Optimizing Outcomes in Hepatitis C: Is Treatment Beyond 48 Weeks Ever Justified?

Abstract

Chronic hepatitis C virus (HCV) infection has emerged as a leading cause of cirrhosis, liver failure, and hepatocellular carcinoma in the United States and other Western countries. In carefully controlled clinical trials, pegylated interferon (IFN) and ribavirin treatment for 24 to 48 weeks in subjects with HCV genotype 2/3 and genotype 1 infection is associated with sustained virological response (SVR) rates of 76% to 82% and 42% to 46%, respectively.1Fried M.W. Shiffman M.L. Reddy R. Smith C. Marinos G. Goncales F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Lin A. Hoffman J. Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5894) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. Koury K. Ling M.H. Albrecht J.K. International Hepatitis Interventional Therapy GroupPeginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C A randomized trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5910) Google Scholar, 3Hadziyannis S.J. Sette H. Morgan T.R. Balan V. Diago M. Marcellin P. Ramadori G. Bodenheimer H. Bernstein D. Rizzetto M. Zeuzem S. Pockros P.J. Lin A. Ackrill A.M. PEGASYS International Study GroupPeginterferon-a2a and ribavirin combination therapy in chronic hepatitis C.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2759) Google Scholar Similar SVR rates have been reported when treating “real-world” HCV patients demonstrating the effectiveness of antiviral treatment in clinical practice.4Lee S.S. Peltekian K. Krajdens M. Yoshida E.M. Deschenes M. Heathcote J. Bailey R.J. Simonyi S. Sherman M. Canadian Pegasys Study groupTreating chronic hepatitis C with pegylated interferon alfa-2a (40kD) and ribavirin in clinical practice.Ailment Pharmacol Ther. 2006; 23: 397-408Crossref PubMed Scopus (74) Google Scholar However, use of these agents requires frequent laboratory and clinical monitoring to detect common side effects including myelotoxicity and neuropsychiatric toxicity, which can preclude many HCV patients from antiviral treatment altogether. In addition, severe dose-dependent side effects lead to medication dose reductions or early discontinuation in up to 40% and 20% of treated patients, respectively, which further reduces SVR rates.5McHutchison J.G. Manns M. Patel K. Poynard T. Lindsay K.L. Trepo C. Dienstag J. Lee W.M. Mak C. Garaud J.J. Albrecht J.K. Adherence to combination therapy enhances sustained response in genotype 1 infected patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1061-1069Abstract Full Text Full Text PDF PubMed Scopus (958) Google Scholar Therefore, newer antiviral agents with improved tolerability are urgently needed to improve clinical outcomes. However, in the absence of newer drugs becoming available in the near future, a multitude of studies have been undertaken to determine the optimal dose and duration of pegylated IFN and ribavirin to use in both treatment naïve and previously treated HCV patients. Use of viral kinetics during treatment measured by quantitative PCR assays has allowed clinicians to identify subjects who are nonresponders early on, as well as subjects who are more likely to achieve an SVR. For example, retrospective analyses consistently demonstrate that failure to decrease HCV RNA by at least 2log10 at week 12 in previously untreated genotype 1 patients can help identify nonresponders with a high degree of accuracy (ie, negative predictive value of 97%–100%).1Fried M.W. Shiffman M.L. Reddy R. Smith C. Marinos G. Goncales F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Lin A. Hoffman J. Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5894) Google Scholar, 6Davis G.L. Wong J.B. McHutchison J.G. Manns M.P. Harvey J. Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C.Hepatology. 2003; 38: 645-652Crossref PubMed Scopus (791) Google Scholar, 7Strader D.B. Wright T. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171Crossref PubMed Scopus (1591) Google Scholar Pilot studies have also suggested that genotype 2 or genotype 3 patients with a low viral load that achieve a rapid virological response at week 4 (ie, undetectable HCV RNA) may have a high SVR rate with only 12 to 16 weeks of treatment.8Dalgard O. Bjoro K. Hellum K.B. Myrvang B. Ritland S. Skaug K. Baknerud N. Bell H. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks a pilot study.Hepatology. 2004; 40: 1260-1265Crossref PubMed Scopus (294) Google Scholar, 9Von Wagner M. Huber M. Berg T. Hinrichsen H. Rasenack J. Heintges T. Bergk A. Bernsmeier C. Haussinger D. Herrmann E. Zeuzem S. Peginterferon-a2a (40 kD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C.Gastroenterology. 2005; 129: 522-527Abstract Full Text Full Text PDF PubMed Google Scholar, 10Mangia A. Santoro R. Minerva N. Ricci G.L. Carretta V. Persico M. Vinelli F. Scotto G. Bacca D. Annese M. Romano M. Aechinin F. Sogari F. Spirito F. Andriulli A. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV Genotype 2 or 3.N Engl J Med. 2005; 352: 2609-2617Crossref PubMed Scopus (601) Google Scholar Similarly, retrospective analyses suggest that there may be a small subgroup of previously untreated HCV genotype 1 patients with a rapid virologic response at week 4 that can achieve SVR with only 24 weeks of therapy but confirmatory prospective studies are still ongoing.11Jensen D. Morgan T. Marcellin P. Pockros P. Reddy R. Hadziyannis S. Ferenci P. Willems B. Rapid virological response at week 4 (RVR) of peginterferon alfa-2a (40kD) plus ribavirin treatment predicts sustained virological response after 24 weeks in genotype 1 patients.Hepatology. 2005; 42 (abstr): 650APubMed Google Scholar, 12Ferenci P. Bergholz U. Laferl H. Gurguta C. Aaieron A. Gschwantler H. Brunner H. Hubmann R. Datz C. Bischof M. Stauber R. Steindl-Munda P. Is shorter treatment with peginterferon alfa-2a (40kD) plus ribavirin possible in HCV genotype 1 “super-responders”? Preliminary results of a prospective randomized clinical trial.Hepatology. 2005; 42 (abstr): 218APubMed Google Scholar Finally, treatment naïve HCV genotype 3 patients with a high viral load may benefit from extending treatment from 24 to 48 weeks. However, the optimal means to treat the large number of genotype 1 patients with unfavorable pretreatment characteristics such as a high viral load, non-Caucasian ethnicity, or high body weight remains largely unknown. For example, high-dose pegIFNα2a (ie, 270 μg/week) monotherapy demonstrated no incremental virological efficacy and a higher incidence of toxicity compared with standard doses.13Reddy K.R. Wright T.L. Pockros P.J. Shiffman M. Everson G. Reindollar R. Fried M.W. Purdum P.P. Jensen D. Smith C. Lee W.M. Boyer T.D. Lin A. Pedder S. DePamphilis J. Efficacy and safety of pegylated (40 kd) interferon a-2a compared with interferon a2a in non-cirrhotic patients with chronic hepatitis C.Hepatology. 2001; 33: 433-438Crossref PubMed Scopus (349) Google Scholar Similarly, preliminary results of multicenter studies of pegylated IFNα2b and high-dose ribavirin (ie, 800 to 1600 mg/d) with or without growth factors demonstrates only a marginal improvement in efficacy compared with fixed doses of ribavirin in previously untreated genotype 1 patients.14Shiffman M.L. Price A. Hubbard S. Wilson M. Salvatori J. Sterling R.K. Stravitz R.T. Luketic V.A. Sanyal A.J. Treatment of chronic hepatitis C virus genotype 1 with peginterferon alfa-2b, high weight based dose ribavirin and epoeitin-alfa enhances sustained virological response.Hepatology. 2005; (abstr): A55PubMed Google Scholar, 15Jacobson I. Brown R.S. Frelich B. Afdhal N. Kwo P. Santoro J. Becker S. Wakil A. et al.Weight-based ribavirin dosing increases sustained viral response in patients with chronic hepatitis C final results of the WIN-R study, a US community based trial.Hepatology. 2005; 42 (abstr): A LB3Google Scholar Therefore, the lack of improved antiviral efficacy coupled with the increased side effects and costs of high-dose ribavirin and growth factors do not currently justify these approaches in clinical practice. In contrast, the possibility of using standard doses of pegylated IFN and ribavirin for more than 48 weeks has been raised for selected treatment naïve genotype 1 patients with a slow virologic response during treatment.16Buti M. Valdes A. Sanchez-Avila F. Esteban R. Lurie Y. Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders a report of 9 cases (letter).Hepatology. 2003; 37: 1226-1227Crossref PubMed Scopus (65) Google Scholar The licensing studies of standard IFN and ribavirin demonstrated a consistently higher SVR and lower relapse rate with 48 weeks of combination therapy compared with 24 weeks.17McHutchison J.G. Gordon S.C. Schiff E.R. Shiffman M.L. Lee W.M. Rustgi V.K. Goodman Z.D. Ling M.H. Cort S. Albrecht J.K. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3360) Google Scholar, 18Poynard T. Lee S.S. Minuk G.S. Ideo G. Bain V. Heathcote J. Zeuzem S. Trepo Albrecht J. Randomised trial of interferona2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2404) Google Scholar Subjects with the lowest likelihood of response (ie, genotype 1, high viral load) experienced the greatest incremental benefit with longer treatment. Similarly, a significantly higher SVR rate was reported when genotype 1 patients were treated with pegylated IFNα2a and standard-dose ribavirin for 48 weeks compared with 24 weeks (52% vs 42%).3Hadziyannis S.J. Sette H. Morgan T.R. Balan V. Diago M. Marcellin P. Ramadori G. Bodenheimer H. Bernstein D. Rizzetto M. Zeuzem S. Pockros P.J. Lin A. Ackrill A.M. PEGASYS International Study GroupPeginterferon-a2a and ribavirin combination therapy in chronic hepatitis C.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2759) Google Scholar Finally, a pilot study of 72 weeks of standard IFN and ribavirin was superior to 24 weeks of combination therapy as well as 72 weeks of standard IFN monotherapy.19Brouwer J.T. Nevens F. Bekkering F.C. Bourgeois N. Vlierberghe H.V. Weegin C.J. Lefebvre V. Hattum J.V. Henrion J. Delwaide J. Hansen B.E. Schalms S.W. Benelux Study group on treatment of chronic hepatitis CReduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients.J Hepatology. 2004; 40: 689-695Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In all of these studies, a greater reduction in the rate of posttreatment relapse was noted as opposed to improved end-of-treatment response (ETR) rates. In addition, retrospective analyses of viral kinetics during pegIFNα2b and ribavirin treatment estimate that at least 32 to 36 weeks of undetectable HCV RNA by quantitative PCR is needed to attain sustained clearance of HCV in previously untreated genotype 1 patients.20Drusano G.L. Preston S.L. A 48-week duration of therapy with pegylated Interferon a2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype 1 hepatitis C virus.J Infect Dis. 2004; 189: 964-970Crossref PubMed Scopus (79) Google Scholar Prolonged suppression of detectable serum HCVRNA may help the immune system clear infected hepatocytes, as well as extrahepatic reservoirs of HCV replication. Therefore, it is reasonable to hypothesize that 72 weeks of pegylated IFN and ribavirin treatment may lead to enhanced SVR in a subgroup of slow virological responders with genotype 1 compared to 48 weeks of treatment. In this issue of Gastroenterology, a prospective study from Germany of 459 treatment naïve genotype 1 patients randomized to 72 versus 48 weeks of pegIFNα2a 180 μg/wk and ribavirin 800 mg per day is reported (Table 1).21Berg T. Von Wagner M. Hinrichsen H. Sarrazin C. Heintges T. Gerlack T. Buggisch P. Goeser T. Rasenack J. Pape G.R. Schmidt W.E. Kallinowski B. Klinker H. Spengler U. Martus P. Alshuth U. Zeuzem S. Extended treatment duration for hepatitis C virus type 1 comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar Since the treatment regimen for the first 48 weeks was identical, the authors hypothesized that 72 weeks of combination therapy would significantly reduce the frequency of posttreatment relapse. But contrary to expectations, the SVR and relapse rates, as well as the ETR rates were not significantly different in the 2 treatment groups (SVR, 54% vs 53%; relapse rate, 21% vs 29%; ETR, 63% vs 71%). Although subgroup analyses suggested that subjects with persistently detectable HCV RNA < 6,000 IU/mL at week 12 may benefit from prolonged treatment, the overall SVR rates in the 2 groups were similar. The frequency of medication dose reductions and adverse events were similar in the treatment groups, but the patients receiving 72 weeks of treatment had significantly higher rates of early treatment discontinuation (41% vs 24%). Explanations for a lack of improved SVR include the high rate of early termination in patients randomized to 72 weeks, many of whom self-discontinued after week 48. In addition, the 800-mg dose of ribavirin may have been inadequate because prior studies have shown that 48 weeks of pegIFNα2a and 1000 to 1200 mg of ribavirin is superior to 800 mg of ribavirin per day in treatment naïve genotype 1 subjects (SVR, 52% vs 41%).3Hadziyannis S.J. Sette H. Morgan T.R. Balan V. Diago M. Marcellin P. Ramadori G. Bodenheimer H. Bernstein D. Rizzetto M. Zeuzem S. Pockros P.J. Lin A. Ackrill A.M. PEGASYS International Study GroupPeginterferon-a2a and ribavirin combination therapy in chronic hepatitis C.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2759) Google Scholar Finally, the randomization of subjects at baseline may have reduced the ability to see a significant difference in the 2 study arms since the large number of subjects who became PCR negative by week 4 (n = 51) and week 12 (n = 130) had a high likelihood of achieving SVR with only 48 weeks of treatment (ie, 84% and 81%, respectively).Table 1Studies of 72 Versus 48 Weeks of Antiviral Therapy in Hepatitis CTreatment Arms (Weeks)NumberStatusTreatment naïveBerg et al21Berg T. Von Wagner M. Hinrichsen H. Sarrazin C. Heintges T. Gerlack T. Buggisch P. Goeser T. Rasenack J. Pape G.R. Schmidt W.E. Kallinowski B. Klinker H. Spengler U. Martus P. Alshuth U. Zeuzem S. Extended treatment duration for hepatitis C virus type 1 comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (471) Google ScholarPegIFNα2a (180) + rib 800 (48)230ETR = 71% SVR = 53%PegIFNα2a (180) + rib 800 (72)225ETR = 63% SVR = 54%TeraViC-4 study22Sanchez-Tapias J.M. Diago M. Escartin P. Enrequez J. Moreno R. Romero-Gomez M. Barcena R. Crespo J. Andrade R. Perez R. Testillano M. Planas R. Sola R. Garcia-Bengoechea M. Garcia-Samaniego J. Munoz-Sanchez M. Moreno-Otero R. 21. TeraViC-4 study GroupPeginterferon alfa-2a plus ribavirin for 72 weeks in chronic hepatitis C patients without a response by week 4.Gastroenterology. 2006; (in press).PubMed Google ScholarPegIFNα2a (180) + rib 800 (48)165ETR = 61% SVR = 32%PegIFNα2a (180) + rib 800 (72)161ETR = 61% SVR = 45%⁎P < .05SUCCESS studyaSUCCESS, A Study to Assess Treatment with Peg-Intron and Rebetol in Naive Patients with Genotype 1 Chronic Hepatitis C and Slow Virologic Response. 1200 HCV genotype 1 patients are to be enrolled but only PCR + patients at week 12 who become PCR − at week 24 will be randomized to 72 versus 48 weeks of treatment.PegIFNα2b (1.5 μg/kg/wk) + rib 1.0–1.2 (48)60OngoingPegIFNα2b (1.5 μg/kg/wk) + rib 1.0–1.2 (72)60NonrespondersREPEAT study32Jensen D.M. Marcellin P. Rationale and design of the REPEAT study a phase III randomized, clinical trial of peginterferon alfa-2a (40kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12 kDa) plus ribavirin.Eur J Gastroenterol Hepatol. 2005; 17: 899-904Crossref PubMed Scopus (26) Google ScholarPegIFNα2a (360) + rib 1.0–1.2 (48)150OngoingPegIFNα2a (360) + rib 1.0–1.2 (72)300PegIFNα2a (180) + rib 1.0–1.2 (48)300PegIFNα2a (180) + rib 1.0–1.2 (72)150a SUCCESS, A Study to Assess Treatment with Peg-Intron and Rebetol in Naive Patients with Genotype 1 Chronic Hepatitis C and Slow Virologic Response. 1200 HCV genotype 1 patients are to be enrolled but only PCR + patients at week 12 who become PCR − at week 24 will be randomized to 72 versus 48 weeks of treatment. P < .05 Open table in a new tab Another study published in this month’s Gastroenterology demonstrates a potential benefit of prolonged antiviral therapy only in patients who remain PCR + at week 4 (Table 1).22Sanchez-Tapias J.M. Diago M. Escartin P. Enrequez J. Moreno R. Romero-Gomez M. Barcena R. Crespo J. Andrade R. Perez R. Testillano M. Planas R. Sola R. Garcia-Bengoechea M. Garcia-Samaniego J. Munoz-Sanchez M. Moreno-Otero R. 21. TeraViC-4 study GroupPeginterferon alfa-2a plus ribavirin for 72 weeks in chronic hepatitis C patients without a response by week 4.Gastroenterology. 2006; (in press).PubMed Google Scholar Sanchez–Tapias et al from Spain gave pegIFNα2a 180 μg/week and ribavirin 800 mg per day to 510 treatment naïve patients 78% of whom had genotype 1 or 4. After 4 weeks of treatment, 326 of the 529 subjects (62%) had persistently detectable HCV RNA by qualitative PCR (lower limit of detection [lld] = 50 IU/mL) and were randomized to either 48 versus 72 weeks of treatment. The remaining 184 patients with undetectable HCV RNA at week 4 were given either 24 (n = 148) or 48 (n = 36) weeks of treatment based upon their genotype and viral load. Although the ETR rates were similar (61% vs 61%), the SVR rate was significantly higher in subjects receiving 72 compared with 48 weeks of treatment (45% vs 32%, P = .01). The improvement in SVR was most apparent in patients with genotype 1 (44% vs 28%, P = .003) versus other genotypes (52% vs 75%, P = NS). As in the Berg study, the frequency of adverse events and dose reductions were similar in the 2 treatment groups. However, the rate of early discontinuation was also significantly higher with 72 versus 48 weeks of treatment (36% vs 18%), largely due to patient preference/withdrawal rather than severe adverse events. Both this study and the Berg study suggest that antiviral treatment beyond 48 weeks may be difficult for patients to adhere to even when reduced doses of ribavirin are used. Limitations of this study include the lack of central virological testing, the inclusion of patients with genotype 2 or 3 in the randomized phase, and the suboptimal dose of ribavirin used. However, even with these caveats, the authors demonstrate that 72 weeks of therapy was better than 48 weeks in subjects who fail to clear HCV RNA at week 4 (ie, nonrapid responders). In order to determine if prolonged antiviral therapy is warranted, future studies should only randomize genotype 1 patients with a partial virological response after 4 to 12 weeks of treatment and also enroll patients with a lower likelihood of response (ie, high viral load, advanced fibrosis, increased body weight). Finally, full-dose ribavirin (ie, 1000 to 1200 mg) should be used since this will increase the response rate in the control arm. A number of ongoing studies are also exploring the optimal dose and duration of pegylated IFN and ribavirin to use in nonresponders and relapsers to prior antiviral therapy. As with treatment naïve subjects, higher doses of either pegIFN or ribavirin have not been associated with improved SVR rates compared with standard doses when given for 48 weeks.23Gross J. Johnson S. Kwo P. Afdhal N. Flamm S. Therneau T. Double-dose peginterferon alfa-2b with weight –based ribavirin improves response for interferon/ ribavirin non-responders with hepatitis C final results of RENEW.Hepatology. 2005; 42 (abstr): A60Google Scholar, 24Gaglio P. Choi J. Zimmerman D. Heller L. Brown R.S. Weight based ribavirin in combination with pegylated interferon alfa2b does not improve SVR in HCV infected patients who failed prior therapy.Hepatology. 2005; 42: A59Google Scholar However, nonresponders and relapsers are a heterogeneous group of HCV patients due to the variable presence of host (race, body mass, insulin resistance), viral (HCV genotype 1, high viral load), and therapeutic (total dose, compliance, side effects) co-factors.25Fontana R.J. Nonresponders to hepatitis C virus antiviral therapy pegylated interferons and beyond.Gastroenterol Clin N Am. 2004; 33: 527-547Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Because virological relapsers are more likely to respond to retreatment than prior flat or null nonresponders, all available treatment records should be reviewed. The decision to retreat a given patient should take into account disease severity, the type, duration, and tolerability of prior treatment, and the likelihood of achieving a response with retreatment. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial is a multicenter study of prior nonresponders and relapsers with advanced fibrosis or compensated cirrhosis.26Shifffman M.L. DiBisceglie A.M. Lindsay K.L. Morishima C. Wright E.C. Everson G.T. Lok A.S. Morgan T.R. Bonkovsky H.L. Lee W.M. Dienstag J.L. Ghany M.G. Goodman Z.D. Everhart J.E. HALT-C trial groupPeginterferon Alfa-2a and ribavirin in patients with chronic hepatitis C who failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar The results of retreatment with pegIFNα2a 180 μg/week and ribavirin 1000 to 1200 mg/day in 604 patients demonstrated that 35% became PCR negative by week 20 and that 32% remained PCR negative at week 48. However, there was a high relapse rate when therapy was stopped and only 18% achieved SVR. Independent predictors of SVR included prior treatment with IFN versus IFN and ribavirin, HCV genotype non-1 versus 1, lower Ishak fibrosis score, and lower baseline HCV RNA level. The role of medication dose reductions and discontinuations in predicting SVR in the HALT-C study is currently being analyzed. Other large multicenter studies of nonresponder/relapsers using 48 weeks of pegylated IFN and ribavirin (ie, EPIC3, RENEW) have also demonstrated a similar overall SVR rate with a high relapse rate (∼50%) in this challenging patient population.23Gross J. Johnson S. Kwo P. Afdhal N. Flamm S. Therneau T. Double-dose peginterferon alfa-2b with weight –based ribavirin improves response for interferon/ ribavirin non-responders with hepatitis C final results of RENEW.Hepatology. 2005; 42 (abstr): A60Google Scholar, 27Poynard T. Schiff E. Terg R. Goncales F. Flamm S. Diago M. Reichen J. Moreno R. Tanno H. et al.Sustained virologic response with PEGinterferon-alfa2b/ ribavirin weight based dosing in previous interferon/ribavirin HCV treatment failures Week 12 virology as a predictor of SVR in the EPIC3 trials.Gastroenterology. 2005; 128 (abstr): A681Google Scholar Whether prolonging treatment to 72 weeks to achieve a longer duration of undetectable HCVRNA in prior nonresponders and relapsers requires further study. Use of the highly sensitive transcription-mediated amplification assay (TMA, Bayer Healthcare LLC, Tarrytown, NY) for HCV RNA detection during treatment has also been proposed as another means of identifying patients at high risk of virologic relapse after discontinuing antiviral therapy.28Morishima C. Morgan T.R. Gretch D.R. Wright E.C. Everhart J.E. HALT-C trial groupUtility of TMA testing during antiviral treatment of advanced hepatitis C.Hepatology. 2005; 42 (abstr): 219AGoogle Scholar, 29Sarrazin C. Teuber G. Kokka R. Rabenau H. Zeuzem S. Detection of residual hepatitis C virus RNA by transcription mediated amplification in patients with complete virologic response according to polymerase chain reaction-based assays.Hepatology. 2000; 32: 818-823Crossref PubMed Scopus (125) Google Scholar In the HALT-C study, week 48 subjects that were TMA + (lld = 10 IU/mL) but PCR negative using the Roche COBAS Amplicor 2.0 assay (lld = 100 IU/mL) had an 89% chance of posttreatment relapse.28Morishima C. Morgan T.R. Gretch D.R. Wright E.C. Everhart J.E. HALT-C trial groupUtility of TMA testing during antiviral treatment of advanced hepatitis C.Hepatology. 2005; 42 (abstr): 219AGoogle Scholar Therefore, TMA testing during or at the end of antiviral treatment may help identify patients that could benefit from extended antiviral treatment. A third study in this issue of Gastroenterology reports on the use of 48 weeks of pegylated IFNα2b 1.5 μg/kg per week and ribavirin 1000 to 1200 mg/day in 141 prior standard IFN and ribavirin nonresponders.30Taliani G. Gemignani G. Aceti A. Bartolozzi D. Blanc P.L. Capanni M. Esperti F. Forte P. Guadagnino V. Mari T. Marino N. Milani S. Pasquazzi C. Rosina F. Tacconi D. Toti M. Zignego A.L. Messerini L. Stroffolini T. Pegylated interferon alfa-2b plus ribavirin in the re-treatment of Interferon-ribavirin non-responder patients.Gastroenterology. 2006; 130: 1098-1106Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Overall, 85% of these Italian patients were genotype 1 or 4 and 22% had histological cirrhosis. Subjects were encouraged to stay on treatment for 48 weeks but therapy was discontinued at week 24 in 60 nonresponders (42%) by the local investigator. The overall SVR rate of 20% was similar to that reported in prior studies.26Shifffman M.L. DiBisceglie A.M. Lindsay K.L. Morishima C. Wright E.C. Everson G.T. Lok A.S. Morgan T.R. Bonkovsky H.L. Lee W.M. Dienstag J.L. Ghany M.G. Goodman Z.D. Everhart J.E. HALT-C trial groupPeginterferon Alfa-2a and ribavirin in patients with chronic hepatitis C who failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 27Poynard T. Schiff E. Terg R. Goncales F. Flamm S. Diago M. Reichen J. Moreno R. Tanno H. et al.Sustained virologic response with PEGinterferon-alfa2b/ ribavirin weight based dosing in previous interferon/ribavirin HCV treatment failures Week 12 virology as a predictor of SVR in the EPIC3 trials.Gastroenterology. 2005; 128 (abstr): A681Google Scholar However, subgroup analyses demonstrated that 12 of the 53 (21%) week 24 PCR + subjects became PCR negative at week 48, and 5 of these patients (10%) achieved SVR. Unfortunately, there were no pretreatment or on-treatment features to identify these late virological responders including medication dose reductions during retreatment. Based upon the study results, the authors suggest that prior IFN and ribavirin nonresponders should be retreated with pegIFN and ribavirin for at least 48 weeks independent of their week-24 virological status. They also speculate that 72 weeks of therapy may be beneficial in selected slow virological responders. Limitations of the Taliani study include its small size and the lack of randomization of treatment duration after 24 weeks in PCR + patients. In addition, since subjects in the EPIC3 and HALT-C trials who remained PCR + at weeks 12 and 20, respectively, were not allowed to continue on treatment for 48 weeks, one cannot corroborate the preliminary findings of Taliani et al. However, 26 of the 109 patients without a week 12 EVR achieved an ETR in the Berg study.21Berg T. Von Wagner M. Hinrichsen H. Sarrazin C. Heintges T. Gerlack T. Buggisch P. Goeser T. Rasenack J. Pape G.R. Schmidt W.E. Kallinowski B. Klinker H. Spengler U. Martus P. Alshuth U. Zeuzem S. Extended treatment duration for hepatitis C virus type 1 comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar But 13 of the 15 subjects (87%) receiving 48 weeks of treatment relapsed after stopping treatment, while only 5 of the 11 subjects (45%) receiving 72 weeks of treatment relapsed.21Berg T. Von Wagner M. Hinrichsen H. Sarrazin C. Heintges T. Gerlack T. Buggisch P. Goeser T. Rasenack J. Pape G.R. Schmidt W.E. Kallinowski B. Klinker H. Spengler U. Martus P. Alshuth U. Zeuzem S. Extended treatment duration for hepatitis C virus type 1 comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar Therefore, these retrospective analyses of patient subgroups suggest a potential role for prolonged antiviral therapy in selected nonresponders with a slow virological response, but confirmatory prospective studies are needed before this approach can be endorsed. The ideal study of prolonged retreatment with pegylated IFN and ribavirin would have stratified randomization for prior nonresponders and relapsers at week 12 or 24 in persistently viremic patients and also incorporate TMA testing. Since the difference in SVR rates may be relatively small with 72 versus 48 weeks of retreatment, a large sample size will likely be required. Currently, the REPEAT study is prospectively comparing the safety and efficacy of 72 versus 48 weeks of high- and low-dose pegIFNα2a and ribavirin in prior pegIFNα2b and ribavirin nonresponders.31Marcellin P. Frelich B. Andreone P. Brandao-Mello C.E. DiBisceglie A. Rai R. Jensen D. Interim safety analysis of patients enrolled in the randomized, international retreatment with pegasys in patients not responding to prior peinterferon alfa-2b/ ribavirin combination therapy (REPEAT) study.Hepatology. 2005; 42 (abstr): ALB04Google Scholar, 32Jensen D.M. Marcellin P. Rationale and design of the REPEAT study a phase III randomized, clinical trial of peginterferon alfa-2a (40kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12 kDa) plus ribavirin.Eur J Gastroenterol Hepatol. 2005; 17: 899-904Crossref PubMed Scopus (26) Google Scholar Week 12 data suggest that the higher dose of pegIFNα2a may lead to a higher rate of early virologic suppression (65% vs 47%), but the study is still ongoing. These preliminary results are consistent with a prior pilot study that suggested that a 12-week high-dose pegIFNα2a induction (ie, 270 μg or 360 μg per week) with ribavirin can lead to a higher SVR than standard dose pegIFNα2a in prior genotype 1 nonresponders.33Diago M. Romero-Gomez M. Crespo J. Olveira A. Perez R. Barcena R. Sanchez-Tapias J.M. Munoz-Sanchez M. Peginterferon alfa-2a (40kD) and ribavirin in patients infected with HCV genotype 1 who failed to respond to interferon and ribavirin final results of the Spanish high-dose induction pilot trial.Hepatology. 2004; 40 (abstr): 389AGoogle Scholar However, antiviral therapy exceeding 48 weeks and high-dose induction with pegylated IFN is not recommended in prior nonresponders and relapsers until the REPEAT study and others are completed and demonstrate an incremental benefit as well as an acceptable safety profile compared with 48 weeks of retreatment. An alternative approach to managing persistently viremic nonresponders who have failed retreatment is to consider maintenance pegylated IFN therapy due to the anti-inflammatory, anti-fibrotic, and anti-carcinogenic properties of IFN.34Shiffman M.L. Hofmann C.M. Contos M.J. Luketic V.A. Sanyal A.J. Sterling R.K. Ferreira-Gonzalez A. Mills A.S. Garret C. A randomized, controlled tiral of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.Gastroenterology. 1999; 117;: 1164-1172Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Three large, randomized controlled trials are underway to determine if prolonged maintenance pegylated IFN may reduce the frequency of disease progression amongst patients with advanced disease at entry compared with no treatment or placebo (ie, HALT-C, EPIC3, Co-PILOT).26Shifffman M.L. DiBisceglie A.M. Lindsay K.L. Morishima C. Wright E.C. Everson G.T. Lok A.S. Morgan T.R. Bonkovsky H.L. Lee W.M. Dienstag J.L. Ghany M.G. Goodman Z.D. Everhart J.E. HALT-C trial groupPeginterferon Alfa-2a and ribavirin in patients with chronic hepatitis C who failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 27Poynard T. Schiff E. Terg R. Goncales F. Flamm S. Diago M. Reichen J. Moreno R. Tanno H. et al.Sustained virologic response with PEGinterferon-alfa2b/ ribavirin weight based dosing in previous interferon/ribavirin HCV treatment failures Week 12 virology as a predictor of SVR in the EPIC3 trials.Gastroenterology. 2005; 128 (abstr): A681Google Scholar, 35Afdhal N. Freilich B. Levine R. Black M. Brown R. Monsour H. O’Brien M. Brass C. Colchicine versus peg-intron long-term trial interim analysis of clinical outcomes at year 2.Hepatology. 2004; 40 (abstr): 239AGoogle Scholar However, until these studies are completed, maintenance pegylated IFN treatment is not recommended for prior nonresponders due to the associated toxicity, costs and uncertain benefit. Other proposed approaches to slow or reduce fibrosis progression in nonresponders include weight loss, phlebotomy, and anti-fibrotic therapy using interferon-γ or interleukin-10.36Hickman I.J. Jonsson J.R. Prins J.B. Ash S. Purdie D.M. Clouston A.D. Powell E.E. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life.Gut. 2004; 53: 413-419Crossref PubMed Scopus (373) Google Scholar, 37Bonkovsky H.L. Iron as a comorbid factor in chronic viral hepatitis.Am J Gastroenterol. 2002; 97: 1-4Crossref PubMed Google Scholar, 38Nelson D.R. Lauwers G.Y. Lau J.Y. Davis G.L. Interleukin-10 treatment reduces fibrosis in patients with chronic hepatitis C a pilot trial of Interferon nonresponders.Gastroenterology. 2000; 118: 655-660Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 39Pockros P.J. Jeffers L. Afdhal N. Goodman Z.D. Nelson D. Gish R. Reddy R.K. Reindollar R. Rodreques-Torres M. Faris-Young S. Sullivan S. Blatt L.M. Final results of a double-blind, placebo controlled trial of the antifibrotic efficacy of IFN Gamma-1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis.Gastroenterology. 2005; 128 (abstr): A715Google Scholar However, none of these investigational approaches have been proven to be safe and/or effective. In summary, our understanding of the optimal means to treat HCV patients with pegylated IFN and ribavirin continues to evolve. Protocols that tailor the duration of treatment suggest that some genotype 2 and 3 patients may be successfully treated with less than 24 weeks of combination treatment, while other genotype 3 patients with high viral load may benefit from 48 weeks of treatment. Optimizing outcomes in the larger group of HCV genotype 1 patients with a high rate of nonresponse to primary treatment remains more problematic. Although the study of Berg et al failed to show a benefit of 72 compared to 48 weeks of antiviral treatment, the TeraViC-4 study, which randomized nonrapid responders at week 4 suggest that a limited subgroup of patients may benefit from extended therapy.21Berg T. Von Wagner M. Hinrichsen H. Sarrazin C. Heintges T. Gerlack T. Buggisch P. Goeser T. Rasenack J. Pape G.R. Schmidt W.E. Kallinowski B. Klinker H. Spengler U. Martus P. Alshuth U. Zeuzem S. Extended treatment duration for hepatitis C virus type 1 comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar, 22Sanchez-Tapias J.M. Diago M. Escartin P. Enrequez J. Moreno R. Romero-Gomez M. Barcena R. Crespo J. Andrade R. Perez R. Testillano M. Planas R. Sola R. Garcia-Bengoechea M. Garcia-Samaniego J. Munoz-Sanchez M. Moreno-Otero R. 21. TeraViC-4 study GroupPeginterferon alfa-2a plus ribavirin for 72 weeks in chronic hepatitis C patients without a response by week 4.Gastroenterology. 2006; (in press).PubMed Google Scholar However, since tolerability may be problematic and efficacy is not established, extended treatment beyond 48 weeks is not currently recommended for treatment naïve genotype 1 patients until additional confirmatory studies using pegylated IFN and full-dose ribavirin are completed. There is a growing consensus that a 48-week course of pegylated IFN and ribavirin is worth considering in selected nonresponders and relapsers based upon their disease severity, prior type, duration, and tolerability of therapy, and other predictors of response.25Fontana R.J. Nonresponders to hepatitis C virus antiviral therapy pegylated interferons and beyond.Gastroenterol Clin N Am. 2004; 33: 527-547Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The interesting preliminary data of Taliani et al and others suggest that there may be a minimal duration of HCV RNA suppression to undetectable levels on PCR-based assays that is associated with sustained viral suppression, but prospective validation studies are needed.20Drusano G.L. Preston S.L. A 48-week duration of therapy with pegylated Interferon a2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype 1 hepatitis C virus.J Infect Dis. 2004; 189: 964-970Crossref PubMed Scopus (79) Google Scholar, 30Taliani G. Gemignani G. Aceti A. Bartolozzi D. Blanc P.L. Capanni M. Esperti F. Forte P. Guadagnino V. Mari T. Marino N. Milani S. Pasquazzi C. Rosina F. Tacconi D. Toti M. Zignego A.L. Messerini L. Stroffolini T. Pegylated interferon alfa-2b plus ribavirin in the re-treatment of Interferon-ribavirin non-responder patients.Gastroenterology. 2006; 130: 1098-1106Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar In addition, utilization of the ultrasensitive TMA assay may further help us identify the optimal duration of treatment to offer individual patients.28Morishima C. Morgan T.R. Gretch D.R. Wright E.C. Everhart J.E. HALT-C trial groupUtility of TMA testing during antiviral treatment of advanced hepatitis C.Hepatology. 2005; 42 (abstr): 219AGoogle Scholar However, until these studies are completed, extending retreatment beyond 48 weeks in prior nonresponders/relapsers remains investigational. Hopefully, newer antiviral agents that suppress HCV RNA replication without development of drug resistance will emerge in the next few years to allow more HCV patients to be treated and improve clinical outcomes. Extended Treatment Duration for Hepatitis C Virus Type 1: Comparing 48 Versus 72 Weeks of Peginterferon-Alfa-2a Plus RibavirinGastroenterologyVol. 130Issue 4PreviewBackground & Aims: The treatment of patients infected with hepatitis C virus (HCV) type 1 remains a challenge necessitating innovative strategies to improve treatment outcome. The extension of treatment duration beyond 48 weeks is one possible strategy to address this problem. Methods: The efficacy and safety of 48 weeks (group A, N = 230) vs 72 weeks (group B, N = 225) of treatment with pegylated–interferon-alfa-2a (180 μg/wk) plus ribavirin (800 mg/day) were studied in treatment-naive patients with HCV type 1 infection. Full-Text PDF Pegylated Interferon Alfa-2b Plus Ribavirin in the Retreatment of Interferon-Ribavirin Nonresponder PatientsGastroenterologyVol. 130Issue 4PreviewBackground & Aims: Inadequate data are available about retreatment of nonresponders to interferon (IFN) and ribavirin. Thus, this study evaluated the efficacy and tolerability of a 48-week therapy with pegylated IFN-α-2b plus high-dose ribavirin in patients who have failed to respond to the combination. Treatment up to 48 weeks also in patients who have failed to clear hepatitis C virus (HCV) RNA by week 24 was also evaluated. Methods: One hundred forty-one patients who previously did not respond to IFN and ribavirin, 86% with genotype 1 or 4 infection, 52% with high viral load (>800.000 IU/mL), 22% with cirrhosis, were retreated with pegylated IFN-α-2b 1.5 μg/kg per week and ribavirin 1000–1200 mg/day for 48 weeks and followed up for 24 weeks. Full-Text PDF