684Crossref PubMed Scopus (519) Google Scholar], who performed a similar analysis in a cohort of 479 patients with chronic hepatitis C and advanced fibrosis or cirrhosis (Ishak score 4–6) treated with interferon-based regimens and followed for a median period of 2.1 years. Of these patients, 142 (30%) achieved SVR, which again was associated with a significant reduction in the hazard of events. In this study, however, the improved outcome was mainly due to a decrease in the incidence of liver decompensation; the authors did not show a significant reduction in HCC in patients who achieved SVR (but most cases occurred in the non-responder group). Models where hepatitis C progression is accelerated, such as co-infection with the human immunodeficiency virus (HIV) and hepatitis C recurrence after liver transplantation, further support the above mentioned findings. In a recent cohort study carried out in 11 HIV units in Spain [[7]Berenguer J. varez-Pellicer J. Martin P.M. Lopez-Aldeguer J. Von-Wichmann M.A. Quereda C. et al.Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus.Hepatology. 2009; 50: 407-413Crossref PubMed Scopus (256) Google Scholar], 711 co-infected patients who started interferon plus ribavirin were followed-up for 2 years after antiviral therapy. The incidence of overall mortality, liver-related mortality, and liver decompensation were significantly lower in patients who achieved SVR compared to non-responders. In the transplant setting, recent data support a strong effect of hepatitis C virus (HCV) clearance on disease progression, as measured by improvement in the hepatic venous pressure gradient [[8]Carrion J.A. Navasa M. Garcia-Retortillo M. Garcia-Pagan J.C. Crespo G. Bruguera M. et al.Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study.Gastroenterology. 2007; 132: 1746-1756Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar] and clinical outcomes [[9]Berenguer M. Palau A. Aguilera V. Rayon J.M. Juan F.S. Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation.Am J Transplant. 2008; 8: 679-687Crossref PubMed Scopus (253) Google Scholar]. The study by Cardoso et al. [[10]Cardoso A. Moucari R. Figueiredo-Mendes C. Ripault M.P. Giuily N. Castelnau C. et al.Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosis.J Hepatol. 2010; 52: 652-657Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar] includes 307 patients with bridging fibrosis or cirrhosis, who were followed for a period of 3.5 years; SVR was achieved in 33% of patients. Sustained virological responders and non-responders were comparable at baseline regarding age, sex, body mass index, alcohol intake, and the presence of diabetes. As expected, non-responders were mostly infected with genotype 1, had a higher viral load, and poorer liver function. The incidence rates per 100-person-years of HCC and liver-related complications were 1.24 and 0.62 for sustained virological responders as compared to 5.85 and 4.16 for non-responders (p <0.01). Despite the fact that liver disease was more advanced at baseline in non-responders, SVR was still independently associated with better outcomes after adjusting for liver function. The results obtained in this study are very similar to those published by Bruno et al. and Veldt et al. There are, however, some weaknesses that are important to stress. As recently derived from the HALT-C study [[4]Everson G.T. Hoefs J.C. Seeff L.B. Bonkovsky H.L. Naishadham D. Shiffman M.L. et al.Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial.Hepatology. 2006; 44: 1675-1684Crossref PubMed Scopus (143) Google Scholar], lower albumin, lower platelet count, and higher total bilirubin are baseline factors independently associated with the development of clinical events in patients with advanced fibrosis or cirrhosis. These variables were significantly different between SVR and non-responders in the study by Cardoso. Though the differences in outcomes between responders and non-responders are remarkable, the retrospective design of this study (and others) weakens the conclusion that viral clearance is independently associated with improved outcomes. A second important point that deserves some discussion is the high incidence of HCC in this French cohort: it is significantly higher than the incidence observed in the studies by Bruno and Veldt [5Bruno S. Stroffolini T. Colombo M. Bollani S. Benvegnu L. Mazzella G. et al.Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.Hepatology. 2007; 45: 579-587Crossref PubMed Scopus (551) Google Scholar, 6Veldt B.J. Heathcote E.J. Wedemeyer H. Reichen J. Hofmann W.P. Zeuzem S. et al.Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.Ann Intern Med. 2007; 147: 677-684Crossref PubMed Scopus (519) Google Scholar]. One of the potential explanations suggested by the authors is the high prevalence of diabetes in their cohort (22%); diabetes has been associated with the development of HCC [[11]Veldt B.J. Chen W. Heathcote E.J. Wedemeyer H. Reichen J. Hofmann W.P. et al.Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.Hepatology. 2008; 47: 1856-1862Crossref PubMed Scopus (242) Google Scholar]. However, the prevalence of diabetes is not different from that reported in the HALT-C trial (24%) [[12]Di Bisceglie A.M. Shiffman M.L. Everson G.T. Lindsay K.L. Everhart J.E. Wright E.C. et al.Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.N Engl J Med. 2008; 359: 2429-2441Crossref PubMed Scopus (391) Google Scholar]. In the latter study (which included more than 1000 hepatitis C virus-positive patients with bridging fibrosis or cirrhosis) the cumulative 5-year HCC incidence was around 5.0%, clearly lower than the one reported by Cardoso (20%) [[13]Lok A.S. Seeff L.B. Morgan T.R. Di Bisceglie A.M. Sterling R.K. Curto T.M. et al.Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.Gastroenterology. 2009; 136: 138-148Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar]. Besides the potential limitations of the study, growing evidence supports a beneficial effect of HCV clearance in patients with advanced liver disease. The decrease in liver necroinflammatory changes and the regression (or stabilization) of liver fibrosis are probably key players in explaining the significant reduction in clinical decompensation after SVR. The latter is directly related to the effect of viral clearance in portal pressure [[8]Carrion J.A. Navasa M. Garcia-Retortillo M. Garcia-Pagan J.C. Crespo G. Bruguera M. et al.Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study.Gastroenterology. 2007; 132: 1746-1756Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. The decreased incidence of HCC in patients who clear HCV but are already cirrhotic, may be the result of several mechanisms and potentially, of some biases in the design of the study itself. As in any retrospective study, it is impossible to ensure that all patients were equally screened and evaluated for the development of HCC. In addition, some risk factors for HCC development may not have been taken into account as has recently been suggested with coffee consumption [[14]Bravi F. Bosetti C. Tavani A. Bagnardi V. Gallus S. Negri E. et al.Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.Hepatology. 2007; 46: 430-435Crossref PubMed Scopus (206) Google Scholar]. Finally, even if diagnosed with cirrhosis, it might well be that the evolutionary stage is not properly stratified. Prospective investigations have shown that the intensity of portal hypertension, as measured by hepatic vein catheterization, correlates with the HCC risk [[15]Ripoll C. Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N. Burroughs A. et al.Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.J Hepatol. 2009; 50: 923-928Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar], and the same correlation has been established with the less invasive measurement of liver stiffness [[16]Masuzaki R. Tateishi R. Yoshida H. Goto E. Sato T. Ohki T. et al.Comparison of liver biopsy and transient elastography based on clinical relevance.Can J Gastroenterol. 2008 Sep; 22: 753-757PubMed Google Scholar]. Nevertheless, leaving aside these methodological questions that cannot be solved, it is worth elaborating upon the possible pathophysiologic mechanisms that may be involved in the beneficial effect of HCV eradication for prevention of HCC in patients with established cirrhosis. We have now two experimental models in mice that reproduce the natural history of liver disease leading to fibrosis and cancer. The first is the platelet derived growth factor (PDGF) mouse model that develops extensive fibrosis leading to cirrhosis and ultimately HCC [[17]Campbell J.S. Hughes S.D. Gilbertson D.G. Palmer T.E. Holdren M.S. Haran A.C. et al.Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.Proc Natl Acad Sci USA. 2005; 102: 3389-3394Crossref PubMed Scopus (283) Google Scholar]. The second consists of the liver-specific overexpression of lymphotoxins alpha and beta that induces liver inflammation and HCC, thus supporting the link between chronic inflammatory events and cancer development [[18]Haybaeck J. Zeller N. Wolf M.J. Weber A. Wagner U. Kurrer M.O. et al.A lymphotoxin-driven pathway to hepatocellular carcinoma.Cancer Cell. 2009; 16: 295-308Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar]. If HCV eradication in humans prevents further collagen deposition to a critical level, we would have a potential first hypothesis for its efficacy. The same applies to the reduction of the inflammatory milieu that accompanies viral infection. Again, a critical degree of accumulated damage or a specific hit would be needed to elicit the oncogenic capacity and if this has not taken place prior to HCV eradication, the necessary events for cancer transformation may not take place. The majority of cancers are supposed to require several simultaneous genomic events and it may be that effective viral treatment can prevent the accumulation of hits responsible for malignant transformation. While this wishful thinking turns into reality, there are several advancements that indicate that we are entering the era of molecular prediction of cancer risk and prognosis. Interestingly, a recent study in hepatitis B patients has shown that the risk of cancer and the efficacy of interferon in preventing HCC recurrence after surgical resection may be predicted by the specific miRNA profile [[19]Ji J. Shi J. Budhu A. Yu Z. Forgues M. Roessler S. et al.MicroRNA expression, survival, and response to interferon in liver cancer.N Engl J Med. 2009; 361: 1437-1447Crossref PubMed Scopus (713) Google Scholar]. This correlation will also be investigated in HCV patients, but it is relevant to recall that disease recurrence is due both to metastatic spread and to de novo oncogenesis. Since not all HCV cirrhotics develop HCC during follow-up it is clear that current research will ultimately define risk categories according to genomic profiling. This has been recently evidenced for the risk of late recurrence after HCC resection in HCV patients [[20]Hoshida Y. Villanueva A. Kobayashi M. Peix J. Chiang D.Y. Camargo A. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (1010) Google Scholar] and preliminary data suggest that this may also be feasible for the first HCC in cirrhotic patients [[21]Hoshida Y. Villanueva A. Sangiovanni A. Sole M. Gould J. Gupta S. et al.Gene expression signature predicts cirrhosis outcome.Hepatology. 2009; 50 ([Abstract]): 312AGoogle Scholar]. If this is confirmed and validated, the patients in need for HCC screening programs would have to be redefined. As a whole, there is a vast area of research ahead and there is no doubt that, our current understanding of liver disease and cancer will become outdated in a few years. However, the benefits of viral eradication are not to be challenged as there are several positive consequences that are currently well established. Pharmaco-economic models analyzing the cost-effectiveness of antiviral therapy in cirrhotic patients will need to take into account the reduction in clinical events in patients who clear HCV and, in a few years, the impact of new anti-HCV drugs in treatment efficacy.