Hepatitis C Virus: A Critical Appraisal of Approaches to Therapy
Authors: David R. Nelson, Gary L. Davis, Ira Jacobson, Gregory T. Everson, Michael W. Fried, Stephen A. Harrison, Tarek Hassanein, Donald M. Jensen, Karen L. Lindsay, Norah Terrault, Nizar Zein
Journal: Clinical Gastroenterology and Hepatology (2008)

See related article, Dahari H et al, on page 1402 in Gastroenterology.See CME exam on page 366. See related article, Dahari H et al, on page 1402 in Gastroenterology. See CME exam on page 366. In early May 2008, a panel of 11 nationally renowned hepatologists assembled to investigate existing clinical controversies in hepatitis C management. The purpose of this hepatitis C virus (HCV) Council was to critically review the existing body of literature and analyze it in the context of contemporary practice and optimal therapeutic outcomes. Each panel member focused on the existing evidence pertaining to a specific controversy in the diagnosis and treatment of patients with HCV, and the Council as a whole evaluated the nature of the existing evidence for each statement. By comparing the Council members' evaluations of the evidence with survey results of practicing clinical physicians, several disparities were revealed. These included varied approaches to the duration of treatment, management of nonresponders, and the use of various histologic markers and adjuvant therapies. Diagnosis strategies and future treatment modalities also were explored. A summary of the pertinent findings of the HCV Council is presented here. Chronic hepatitis C virus (HCV) represents a serious viral illness that can lead to cirrhosis, liver failure, and hepatocellular cancer (HCC). From the time HCV was discovered in 1989, there have been rapid advancement in our knowledge of this disease, which has led to marked changes in our management of the HCV-infected patient. In fact, during the past decade, there have been close to 25,000 articles published regarding HCV, and more than 3000 of these were published in the past year. This article represents a summary of the HCV Council, a diverse panel of clinical investigators who met in the spring of 2008 with the goal of assessing the quality of evidence supporting critical clinical aspects of HCV infection and treatment. Ten clinical practice statements were drafted by the chair (D.R.N.) and the 2 workshop leaders (I.J. and G.L.D.) (Table 1). One statement was assigned to each of 10 panel members, who are recognized experts in gastroenterology and hepatology. Before the Council convened, each panel member systematically reviewed the evidence supporting or refuting that statement. During the Council, each panel member presented and summarized their findings, and the statements subsequently were discussed and evaluated by the entire 11-member panel.Table 1HCV Council Statements for EvaluationWorkshop 1: HCV Natural History Statements (statements 1–5) 1SVR equates to a life-long cure and results in improved clinical outcomes. 2Maintenance PEG-IFN therapy leads to positive histologic and clinical benefits in viral nonresponders. 3Serum AFP and ultrasonography every 6 months have sufficient sensitivity and specificity for hepatocellular carcinoma screening. 4Liver biopsy is the most accurate method to assess fibrosis in chronic HCV. 5Before initiating PEG-IFN–based therapy, insulin resistance must be assessed and treated, if present.Workshop 2: HCV Therapy (statements 6–10) 6Week 4 RVR should be used to shorten duration of HCV therapy across all genotypes. 7Genotype 1 patients who are slow responders and who clear virus between weeks 12 and 24 require 72 weeks of therapy. 8EPO should be used to avoid RBV dose reductions for genotype 1 patients. 9Doses of PEG-IFN and RBV beyond standard of care can overcome poor antiviral response. 10Small-molecule therapy will replace PEG-IFN–based therapy for HCV in the next 10 years. Open table in a new tab During the first day of the Council, the panel members divided into 2 simultaneously conducted workshops: "HCV Natural History" and "HCV Therapy." Each workshop included a leader and 4 other content experts, and those workshops served as a forum for the individual panel members to present the evidence for their assigned statements. During the presentation of the data, primary attention was given to the study methodology, number of patients enrolled, and outcome events. After each presentation, the workshop members discussed the evidence, graded the strength of the evidence, and assigned the statement a consensus numeric grade through the voting process (Table 2).Table 2Council Voting SchemesCategoryNature of evidenceI Evidence obtained from at least 1 well-designed, randomized, controlled trialII Evidence obtained from well-designed cohort or case-control studiesIII Evidence obtained from case series, case reports, or flawed clinical trialsIV Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committeesV Insufficient evidence to form an opinionLevel of support for the statement1 Accept recommendation completely2 Accept recommendation with some reservations3 Accept recommendation with major reservations4 Reject recommendation with reservations5 Reject recommendation completely Open table in a new tab In the second phase of the Council, all panelists reconvened in 1 group. Together, they reviewed the workshop summaries and discussed each statement in greater detail. Afterward, all Council participants individually voted on their level of support for the statement, using the grading scheme shown in Table 2. In addition to defining the level of evidence in support of each statement, panel members also identified additional clinical studies that would be of benefit to the evaluation of these statements. Before the Council convened, an e-mail invitation was sent to members of the American Gastroenterological Association (AGA) (ie, all active members who elect to receive these types of communications) to participate in a web-based survey. This was performed to ascertain the clinical perspectives of practicing physicians. A total of 289 survey participants recorded their level of support for the same 10 statements that were evaluated by the Council panelists. The purpose of the electronic survey was to provide information that would allow for the comparison of data-driven responses from the content experts at the Council with those of clinicians practicing in the field. Both the Council participants and survey respondents used the same grading scale to rate the statements (Table 2). This comparison was useful to determine the prevailing current opinions regarding HCV and to identify knowledge gaps and areas in which additional research is needed. In this era of rapid advances in our understanding of the virology, natural history, and treatment of patients with HCV, the clinical management of this disease has become increasingly complex. In the summaries that follow, we have attempted to determine where evidence-based medicine ends and expert opinion predominates in the guidance of patient management decisions. Generally, a sustained virologic response (SVR) can be defined as the absence of detectable HCV RNA in a patient's blood 6 months after the completion of antiviral treatment. This event occurs in more than half of patients treated with the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV),1Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (4287) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. 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 (4482) Google Scholar and it connotes a clinical cure of the infection. However, evidence of cure and resulting reduction in the risk of detrimental outcomes of liver disease have been slow to appear in the medical literature. This section presents evidence supporting this statement. To support or refute the first part of the statement regarding cure of infection, evidence addressing the durability of viral clearance, clinical or virologic relapse with immunosuppression, persistence of clinical improvement, and residual hepatic and extrahepatic reservoirs was examined. Literature focusing on long-term histologic changes and clinical outcomes such as hepatic decompensation and HCC was used to address the question of improved clinical outcomes. Seven published, retrospective, follow-up case studies were considered in the review. Of these, 4 included only immune-competent patients, and 3 involved immunocompromised individuals (ie, 2 post–liver transplantations, 1 human immunodeficiency virus [HIV] co-infected).3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar, 4Desmond C.P. Roberts S.K. Dudley F. et al.Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting.J Viral Hepat. 2006; 13: 311-315Crossref PubMed Scopus (31) Google Scholar, 5Everson G.T. Trotter J. Forman L. et al.Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy.Hepatology. 2005; 42: 255-262Crossref PubMed Scopus (212) Google Scholar, 6Formann E. Steindl-Munda P. Hofer H. et al.Long-term follow-up of chronic hepatitis C patients with sustained virological response to various forms of interferon-based anti-viral therapy.Aliment Pharmacol Ther. 2006; 23: 507-511Crossref PubMed Scopus (43) Google Scholar, 7Soriano V. Maida I. Nunez M. et al.Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies.Antivir Ther. 2004; 9: 987-992PubMed Google Scholar, 8Tsuda N. Yuki N. Mochizuki K. et al.Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy.J Med Virol. 2004; 74: 406-413Crossref PubMed Scopus (36) Google Scholar, 9Yu M.L. Dai C.Y. Chen S.C. et al.High versus standard doses interferon-alpha in the treatment of naive chronic hepatitis C patients in Taiwan: a 10-year cohort study.BMC Infect Dis. 2005; 5: 27Crossref PubMed Scopus (9) Google Scholar A total of 554 patients were followed up, with a mean follow-up period of 3.5 years after SVR. Of these patients, there were only 2 recurrent or late-relapsed infections, for an annual recurrence rate of 0.1% per annum. The presence of immunosuppression did not appear to increase the risk of recurrent or relapsed infection. Five studies examined long-term persistence of clinical improvement by using serial liver biopsies after SVR,3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar, 10Bizollon T. Ahmed S.N. Radenne S. et al.Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.Gut. 2003; 52: 283-287Crossref PubMed Scopus (122) Google Scholar, 11Marcellin P. Boyer N. Gervais A. et al.Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.Ann Intern Med. 1997; 127: 875-881Crossref PubMed Google Scholar, 12Poynard T. McHutchison J. Davis G.L. et al.Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.Hepatology. 2000; 32: 1131-1137Crossref PubMed Google Scholar, 13Shiratori Y. Imazeki F. Moriyama M. et al.Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.Ann Intern Med. 2000; 132: 517-524Crossref PubMed Google Scholar and 2 of these studies focused on outcomes in SVR achieved after liver transplantation.3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar, 10Bizollon T. Ahmed S.N. Radenne S. et al.Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.Gut. 2003; 52: 283-287Crossref PubMed Scopus (122) Google Scholar A total of 747 patients were included, and all studies showed histologic improvement. The greatest improvement occurred during antiviral treatment, with slower regression of hepatic injury thereafter.3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar, 10Bizollon T. Ahmed S.N. Radenne S. et al.Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.Gut. 2003; 52: 283-287Crossref PubMed Scopus (122) Google Scholar, 11Marcellin P. Boyer N. Gervais A. et al.Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.Ann Intern Med. 1997; 127: 875-881Crossref PubMed Google Scholar, 12Poynard T. McHutchison J. Davis G.L. et al.Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.Hepatology. 2000; 32: 1131-1137Crossref PubMed Google Scholar, 13Shiratori Y. Imazeki F. Moriyama M. et al.Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.Ann Intern Med. 2000; 132: 517-524Crossref PubMed Google Scholar In 2 studies, researchers suggested that resolution of inflammation might be slower in liver transplantation recipients who achieve an SVR.3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar, 10Bizollon T. Ahmed S.N. Radenne S. et al.Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.Gut. 2003; 52: 283-287Crossref PubMed Scopus (122) Google Scholar Ultimately, up to 62% of patients followed up by Marcellin et al11Marcellin P. Boyer N. Gervais A. et al.Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.Ann Intern Med. 1997; 127: 875-881Crossref PubMed Google Scholar normalized their histology after showing SVR. Abdelmalek et al3Abdelmalek M.F. Firpi R.J. Soldevila-Pico C. et al.Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 199-207Crossref PubMed Scopus (101) Google Scholar reported a regression of fibrosis up to 0.8 Metavir units per year, with 67% improving by at least one stage at 3 to 5 years of follow-up evaluation. Both viral proteins and negative strands of HCV have been detected in extrahepatic sites, including peripheral blood mononuclear cells, dendritic cells, lymph nodes, gut epithelial cells, and brain cells during active infection, usually during periods of high viremia.14Blackard J.T. Hiasa Y. Smeaton L. et al.Compartmentalization of hepatitis C virus (HCV) during HCV/HIV coinfection.J Infect Dis. 2007; 195: 1765-1773Crossref PubMed Scopus (27) Google Scholar, 15Deforges S. Evlashev A. Perret M. et al.Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo.J Gen Virol. 2004; 85: 2515-2523Crossref PubMed Scopus (30) Google Scholar, 16Forton D.M. Karayiannis P. Mahmud N. et al.Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants.J Virol. 2004; 78: 5170-5183Crossref PubMed Scopus (118) Google Scholar, 17Goutagny N. Fatmi A. De Ledinghen V. et al.Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection.J Infect Dis. 2003; 187: 1951-1958Crossref PubMed Scopus (108) Google Scholar, 18Laskus T. Operskalski E.A. Radkowski M. et al.Negative-strand hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells from anti-HCV-positive/HIV-infected women.J Infect Dis. 2007; 195: 124-133Crossref PubMed Scopus (37) Google Scholar, 19Pal S. Sullivan D.G. Kim S. et al.Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism.Gastroenterology. 2006; 130: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar It is thought that such sites might serve as residual reservoirs of virus that also could lead to resistance to antiviral therapy or late relapse of infection. In fact, an early study found that HCV RNA was present in liver tissue of 7 of 400 patients with undetectable serum HCV RNA 6 months after completing antiviral treatment.20McHutchison J.G. Poynard T. Esteban-Mur R. et al.Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin.Hepatology. 2002; 35: 688-693Crossref PubMed Scopus (80) Google Scholar Of these, 2 eventually relapsed. Two other laboratories reported persistent HCV RNA in liver tissue, peripheral blood mononuclear cells, lymphocytes, and/or dendritic cells long after patients achieved SVR,21Pham T.N. MacParland S.A. Mulrooney P.M. et al.Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C.J Virol. 2004; 78: 5867-5874Crossref PubMed Scopus (188) Google Scholar, 22Radkowski M. Gallegos-Orozco J.F. Jablonska J. et al.Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.Hepatology. 2005; 41: 106-114Crossref PubMed Scopus (183) Google Scholar whereas another laboratory reported detection of HCV RNA in liver and peripheral blood mononuclear cells of patients with either no serologic markers of HCV infection or the presence of HCV antibody in the absence of HCV RNA in the blood.23Carreno V. Pardo M. Lopez-Alcorocho J.M. et al.Detection of hepatitis C virus (HCV) RNA in the liver of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients with normal alanine aminotransferase levels.J Infect Dis. 2006; 194: 53-60Crossref PubMed Scopus (49) Google Scholar, 24Castillo I. Pardo M. Bartolome J. et al.Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown.J Infect Dis. 2004; 189: 7-14Crossref PubMed Scopus (131) Google Scholar In contrast, a recent study using a highly sensitive transcription-mediated amplification method failed to detect HCV RNA in the peripheral blood mononuclear cells of any patients with undetectable virus in blood.25Bernardin F. Tobler L. Walsh I. et al.Clearance of hepatitis C virus RNA from the peripheral blood mononuclear cells of blood donors who spontaneously or therapeutically control their plasma viremia.Hepatology. 2008; 47: 1446-1452Crossref PubMed Scopus (39) Google Scholar Although evidence for residual viremia in extrahepatic sites in patients without detectable HCV RNA in blood is quite limited, available data suggest this to be a rare occurrence. In addition to the histologic improvement described earlier, several studies have reported the risk of long-term complications of liver disease in patients with SVR. Nine studies comprising a total of 5381 patients who were followed up for a weighted mean of 5.4 ± 0.5 years were included in the review.8Tsuda N. Yuki N. Mochizuki K. et al.Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy.J Med Virol. 2004; 74: 406-413Crossref PubMed Scopus (36) Google Scholar, 26Arase Y. Ikeda K. Suzuki F. et al.Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C.Intervirology. 2007; 50: 16-23Crossref PubMed Scopus (29) Google Scholar, 27Braks R.E. Ganne-Carrie N. Fontaine H. et al.Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin.World J Gastroenterol. 2007; 13: 5648-5653Crossref PubMed Google Scholar, 28Bruno S. Stroffolini T. Colombo M. 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 (259) Google Scholar, 29Chavalitdhamrong D. Tanwandee T. Long-term outcomes of chronic hepatitis C patients with sustained virological response at 6 months after the end of treatment.World J Gastroenterol. 2006; 12: 5532-5535PubMed Google Scholar, 30Hung C.H. Lee C.M. Lu S.N. et al.Long-term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis.J Viral Hepat. 2006; 13: 409-414Crossref PubMed Scopus (60) Google Scholar, 31Kim J.H. Han K.H. Lee K.S. et al.Efficacy and long-term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea.Yonsei Med J. 2006; 47: 793-798Crossref PubMed Google Scholar, 32Veldt B.J. Heathcote E.J. Wedemeyer H. 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 Google Scholar, 33Yoshida H. Shiratori Y. Moriyama M. et al.Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy.Ann Intern Med. 1999; 131: 174-181Crossref PubMed Google Scholar Fibrosis at stages 2, 3, or 4 was present in 53% of patients, and at least 32% of the combined cohort had cirrhosis at the time of antiviral treatment. These studies present a clear picture of a striking reduction in the risk of complications of liver disease after SVR. The study by Veldt et al32Veldt B.J. Heathcote E.J. Wedemeyer H. 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 Google Scholar included patients with either bridging fibrosis or cirrhosis, whereas the study by Bruno et al28Bruno S. Stroffolini T. Colombo M. 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 (259) Google Scholar included only those with cirrhosis. Among cirrhotic patients, the annual risk of hepatic decompensation after SVR declined from 1.88% to 0% (P < .001), HCC declined from 2.10% to 0.66% (P < .001), and liver-related mortality declined from 1.44% to 0.19% (P < .001). Non–liver mortality, however, was unchanged.28Bruno S. Stroffolini T. Colombo M. 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 (259) Google Scholar In summary, data support the statement that SVR equates to a life-long cure. Durable loss of detectable virus from serum is observed in almost all patients (ie, >99%), and there is no consistent evidence of residual HCV RNA in the liver or extrahepatic sites after SVR. Furthermore, there is clear and overwhelming evidence showing that SVR results in improved clinical outcomes. Chronic infection with HCV may lead to liver failure, HCC, and death. In patients who do not achieve SVR with combination PEG-IFN plus RBV antiviral therapy, long-term, low-dose PEG-IFN therapy may slow the progression of hepatic fibrosis and improve clinical outcomes. Two large, randomized controlled trials reported the effects of long-term, low-dose PEG-IFN therapy in nonresponders to combination PEG-IFN plus RBV treatment. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial,34Lee W.M. Dienstag J.L. Lindsay K.L. et al.Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders.Control Clin Trials. 2004; 25: 472-492Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar nonresponders with an Ishak score of stage 3 or greater hepatic fibrosis, a Child–Turcotte–Pugh score of 6 or less, and no history of ascites, encephalopathy, or bleeding varices were randomized to groups receiving either PEG-IFN alfa-2a 90 μg/wk or no treatment for 3.5 years. Patients were seen every 3 months. Liver biopsies were performed at baseline and at 1.5 and 3.5 years. Negative clinical outcomes in the study included death, HCC, and hepatic decompensation (ie, variceal bleeding, ascites, spontaneous bacterial peritonitis, encephalopathy, or a Child–Turcotte–Pugh score ≥7). For patients with precirrhotic fibrosis at baseline (ie, Ishak stages 3 or 4), fibrosis progression was defined as an increase in fibrosis score of 2 or more points. A total of 1050 patients were randomized (ie, 517 patients to the treatment group, 533 patients to the control group).35Di Bisceglie A. Shiffman M. Everson G. Prolonged antiviral therapy with peginterferon to prevent complications of advanced liver disease associated with hepatitis C: results of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial.Hepatology. 2007; 46 ([AASLD abstracts]): 290AGoogle Scholar By the end of the study, the frequency of outcomes in the treated and control groups was not different (ie, 34.1% in the treated group, 33.8% in the control group; hazard ratio, 1.1; P = .91). Despite a significant reduction in mean serum alanine aminotransferase (ALT) level, HCV RNA level, and necroinflammatory scores in the treatment group when compared with the control group, there was no significant difference between the 2 groups in any of the primary outcomes between the treatment and control groups (eg, death, 6.6% vs 4.6%; decompensation, 14.3% vs 13.2%; HCC, 2.8% vs 3.2%; increased fibrosis, 28.2% vs 31.9%, respectively). The COPILOT trial36Afdhal N. Levine R. Brown Jr, R. et al.Colchicine versus peg-interferon alfa 2b long term therapy: results of the 4 year copilot trial.J Hepatol. 2008; 48: S4Abstract Full Text PDF Google Scholar was a prospective, randomized, colchicine-controlled trial in which 555 patients who had failed IFN therapy and who had Ishak stages 3 to 6 hepatic fibrosis, a Child–Turcotte–Pugh score of 7 or less, and no evidence of HCC or liver decompensation were randomized to receive either PEG-IFN alfa-2b 0.5 μg/kg/wk (n = 286) or colchicine 0.6 mg twice daily (n = 269) for 4 years. Patients were followed up every 3 months and screened for HCC by hepatic ultrasound every 6 months. Primary end points of the study included a Child–Turcotte–Pugh score increase of more than 2 points with jaundice, encephalopathy, or ascites; variceal bleeding; portal hypertension; liver transplantation; HCC; or death. At study entry, 83% of each group had cirrhosis, and portal hypertension was present in 48% of the colchicine group and in 42% of the PEG-IFN group. After 4 years of treatment, there was no significant difference in event-free survival or the rates of clinical outcomes between the 2 groups (P = .311). Data on the degree to which HCV RNA was suppressed during the patient's prestudy course of PEG-IFN plus RBV and HCV RNA levels during the trial are not yet available. Based on the results of these large, randomized, controlled trials, long-term, low-dose PEG-IFN therapy does not show clinical benefit or a reduction in hepatic fibrosis in patients with chronic HCV infection and clinically compensated liver disease who have not responded to antiviral combination PEG-IFN plus RBV therapy. However, because viral suppression was not an end point of either of these large trials, the question remains whether long-term suppression of HCV RNA may reduce hepatic inflammation, fibrosis, and subsequent negative clinical outcomes related to advanced liver disease. Data from the HALT-C trial support the potential benefit of viral suppression. In a subanalysis of 764 randomized patients who received PEG-IFN alfa-2a 180 μg/wk and RBV 1.0 to 1.2 g/d during the lead-in phase of the trial and who did not develop an SVR, 425 (56%) had less than a 2 log10 decline in HCV RNA at week 20 of combination therapy. A total of 178 (23%) had a greater than 4 log10 decline and/or they developed undetectable HCV RNA and were later randomized when they continued combination therapy but relapsed. Only 30 of the 88 patients (34%) with greater than 4 log10 suppression during lead-in treatment continued to have greater than 4 log10 suppression during maintenance PEG-IFN therapy. However, patients with greater than 4 log10 reduction or undetectable HCV RNA during lead-in treatment had the lowest likelihood of negative outcomes (eg, progression of fibrosis), regardless of whether