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Treatment Options for Patients With Chronic Hepatitis C Not Responding to Initial Antiviral Therapy

  • Ira M. Jacobson
    Correspondence
    Reprint requests Address requests for reprints to: Ira M. Jacobson, MD, Weill Cornell Medical College, 1305 York Avenue, New York, New York 10021; fax: (646) 962-0355
    Affiliations
    Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, New York
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Published:April 13, 2009DOI:https://doi.org/10.1016/j.cgh.2009.03.033
      Pegylated interferon alfa-2a or alfa-2b plus ribavirin for 24 or 48 weeks, depending on genotype, is the standard of care for patients with chronic hepatitis C. However, up to 50% of patients are nonresponsive or experience relapse after treatment ends. Consequently, effective retreatment approaches for this population are urgently needed. Retreatment strategies aimed at viral eradication have included retreatment with the same or higher doses of the first pegylated interferon alfa used plus the same or higher doses of ribavirin, switching from one pegylated interferon alfa to the other, increasing the duration of therapy, or using other interferon formulations. Recent studies have demonstrated that sustained virologic response can be attained in 10% to 20% of patients retreated with pegylated interferon alfa plus ribavirin after previous nonresponse to standard interferon plus ribavirin and in 6% to 8% of prior nonresponders to pegylated interferon plus ribavirin retreated for 48 weeks. Extending the duration of retreatment to 72 weeks increases sustained virologic response rates. Prior relapsers to interferon-based therapy have higher rates of sustained virologic response with retreatment than prior nonresponders. Three large multicenter studies evaluating the capacity of long-term, low-dose, maintenance interferon-based therapy to delay or halt disease progression have been conducted, demonstrating no significant impact on overall clinical outcomes in the intent-to-treat analyses. Finally, specifically targeted antiviral therapies for hepatitis C have shown promising results in preclinical and early-stage clinical trials when combined with pegylated interferon alfa plus ribavirin. Novel approaches, including combinations of direct antiviral agents, are needed to achieve major improvements in the treatment of nonresponders.

      Abbreviations used in this paper:

      Alb-IFN (albinterferon), CIFN (consensus interferon), DIRECT (Daily-Dose Consensus Interferon and RBV: Efficacy of Combined Therapy), EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), FDA (Food and Drug Administration), G1 (genotype 1), G2 (genotype 2), G3 (genotype 3), HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), IFN (interferon), PEG-IFN (pegylated interferon), RBV (ribavirin), SVR (sustained virologic response), STAT-C (specifically targeted antiviral therapies for hepatitis C), COPILOT (Colchicine versus PegIntron Long-term)
      Approximately 3–4 million persons in the United States and 170 million worldwide are infected with the hepatitis C virus (HCV),
      • Dienstag J.L.
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      and nearly 80% of new infections progress to chronic infection, which is a major cause of chronic liver disease.
      World Health Organization
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      Rising incidence of hepatocellular carcinoma in the United States.
      Hepatocellular carcinoma (HCC) develops in 1% to 5% of chronically infected persons over a 10- to 20-year period and has an annual incidence of 1% to 4% once cirrhosis is present.
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      Hepatitis C. World Health Organization, 2000 October.
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      The morbidity and mortality associated with chronic hepatitis C are projected to increase dramatically between 2010 and 2019, resulting in 165,900 deaths from chronic liver disease, 27,200 deaths from HCC, and $10.7 billion in direct medical expenditures.
      • Dienstag J.L.
      • McHutchison J.G.
      American Gastroenterological Association technical review on the management of hepatitis C.
      Treatment approaches to chronic hepatitis C have advanced substantially in the past decade. The standard of care for patients with chronic hepatitis C is pegylated interferon (PEG-IFN) alfa-2a 180 μg/wk plus ribavirin (RBV) 1000–1200 mg/d or PEG-IFN alfa-2b 1.5 μg/kg/wk plus weight-based RBV (800–1400 mg/d) for 24 or 48 weeks, depending on factors such as HCV genotype and baseline viral load.
      • Strader D.B.
      • Wright T.
      • Thomas D.L.
      • Seeff L.B.
      Diagnosis, management, and treatment of hepatitis C.
      Despite substantial improvements in antiviral therapy, the overall sustained virologic response (SVR) rate after treatment with PEG-IFN alfa plus RBV is only 50% to 55%. Factors associated with nonresponsiveness include genotype 1 (G1) infection, African American ethnicity, high baseline viral load, and cirrhosis.
      • Hadziyannis S.J.
      • Sette Jr, H.
      • Morgan T.R.
      • et al.
      Peginterferon-a2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
      • Jacobson I.M.
      • Brown Jr, R.S.
      • Freilich B.
      • et al.
      Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.
      • Zeuzem S.
      • Hultcrantz R.
      • Bourliere M.
      • et al.
      Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3.
      Those who do not attain SVR are either nonresponders (never attained undetectable HCV RNA during treatment) or relapsers (attained undetectable HCV RNA at end of treatment but regained detectable HCV RNA after treatment). Relapse occurs in 20% to 30% of patients with G1 infection
      • Jacobson I.M.
      • Brown Jr, R.S.
      • Freilich B.
      • et al.
      Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.
      • Manns 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.
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      and in a smaller proportion of patients with genotype 2 (G2) or genotype 3 (G3) infection. A small proportion of patients have viral breakthrough, defined as the reappearance of HCV RNA while still on therapy after it had become undetectable.
      Nonresponders can be categorized as not initially responding to (1) conventional interferon (IFN) alfa monotherapy, (2) conventional IFN alfa plus RBV therapy, and (3) PEG-IFN alfa plus RBV therapy. Retreatment options for patients in whom initial treatment with PEG-IFN alfa plus RBV fails remain limited. Results of several important trials in this patient population have been reported recently, and there is an expanded indication for the use of PEG-IFN alfa-2b in patients with prior treatment failure in both the European Union and the United States.

      FDA approves an expanded indication for peginterferon-based combination therapy for patients with chronic hepatitis C [press release]. Kenilworth, NJ: Schering-Plough Corporation; March 11, 2009. http://www.schering-plough.com/news/news_article.aspx?reqid=1265325. Accessed July 7, 2009.

      In this review, we will trace the evolution of the approach to treatment of nonresponders and highlight lessons learned that are applicable to this population. Data from some studies have been derived from conference materials, abstracts, posters, and slide presentations and should be considered with due caution.

      Nonresponse to Conventional Interferon Alfa Monotherapy

      Meta-analyses suggest that 13% to 16% of patients who were nonresponsive to previous conventional IFN monotherapy attain SVR when retreated with conventional IFN plus RBV.
      • Cheng S.J.
      • Bonis P.A.L.
      • Lau J.
      • et al.
      Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials.
      • Camma C.
      • Bruno S.
      • Schepis F.
      • et al.
      Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data.
      • Cummings K.J.
      • Lee S.M.
      • West E.S.
      • et al.
      Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: a meta-analysis of randomized trials.
      Although 2 analyses
      • Cheng S.J.
      • Bonis P.A.L.
      • Lau J.
      • et al.
      Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials.
      • Camma C.
      • Bruno S.
      • Schepis F.
      • et al.
      Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data.
      were exclusively of nonresponders, a third included studies of nonresponders and relapsers
      • Cummings K.J.
      • Lee S.M.
      • West E.S.
      • et al.
      Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: a meta-analysis of randomized trials.
      and reported that retreatment with IFN alfa plus RBV was significantly more effective than a repeat course of IFN alfa monotherapy. Pooled response rates (nonresponders and relapsers) were 14% with IFN alfa plus RBV and 2% with IFN alfa monotherapy, with an overall risk difference favoring combination therapy over monotherapy of 7% (95% CI, 2%–13%; P = .01).
      Additional improvements in retreatment outcomes were realized with the introduction of PEG-IFN alfa plus RBV combination therapy (Table 1).
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      • Heathcote E.J.L.
      • Keeffe E.B.
      • Lee S.S.
      • et al.
      Re-treatment of chronic hepatitis C with consensus interferon.
      As expected, SVR rates varied according to whether the study population included IFN alfa monotherapy nonresponders, relapsers, or both. SVR rates were lowest (21%–28%) among nonresponders to monotherapy
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      and highest (52.2%) among relapsers.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      For additional details, see Relapse After Conventional IFN Therapy. SVR rates among mixed populations of nonresponders and relapsers yielded intermediate SVR rates ranging from 28% to 35%.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      Table 1Clinical Trials of Retreatment in Patients With Chronic Hepatitis C Who Did Not Respond to Conventional IFN Monotherapy
      StudyTreatment regimenNStudy designDuration, wkSVR, %
      Bocher et al
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      CIFN 27 μg/d for 2 wk, then 18 μg/d for 10 wk, then 9 μg/d for 12 wk, then 9 μg 3×/wk for 24 wk + RBV 800 mg/d from wk 3 to 4818Prospective, randomized4817
      CIFN 18 μg 3×/wk for 24 wk, then 9 μg 3×/wk for 24 wk + RBV 800 mg/d for all 48 wk104840
      Cornberg et al
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      CIFN 18 μg/d for 8 wk, then 9 μg/d for 40 wk + RBV 1000–1200 mg/d, or CIFN 9 μg/d for 48 wk + RBV36Open-label, randomized4839
      Jacobson et al
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (800 mg/d) or PEG-IFN alfa-2b (1.0 μg/kg/wk) + RBV (1000–1200 mg/d)47Prospective, randomized4821
      Krawitt et al
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      PEG-IFN alfa-2b (100–150 μg/wk) + RBV (1000 mg/d)22Prospective open-label4827
      Sherman et al
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      PEG-IFN alfa-2a (180 μg/wk) + RBV (800 mg/d)45Open-label, noncontrolled, multicenter24 or 4827
      Shiffman et al
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      ,
      Preliminary analysis of data from HALT-C, including the first 604 patients enrolled, 219 of whom had previously received IFN monotherapy.
      PEG-IFN alfa-2a (180 μg/wk) + RBV (1000–1200 mg/d)219Prospective, randomized, controlled4828
      Heathcote et al
      • Heathcote E.J.L.
      • Keeffe E.B.
      • Lee S.S.
      • et al.
      Re-treatment of chronic hepatitis C with consensus interferon.
      CIFN 15 μg 3×/wk46Open-label, randomized, multicenter247
      CIFN 15 μg 3×/wk354814
      a Preliminary analysis of data from HALT-C, including the first 604 patients enrolled, 219 of whom had previously received IFN monotherapy.
      A large body of data on response to PEG-IFN alfa plus RBV in nonresponders to previous treatment with IFN monotherapy derives from Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C), a multicenter, randomized, controlled trial designed to determine whether long-term PEG-IFN alfa treatment prevents the progression of liver disease, HCC, or both, or reduces the need for liver transplantation.
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      A total of 1145 patients who were nonresponsive to at least 12 weeks of conventional IFN alfa-based therapy (with or without RBV) were enrolled in the lead-in phase and were retreated with PEG-IFN alfa-2a (180 μg/wk) plus RBV (1000–1200 mg/d) for 20 weeks.
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      Patients with undetectable (<50 IU/mL) HCV RNA at 20 weeks of treatment continued treatment for up to 48 weeks. Patients with detectable HCV RNA at week 20 entered the maintenance phase of the trial (see Maintenance Therapy Trials). An early analysis of this study, which included only the first 604 enrolled patients, reported SVR rates for those patients who previously did not respond to IFN monotherapy (n = 219).
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      In this cohort of patients, end-of-treatment response was attained by 44% and SVR by 28%.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      In trials using consensus IFN (CIFN) to retreat patients who were nonresponsive to treatment with conventional IFN alfa monotherapy, SVR rates ranged from 13% to 40%.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      • Heathcote E.J.L.
      • Keeffe E.B.
      • Lee S.S.
      • et al.
      Re-treatment of chronic hepatitis C with consensus interferon.
      Heathcote et al
      • Heathcote E.J.L.
      • Keeffe E.B.
      • Lee S.S.
      • et al.
      Re-treatment of chronic hepatitis C with consensus interferon.
      reported an SVR rate of 13% among nonresponders to IFN alfa-2b 3 MU or CIFN 9 µg three times weekly who received retreatment with CIFN 15 µg three times weekly for 48 weeks, and it was on the basis of these findings that CIFN was the first agent to receive Food and Drug Administration (FDA) approval for the retreatment of nonresponders in 1997, before the introduction of PEG-IFN alfa. More recent studies have evaluated a combination of CIFN plus RBV in nonresponders. In a randomized, open-label pilot study, Cornberg et al
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      investigated the effects of induction CIFN plus RBV therapy in patients who were nonresponsive to conventional IFN alfa monotherapy (Table 2).
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      • Moucari R.
      • Ripault M.-P.
      • Oules V.
      • et al.
      High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy.
      • Basso M.
      • Torre F.
      • Grasso A.
      • et al.
      Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients.
      • Goncales Jr, F.L.
      • Vigani A.
      • Goncales N.
      • et al.
      Weight-based combination therapy with peginterferon a-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C.
      • Parise E.
      • Cheinquer H.
      • Crespo D.
      • et al.
      Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy.
      • Taliani G.
      • Gemignani G.
      • Ferrari C.
      • et al.
      Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients.
      • Gross J.
      • Johnson S.
      • Kwo P.
      • et al.
      Double-dose peginterferon alpha-2b with weight-based ribavirin improves response for interferon/ribavirin nonresponders with hepatitis C: final results of “RENEW.”.
      SVR was attained by 14 of 36 patients (39%). Induction dosing resulted in a greater first-phase rate of HCV RNA decay; however, this increased rate did not translate to better SVR rates, possibly because more patients in this group experienced dose modifications.
      Table 2Clinical Trials of Retreatment in Patients With Chronic Hepatitis C Who Did Not Respond to Conventional IFN Plus RBV Combination Therapy
      StudyTreatment regimenNStudy designDuration, wkSVR, %
      Bocher et al
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      CIFN 27 μg/d for 2 wk, then 18 μg/d for 10 wk, then 9 μg/d for 12 wk, then 9 μg 3×/wk for 24 wk + RBV 800 mg/d from wk 3 to 4820Prospective, randomized4835
      18 μg 3×/wk for 24 wk, then 9 μg 3×/wk for 24 wk + RBV 800 mg/d for all 48 wk214819
      Cornberg et al
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      CIFN 18 μg/d for 8 wk, then 9 μg/d for 40 wk + RBV 1000–1200 mg/d, or CIFN 9 μg/d for 48 wk + RBV41Open-label, randomized4822
      Gonçales et al
      • Goncales Jr, F.L.
      • Vigani A.
      • Goncales N.
      • et al.
      Weight-based combination therapy with peginterferon a-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (800–1200 mg/d)40Open-label, prospective, multicenter4838
      Jacobson et al
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (800 mg/d) or PEG-IFN alfa-2b (1.0 μg/kg/wk) + RBV (1000–1200 mg/d)219Prospective, randomized488
      Krawitt et al
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      PEG-IFN alfa-2b (100–150 μg /wk) + RBV (1000 mg/d)94Prospective, open-label4818
      Moucari et al
      • Moucari R.
      • Ripault M.-P.
      • Oules V.
      • et al.
      High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (1000–1200 mg/d)101Unselected consecutive patients4813
      Parise et al
      • Parise E.
      • Cheinquer H.
      • Crespo D.
      • et al.
      Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy.
      PEG-IFN alfa-2a (180 μg/wk) + RBV (800 mg/d)97Open-label, nonrandomized4826
      Sherman et al
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      PEG-IFN alfa-2a (180 μg/wk) + RBV (800 mg/d)167Open-label, noncontrolled, multicenter24 or 4822
      Shiffman et al
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      ,
      Preliminary analysis of data from HALT-C, including the first 604 patients enrolled, 385 of whom had previously received IFN + RBV.
      PEG-IFN alfa-2a (180 μg/wk) + RBV (1000–1200 mg/d)385Prospective, randomized, controlled4812
      Taliani et al
      • Taliani G.
      • Gemignani G.
      • Ferrari C.
      • et al.
      Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (1000–1200 mg/d)140Multicenter4820
      Gross et al
      • Gross J.
      • Johnson S.
      • Kwo P.
      • et al.
      Double-dose peginterferon alpha-2b with weight-based ribavirin improves response for interferon/ribavirin nonresponders with hepatitis C: final results of “RENEW.”.
      PEG-IFN alfa-2b (1.5 μg/kg/wk) + RBV (800–1400 mg/d)352Multicenter4812
      PEG-IFN alfa-2b (3.0 μg/kg/wk) + RBV (800–1400 mg/d)352Multicenter4817
      a Preliminary analysis of data from HALT-C, including the first 604 patients enrolled, 385 of whom had previously received IFN + RBV.

      Nonresponse to Conventional IFN Alfa Plus RBV

      Clinical trials of PEG-IFN alfa plus RBV in patients who were nonresponsive to previous IFN alfa plus RBV are summarized in Table 2.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      • Krawitt E.L.
      • Ashikaga T.
      • Gordon S.R.
      • et al.
      Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      • Moucari R.
      • Ripault M.-P.
      • Oules V.
      • et al.
      High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy.
      • Basso M.
      • Torre F.
      • Grasso A.
      • et al.
      Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients.
      • Goncales Jr, F.L.
      • Vigani A.
      • Goncales N.
      • et al.
      Weight-based combination therapy with peginterferon a-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C.
      • Parise E.
      • Cheinquer H.
      • Crespo D.
      • et al.
      Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy.
      • Taliani G.
      • Gemignani G.
      • Ferrari C.
      • et al.
      Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients.
      • Gross J.
      • Johnson S.
      • Kwo P.
      • et al.
      Double-dose peginterferon alpha-2b with weight-based ribavirin improves response for interferon/ribavirin nonresponders with hepatitis C: final results of “RENEW.”.
      SVR rates ranged from 8% to 35% and were generally lower than those attained in patients nonresponsive to IFN alfa monotherapy. For example, in a study by Jacobson et al,
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      17 of 219 patients (8%) who were nonresponsive to IFN alfa plus RBV attained SVR after retreatment with PEG-IFN alfa-2b (1.0 or 1.5 μg/kg/wk) plus RBV (1000–1200 or 800 mg/d). The likelihood of SVR was more than 4 times greater among patients who had HCV RNA levels <100,000 copies/mL than those who had higher viral levels at the end of a previous course of IFN alfa plus RBV (21% vs 5%; P = .002). This observation underscores the importance of considering the degree of response to previous therapy when planning retreatment with IFN alfa-based regimens.
      Results from the early analysis of the HALT-C trial (which included only the first 604 patients enrolled) revealed that among the 385 nonresponders to IFN plus ribavirin, the end-of-treatment response rate was 25% and the SVR rate was 12%.
      • Shiffman M.L.
      • Di Bisceglie A.M.
      • Lindsay K.L.
      • et al.
      Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.
      In this analysis, factors associated with SVR included infection with HCV G2 or G3, baseline HCV RNA level <1.5 × 106 IU/mL, and absence of cirrhosis. A later report from HALT-C described the impact of PEG-IFN alfa and ribavirin dose reductions on SVR.
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      In patients who received their full allocated dose of ribavirin during the first 20 weeks, SVR was 17% in those who also received their full dose of PEG-IFN alfa but only 7% in those who received ≤60% of their PEG-IFN alfa dose. In contrast, among patients who received the full dose of PEG-IFN alfa, reductions in ribavirin dosing during the first 20 weeks of therapy, even to cumulative doses of ≤60%, had little effect on treatment outcome. Discontinuation of ribavirin during the first 20 weeks, however, resulted in SVR rates of 6% or less, even among patients who remained fully compliant with their PEG-IFN alfa dosing (SVR rate, 4%).
      • Shiffman M.L.
      • Ghany M.G.
      • Morgan T.R.
      • et al.
      Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.
      The Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC3) clinical trial is the largest study to evaluate the retreatment of chronic hepatitis C patients with significant fibrosis or cirrhosis who were nonresponsive to at least 12 weeks of therapy with any IFN alfa plus RBV combination therapy, composed of conventional IFN alfa and PEG-IFN alfa.
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      Like the HALT-C trial, EPIC3 was designed predominantly as a long-term maintenance trial. However, in the first part of this 3-part program, patients who had failed treatment with prior IFN alfa-based therapy were retreated with PEG-IFN alfa-2b and RBV. Of the 2312 evaluable patients, 61% were nonresponders, 28% were relapsers and 11% were treatment failures (patients with inadequate virology documentation to accurately categorize as a nonresponder or relapser) to previous combination therapy with either standard or pegylated interferon plus ribavirin.
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      Patients with undetectable HCV RNA by week 12 were retreated with PEG-IFN alfa-2b (1.5 μg/kg/wk) plus weight-based RBV (800–1400 mg/d, according to body weight) for up to 48 weeks. Overall, SVR was attained by 22% of patients, with rates higher among relapsers than nonresponders (38% vs 14%). In patients who had previously failed to attain SVR after standard IFN and RBV, SVR with retreatment was attained in 25% (18% of prior nonresponders and 43% of prior relapsers). Among patients with undetectable HCV RNA at week 12 (n = 821), the SVR rate was 56%, but no patient with HCV RNA above 750 IU/mL at week 12 attained SVR.
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      These data imply a more stringent requirement for continuation of full-dose therapy in previous nonresponders than the 2 log10 reduction by week 12 required in treatment-naive patients. Genotype, degree of fibrosis, baseline viral load, previous treatment, and previous response were identified as important predictors of treatment outcome (Table 3).
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      Table 3Sustained Virologic Response Rates From EPIC
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      Previous therapy
      IFN-alfa plus RBV, % (n/N)PEG-IFN alfa plus RBV, % (n/N)
      SVR according to previous response
      Relapser
       G132 (67/208)23 (56/243)
       G2/367 (54/81)57 (52/92)
      Nonresponder
       G113 (98/761)4 (19/431)
       G2/349 (53/109)36 (10/28)
      Treatment failure
       G116 (27/166)10 (3/30)
       G2/364 (32/50)29 (2/7)
      SVR according to METAVIR score
      F2
       G124 (79/328)16 (31/196)
       G2/373 (53/73)55 (16/29)
      F3
       G119 (63/339)10 (19/188)
       G2/354 (39/72)55 (22/40)
      F4
       G111 (50/466)9 (28/320)
       G2/350 (47/95)45 (26/58)
      SVR according to baseline viral load
      > 600,000 IU/mL20 (170/864)12 (69/573)
      ≤ 600,000 IU/mL32 (178/557)27 (78/288)
      NOTE. All patients were previous nonresponders or relapsers receiving PEG-IFN alfa-2b (1.5 μg/kg/wk) plus weight-based RBV (800–1400 mg/d).
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      In trials investigating retreatment of patients who had not responded to IFN alfa plus RBV combination therapy, daily CIFN plus RBV produced SVR rates of 22% and 35%.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      An SVR rate of 35% was reported by Bocher et al
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      using an induction regimen of CIFN in combination with ribavirin (Table 2). Although SVR rates were favorable with this regimen, the incidence of safety events was elevated: 27% of patients required dose modification (primarily because of cytopenias) compared with only 5% of patients who received the standard noninduction treatment.
      • Bocher W.O.
      • Schuchmann M.
      • Link R.
      • et al.
      Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-a therapy.
      Similarly, Cornberg et al
      • Cornberg M.
      • Hadem J.
      • Herrmann E.
      • et al.
      Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study.
      reported that a different induction regimen of CIFN (Table 2) was also associated with an unfavorable tolerability profile during the early stage of treatment. In total, 49% of patients receiving the induction therapy regimen in this study required a reduction in CIFN dose, primarily because of cytopenias. Overall, induction regimens using CIFN have so far been met with limited success because of the difficulties in establishing an appropriate balance between optimized SVR while retaining an acceptable tolerability profile.

      Relapse After Conventional IFN Alfa Monotherapy or IFN Plus Ribavirin Combination Therapy

      In general, SVR rates are higher among relapsers than nonresponders after retreatment. Davis et al
      • Davis G.L.
      • Esteban-Mur R.
      • Rustgi V.
      • et al.
      Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C.
      reported SVR rates of 49% and 5%, respectively, after retreatment of patients who experienced relapses after IFN monotherapy with IFN plus RBV or with a repeat course of IFN monotherapy (P < .001). Saracco et al
      • Saracco G.
      • Olivero A.
      • Ciancio A.
      • et al.
      A randomized 4-arm multicenter study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C relapsing after interferon monotherapy.
      reported slightly lower SVR rates (33%–39%) when patients who experienced relapses after IFN monotherapy were retreated with IFN alfa plus RBV.
      Additional studies examined the use of PEG-IFN alfa plus RBV to treat patients who experienced relapse after IFN alfa-based therapy. The highest SVR rates were attained when IFN monotherapy relapsers were retreated with PEG-IFN alfa plus RBV (G1, 47%; G2/3, 63%).
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      By contrast, SVR rates ranged between 38% and 45% for IFN alfa plus RBV relapsers who were retreated with PEG-IFN alfa plus RBV.
      • Sherman M.
      • Yoshida E.M.
      • Deschenes M.
      • et al.
      Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.
      • Jacobson I.M.
      • Gonzalez S.A.
      • Ahmed F.
      • et al.
      A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.
      • Basso M.
      • Torre F.
      • Grasso A.
      • et al.
      Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients.

      Nonresponse/Relapse to PEG-IFN Alfa-Based Therapy

      Available clinical data on alternative treatment regimens are summarized in Table 4.
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Pegylated interferon alfa-2a (40KD) plus ribavirin (RBV) in prior non-responders to pegylated interferon alfa-2b (12KD)/RBV: final efficacy and safety outcomes of the REPEAT study.
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon alfa-2b.
      • Rustgi V.K.
      • Esposito S.
      • Hamzeh F.M.
      • et al.
      Safety and tolerability of peginterferon alpha-2a/ribavirin in HCV patients non-tolerant or nonresponsive to peginterferon alpha-2b/ribavirin.
      • Kaiser S.
      • Hass H.
      • Gregor M.
      Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy.
      • Leevy C.B.
      Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.
      • Kaiser S.
      • Hass H.
      • Lutze B.
      • et al.
      Comparison of daily consensus interferon versus peginterferon alfa 2a extended therapy of 72 weeks for peginterferon/ribavirin relapse patients with chronic hepatitis C.
      • Bacon B.R.
      • Shiffman M.L.
      • Mendes F.
      • et al.
      Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
      Most clinical trial approaches—retreating patients with the same PEG-IFN alfa at the same or a higher dose of PEG-IFN alfa and/or RBV, switching from one PEG-IFN alfa to the other, and using CIFN-based therapy—have a goal of viral eradication, whereas other approaches, such as low-dose, maintenance IFN alfa–based therapy, aim to delay or halt disease progression.
      Table 4Clinical Trials of Repeat Antiviral Treatment in Patients With HCV Who Did Not Respond to PEG-IFN Alfa Plus RBV Combination Therapy
      StudyTreatment regimenDuration, wkStudy designVirologic response, %
      Bacon et al
      • Bacon B.R.
      • Shiffman M.L.
      • Mendes F.
      • et al.
      Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
      N = 487
      CIFN (9 μg/d) + RBV (1000–1200 mg/d)48Open-label, multicenterEOT, 15: SVR, 7
      CIFN (15 μg/d) + RBV (1000–1200 mg/d)48EOT, 19; SVR, 11
      Kaiser et al
      • Kaiser S.
      • Hass H.
      • Gregor M.
      Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy.
      N = 60
      Data were not fully published but were derived from abstract, poster, or slide presentations.
      CIFN 27 μg/d for 4 wk, then 18 μg/d for 12 wk, then 9 μg/d + weight-based RBV48–72
      Treatment was continued to ensure a minimum on-treatment period of undetectable HCV RNA of 48 weeks.
      Not statedEOT, 50; SVR, 27
      CIFN 9 μg/d alone for 16 wk, then combined with weight-based RBV48–72
      Treatment was continued to ensure a minimum on-treatment period of undetectable HCV RNA of 48 weeks.
      EOT, 43; SVR, 23
      Kaiser et al
      • Kaiser S.
      • Hass H.
      • Lutze B.
      • et al.
      Comparison of daily consensus interferon versus peginterferon alfa 2a extended therapy of 72 weeks for peginterferon/ribavirin relapse patients with chronic hepatitis C.
      N = 81
      Data were not fully published but were derived from abstract, poster, or slide presentations.
      ,
      All patients were previous relapsers to 48 weeks of treatment with PEG-IFN alfa plus RBV.
      CIFN 9 μg/d + weight-based RBV
      RBV dose not specified.
      72Not statedSVR, 69
      PEG-IFN alfa-2a 180 μg/wk + weight-based RBV
      RBV dose not specified.
      SVR, 44
      Leevy et al
      • Leevy C.B.
      Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.
      N = 137
      CIFN (15 μg/d) + RBV (1000–1200 mg/d) for 12 wk, then CIFN (15 μg 3×/wk) + RBV (1000–1200 mg/d) for 36 wk48RetrospectiveSVR, 37
      Jensen et al
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Pegylated interferon alfa-2a (40KD) plus ribavirin (RBV) in prior non-responders to pegylated interferon alfa-2b (12KD)/RBV: final efficacy and safety outcomes of the REPEAT study.
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon alfa-2b.
      N = 942
      Data were not fully published but were derived from abstract, poster, or slide presentations.
      PEG-IFN alfa-2a 360 μg/wk × 12 wk, then 180 μg/wk × 60 wk + RBV (1000–1200 mg/d)72International, multicenter, randomizedSVR, 16
      P = .006 vs PEG-IFN alfa-2a 180 μg/wk for 48 weeks.
      PEG-IFN alfa-2a 360 μg/wk × 12 wk, then 180 μg/wk × 36 wk + RBV (1000–1200 mg/d)48SVR, 7
      PEG-IFN alfa-2a 180 μg/wk × 72 wk + RBV (1000–1200 mg/d)72SVR, 14
      PEG-IFN alfa-2a 180 μg/wk × 48 wk + RBV (1000–1200 mg/d)48SVR, 9
      Rustgi et al
      • Rustgi V.K.
      • Esposito S.
      • Hamzeh F.M.
      • et al.
      Safety and tolerability of peginterferon alpha-2a/ribavirin in HCV patients non-tolerant or nonresponsive to peginterferon alpha-2b/ribavirin.
      N = 57
      Data were not fully published but were derived from abstract, poster, or slide presentations.
      PEG-IFN alfa-2a + RBV (no doses given)12Open-label, multicenterSVR, 56 (previous nontolerant patients); 3 (previous NRs)
      Nelson et al
      • McHutchison J.G.
      • Bartenschlager R.
      • Patel K.
      • Pawlotsky J.-M.
      The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice.
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.
      N = 115
      Alb-IFN (900 μg 2×/wk) + RBV (1000–1200 mg/d)48Open-label, multicenter, dose-ranging30
      Alb-IFN (1200 μg 2×/wk) + RBV (1000–1200 mg/d)4813
      Alb-IFN (1200 μg 4×/wk) + RBV (1000–1200 mg/d)4825
      Alb-IFN (1500 μg 2×/wk) + RBV (1000–1200 mg/d)489
      Alb-IFN (1800 μg 2×/wk) + RBV (1000–1200 mg/d)489
      EOT, end of treatment; NR, nonresponder.
      a Data were not fully published but were derived from abstract, poster, or slide presentations.
      b Treatment was continued to ensure a minimum on-treatment period of undetectable HCV RNA of 48 weeks.
      c All patients were previous relapsers to 48 weeks of treatment with PEG-IFN alfa plus RBV.
      d RBV dose not specified.
      e P = .006 vs PEG-IFN alfa-2a 180 μg/wk for 48 weeks.

      Viral Eradication Trials

       Retreatment With PEG-IFN Alfa

      PEG-IFN alfa-2a and PEG-IFN alfa-2b have different pharmacokinetic and pharmacodynamic profiles. One hypothesis is that patients who do not respond to one of these agents may respond to the other.
      In a study of re-treatment of patients who failed to respond to peginterferon alfa-2b (REPEAT), the use of an expanded PEG-IFN alfa-2a–based regimen (based on an induction dose of PEG-IFN alfa-2a [360 μg/wk for the first 12 weeks] and/or increased treatment duration [72 weeks]; Table 4) was examined in nonresponders to PEG-IFN alfa-2b plus RBV.
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Pegylated interferon alfa-2a (40KD) plus ribavirin (RBV) in prior non-responders to pegylated interferon alfa-2b (12KD)/RBV: final efficacy and safety outcomes of the REPEAT study.
      • Jensen D.M.
      • Freilich B.
      • Andreone P.
      • et al.
      Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon alfa-2b.
      No PEG-IFN alfa-2b control group was included. More than 90% of patients in this study were infected with HCV G1; mean age was approximately 48 to 49 years, 88% to 90% were white, and 25% to 30% had bridging fibrosis or cirrhosis. Overall SVR rates were significantly higher in arm A (induction therapy and total duration 72 weeks) than arm D (standard therapy for 48 weeks) (16% vs 9%; P = .006; Figure 1). When the 2 induction arms were pooled and compared with the noninduction arms, SVR rates were 13% and 10% (P = .92), whereas a comparison between the 72-week and the 48-week groups yielded SVR rates of 16% and 8% (P < .001). Thus, extension of therapy significantly improved treatment outcome, whereas induction therapy alone had no effect. Consistent with previous nonresponder studies in which relapse rates were generally higher than those reported in treatment-naive patients, relapse rates in all 4 treatment arms of REPEAT were 49% to 78% (Figure 1). The principle that extended treatment duration reduces relapse rates in nonresponders is an important one and may prove relevant as trials evaluating novel antiviral agents are developed for this important patient population. Additional analyses of the data from REPEAT have revealed that undetectable HCV RNA at week 12 of therapy is a strong predictor of SVR, regardless of baseline characteristics, and also that response to initial treatment with PEG-IFN alfa-2b accurately predicts response during retreatment with PEG-IFN alfa-2a.
      • Marcellin P.
      • Freilich B.
      • Andreone P.
      • et al.
      HCV-RNA status at week 12 of treatment with peginterferon alfa-2a/RBV predicts SVR in patients with prior non-response to pegylated interferon alfa-2b/RBV: results from REPEAT study.
      • Marcellin P.
      • Freilich B.
      • Andreone P.
      • et al.
      Type of response to prior pegylated interferon alfa-2b (12KD)/RBV predicts subsequent response to retreatment with peginterferon alfa-2a (40KD)/RBV.
      Figure thumbnail gr1
      Figure 1Retreatment of PEG-IFN alfa-2b nonresponders with PEG-IFN alfa-2a in the REPEAT study.
      • Saracco G.
      • Olivero A.
      • Ciancio A.
      • et al.
      A randomized 4-arm multicenter study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C relapsing after interferon monotherapy.
      All patients also received RBV (1000–1200 mg/d).
      The EPIC3 trial efficacy analysis was based on 2293 patients who failed treatment with prior combination therapy, including 375 patients who failed previous treatment with PEG-IFN alfa-2a plus RBV and 488 patients who failed previous treatment with PEG-IFN alfa-2b plus RBV. Among prior nonresponders, patients previously treated with IFN alfa plus RBV had an SVR rate of 18% compared with 6% of those previously treated with PEG-IFN alfa plus RBV. The SVR rates in prior relapsers were 43% and 33%, respectively (Table 3).
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      SVR rates were similar in prior recipients of PEG-IFN alfa-2a and PEG-IFN alfa-2b. Predictors of response included G2 and G3, lesser stages of fibrosis, and low baseline viral load (<600,000 IU/mL). Overall, 56% of patients with undetectable HCV RNA at week 12 had SVR. In patients with HCV RNA undetectability at week 12, previous therapy (IFN versus PEG-IFN) and previous response (relapse versus nonresponse) were no longer significant predictors of response. Of 188 patients with ≥2 log reduction in HCV RNA but with residual viremia at week 12 who continued full combination therapy, only 12% had SVR.
      • Poynard T.
      • Colombo M.
      • Bruix J.
      • et al.
      Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa ribavirin therapy.
      Moreover, no patient with HCV RNA >750 IU/mL at week 12 attained SVR. Thus, in patients with prior treatment failure undergoing retreatment, there is a rigorous requirement for very profound viral load reduction or, far better, HCV RNA clearance by week 12 for SVR to remain a realistic goal.

       Retreatment With CIFN or Albumin-IFN

      Clinical trials in which PEG-IFN alfa plus RBV nonresponders were retreated with CIFN have shown promising results.
      • Kaiser S.
      • Hass H.
      • Gregor M.
      Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy.
      • Leevy C.B.
      Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.
      • Bacon B.R.
      • Shiffman M.L.
      • Mendes F.
      • et al.
      Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
      In a recent study, daily CIFN (15 μg/d) plus RBV (1000–1200 mg/d) for 12 weeks, followed by CIFN (15 μg 3 times weekly) plus RBV (1000–1200 mg/d) for 36 weeks, resulted in SVR in 37% of 137 patients who did not have ≥2 log10 decreases in HCV RNA from baseline after a previous 12-week course of PEG-IFN alfa-2b (1.5 μg/kg/wk) plus RBV (1000–1200 mg/d).
      • Leevy C.B.
      Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.
      Similarly, Kaiser et al reported SVR rates of 27% and 23% among patients receiving induction and standard regimens of CIFN plus ribavirin (Table 4).
      • Kaiser S.
      • Hass H.
      • Gregor M.
      Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy.
      In the wake of these provocative early findings, the results of the Daily-Dose Consensus Interferon and RBV: Efficacy of Combined Therapy (DIRECT) trial were awaited with intense interest.
      • Bacon B.R.
      • Shiffman M.L.
      • Mendes F.
      • et al.
      Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
      This phase 3, open-label, multicenter, United States–based study evaluated 2 dosages of CIFN (9 μg/d and 15 μg/d) plus RBV in 343 PEG-IFN alfa plus RBV nonresponders. At least 90 days had to elapse between the end of PEG-IFN alfa plus RBV therapy and the start of CIFN therapy. Growth factors were not permitted. Among patients randomized to receive CIFN 9 μg/d and 15 μg/d, the mean age of patients was 51 and 50 years; 21% and 17% were African American, and 58% and 62% had evidence of bridging fibrosis or cirrhosis. SVR rates were 7% and 11% for the 9- and 15-μg/d arms, respectively.
      • Bacon B.R.
      • Shiffman M.L.
      • Mendes F.
      • et al.
      Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
      In addition, SVR was attained by 2 of 53 (3.8%) and 3 of 67 (4.5%) patients with cirrhosis receiving CIFN 9 μg/d and CIFN 15 μg/d, respectively. Conversely, in patients without cirrhosis, SVR was attained by 15 of 192 (7.8%) and 23 of 175 (13.1%) patients in each arm, respectively. When results from both treatment arms were pooled, SVR rates were 4.2% in African American patients compared with 11% in Caucasian patients. The degree of reduction in viral load achieved during previous therapy was also predictive of treatment response: 13.3% of patients receiving CIFN 9 μg/d and 30.0% of those receiving CIFN 15 μg/d with absent or mild liver disease who had a >2 log10 viral reduction with previous therapy attained SVR, leaving open the option of selective use of CIFN and RBV as an off-label option in selected nonresponders to PEG-IFN alfa and RBV. Overall, SVR rates were lower in the DIRECT trial than in earlier, single-center trials and the lowest SVR rates were in patients with cirrhosis, who have the most urgent need for retreatment.
      Much higher rates of SVR were noted by Kaiser et al
      • Kaiser S.
      • Hass H.
      • Lutze B.
      • et al.
      Comparison of daily consensus interferon versus peginterferon alfa 2a extended therapy of 72 weeks for peginterferon/ribavirin relapse patients with chronic hepatitis C.
      in prior relapsers to PEG-IFN alfa plus RBV retreated for 72 weeks. In this study, the SVR rate was 69% for patients receiving CIFN (9 μg/day) compared with 44% for patients retreated with PEG-IFN alfa-2a plus ribavirin for the same treatment duration.
      Albinterferon (Alb-IFN) is a fusion molecule in which albumin is attached to an interferon alfa-2b molecule, resulting in a long half-life of 6 days, leading to trials of dosing at 2- to 4-week intervals.
      • McHutchison J.G.
      • Bartenschlager R.
      • Patel K.
      • Pawlotsky J.-M.
      The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice.
      In a recent phase 2 study, prior nonresponders were randomly assigned to 1 of 5 Alb-IFN treatment groups (Table 4).
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.
      Most patients in this study were G1 (93%) and were nonresponders to PEG-IFN alfa plus RBV (69.6%): 48% to 73% had received 2 or more previous IFN alfa regimens. None of these patients previously attained undetectable HCV RNA.
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.
      SVR was attained in 30%, 13%, 9%, and 9% of patients receiving Alb-IFN 900 μg, 1200 μg, 1500 μg, or 1800 μg every 2 weeks, respectively, and in 25% of patients receiving Alb-IFN 1200 μg every 4 weeks.
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.
      • Nelson D.
      • Rustgi V.
      • Balan V.
      • et al.
      Sustained virologic response rates with albumin interferon alfa-2b in combination with ribavirin in non-responders to prior interferon therapy: interim results from a phase 2 study.
      In total, 68% of patients with undetectable HCV RNA at week 12 attained SVR. In previous null responders to PEG-IFN alfa plus ribavirin, 6 of 12 patients receiving 1800 μg Alb-IFN every 2 weeks attained ≥2 log10 reductions in HCV RNA by week 12 (mean reduction, 4.1 log10 IU/mL). Across all treatment arms, the SVR rate was 11% in G1 nonresponders to PEG-IFN alfa plus RBV.
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.

      Maintenance Therapy Trials

      Three clinical trials (HALT-C, EPIC3, Colchicine versus PegIntron Long-Term [COPILOT]) have investigated whether PEG-IFN alfa plus RBV, in the absence of viral eradication (ie, nonresponders), can delay or stop disease progression.

       HALT-C

      HALT-C was the first of these studies to report final data, and—surprisingly to many—raised serious questions regarding the clinical value of long-term maintenance therapy.
      • Di Bisceglie A.M.
      • Shiffman M.L.
      • Everson G.T.
      • et al.
      Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.
      All patients in the study had advanced fibrosis or cirrhosis (Ishak score 3–6). Those with detectable HCV RNA after 20 weeks of treatment with PEG-IFN alfa-2a (180 μg/wk) plus RBV (1000–1200 mg/d) received low-dose PEG-IFN alfa-2a (90 μg/wk) or no treatment over a 3.5-year period.
      • Di Bisceglie A.M.
      • Shiffman M.L.
      • Everson G.T.
      • et al.
      Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.
      Significant benefits of maintenance therapy on HCV RNA level, alanine aminotransferase level, and necroinflammation on liver biopsy were noted. Between treated and untreated patients, however, there was no difference in the rates of death (6.6% vs 4.6%), primary treatment outcomes (30% vs 30%), progression to cirrhosis among patients with noncirrhotic fibrosis (28.2% vs 31.9%), or HCC as a primary outcome (2.3% vs 2.8%) (Figure 2). Among treated patients, 30.4% had withdrawn from treatment by 3.5 years; the most frequently reported adverse events leading to discontinuation were neutropenia, thrombocytopenia, and depression.
      • Di Bisceglie A.M.
      • Shiffman M.L.
      • Everson G.T.
      • et al.
      Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.
      Figure thumbnail gr2
      Figure 2Maintenance therapy clinical outcomes from (A) HALT-C and (B) COPILOT.
      • Nelson D.R.
      • Rustgi V.
      • Balan V.
      • et al.
      Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.
      • Nelson D.
      • Rustgi V.
      • Balan V.
      • et al.
      Sustained virologic response rates with albumin interferon alfa-2b in combination with ribavirin in non-responders to prior interferon therapy: interim results from a phase 2 study.
      CPT, Child-Pugh-Turcotte.

       EPIC3

      Patients in the EPIC3 trial who did not respond to retreatment could enroll in the maintenance phase of the program, consisting of PEG-IFN alfa-2b (0.5 μg/kg/wk) monotherapy or no treatment for 3 (F2–3) or 5 (F4) years. Patients with cirrhosis who were nonresponsive to any IFN alfa plus RBV treatment could enroll directly in the maintenance protocol of the study. Recently reported data indicate that peginterferon alpha-2b maintenance was not superior to control in preventing clinical events, but there was a significant reduction in clinical events of hepatic decompensation in the protocol-defined secondary analysis and in subjects with pre-existing esophageal varices.
      • Bruix J.
      • Poynard T.
      • Colombo M.
      • et al.
      Pegintron maintenance therapy in cirrhotic (Metavir F4) HCV patients who failed to respond to interferon/ribavirin (IR) therapy: final results of the EPIC3 cirrhosis maintenance trial.

       COPILOT

      COPILOT was a randomized, controlled, multicenter, United States–based trial that evaluated whether the progression of hepatitis C–associated liver disease could be delayed and possibly prevented in 555 previous IFN or PEG-IFN plus RBV nonresponders with compensated liver disease (Ishak score 3–6).
      • Afdhal N.
      • Levine R.
      • Brown Jr, R.
      • et al.
      Colchicine versus peg-interferon alfa 2b long term therapy: results of the 4 year COPILOT trial.
      This trial compared low-dose PEG-IFN alfa-2b (0.5 μg/kg/wk) with the anti-inflammatory drug colchicine (0.6 mg orally, twice daily) over a treatment period of 4 years. Primary end points of the study were death, liver transplant, HCC, variceal bleeding, or a 2-point increase in Child-Turcotte-Pugh score with ascites, jaundice, or encephalopathy.
      • Afdhal N.
      • Levine R.
      • Brown Jr, R.
      • et al.
      Colchicine versus peg-interferon alfa 2b long term therapy: results of the 4 year COPILOT trial.
      Forty-nine percent of patients failed to complete four years of the trial. After 4 years, there was no significant difference in event-free survival between treatment arms (P = .311), and the overall incidence of primary end points was similar between groups (Figure 2). Intention-to-treat analysis of only patients with portal hypertension at baseline also showed a trend toward event-free survival between treatment groups (P = .057). An on-drug analysis (which excluded those patients not taking medication) of patients with baseline endoscopic stigmata of portal hypertension revealed that event-free survival was significantly longer in patients receiving PEG-IFN alfa-2b than those receiving colchicine (P = .038), largely attributable to a greater incidence of variceal bleeding among patients receiving colchicine compared with those receiving PEG-IFN alfa-2b (Figure 2).
      • Afdhal N.
      • Levine R.
      • Brown Jr, R.
      • et al.
      Colchicine versus peg-interferon alfa 2b long term therapy: results of the 4 year COPILOT trial.
      In summary, results of the maintenance therapy clinical trials reported thus far discourage the widespread use of maintenance therapy. The improvement in alanine aminotransferase, necroinflammation, and HCV RNA levels in the HALT-C trial do not justify such treatment in the absence of a concurrent reduction in adverse clinical outcomes. Whether the reduced variceal bleeding observed in patients with portal hypertension in COPILOT and EPIC3 will fuel interest in the use of PEG-IFN alfa maintenance therapy in the absence of additional data—especially given the already available options for the prophylaxis of variceal bleeding and the unknown degree of incremental protection provided by maintenance therapy—has not been established.

      Future Treatment Options

      Numerous trials are investigating the efficacy of novel agents, including specifically targeted antiviral therapies for hepatitis C (STAT-C) such as inhibitors of the HCV NS3/4A protease and HCV RNA-dependent RNA polymerase. Some of these trials are investigating the efficacy of these agents in nonresponders and relapsers.
      Several inhibitors of the HCV RNA–dependent RNA polymerase have been studied in prior nonresponders. Valopicitabine, a nucleoside inhibitor, was ineffective when combined with PEG-IFN in G1-infected prior nonresponders to PEG-IFN and RBV.
      • Afdhal N.
      • O'Brien C.
      • Godofsky E.
      • et al.
      Valopicitabine (NM283), alone or with peginterferon, compared to peginterferon/ribavirin (PEGIFN/RBV) retreatment in patients with HCV-1 infection and prior non-response to PEGIFN/RBV: one-year results.
      In contrast, when HCV-796, a nonnucleoside polymerase inhibitor, was given in combination with PEG-IFN alfa-2b and RBV, 23% of G1-infected patients attained undetectable HCV RNA. Unfortunately, dosing was halted because of apparent hepatotoxicity.
      Potential safety issue identified in ongoing phase 2 clinical study of HCV-796.
      A nucleoside polymerase inhibitor undergoing active investigation, R7128, was given in 4 doses to G1-infected patients with prior treatment failure in a 14-day monotherapy trial and showed as much as a mean 2.7 log10 reduction in HCV RNA without viral rebound.
      • Reddy R.
      • Rodriguez-Torres M.
      • Gane E.
      • et al.
      Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy.
      This drug was recently evaluated in a small cohort of G2/3-infected patients with prior treatment failure; 90% of patients attained rapid virologic response.
      • Gane E.J.
      • Rodriguez-Torres M.
      • Nelson D.R.
      • et al.
      Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior non-responders: interim results of R7128 1500mg bid with PEG-IFN and ribavirin for 28 days.
      Boceprevir and telaprevir are inhibitors of the HCV NS3/4A serine protease and have been granted fast-track designations by the FDA. A phase 2 study of boceprevir in G1 patients without cirrhosis who did not achieve 2 log10 decreases in HCV RNA after 12 weeks of PEG-IFN plus RBV or who did not attain undetectable HCV RNA after >12 weeks of PEG-IFN plus RBV has recently been reported.
      • Schiff E.
      • Poordad F.
      • Jacobson I.
      • et al.
      Boceprevir (NS3 protease inhibitor) combination therapy in non responders: phase II dose finding study.
      Multiple treatment arms were included in the study design. Patients initially received PEG-IFN alfa-2b (1.5 μg/kg/wk) monotherapy for 1 week, after which RBV (800–1400 mg/d), boceprevir (100–800 mg tid), or RBV plus boceprevir was added to their regimens. Planned treatment duration was 24 or 48 weeks. During this study, an unblinded review by the Data Safety Monitoring Board led to a protocol amendment such that all responding patients (HCV RNA <10,000 IU/mL and no sign of breakthrough) received PEG-IFN alfa-2b (1.5 μg/kg/wk) and RBV (800–1400 mg/d) plus boceprevir (800 mg tid) for an additional 24 weeks. In total, 357 patients were enrolled and 348 patients received boceprevir at some point in the study. The overall SVR rates were 2% among patients retreated solely with PEG-IFN alfa plus RBV and 7% to 14% among patients in the boceprevir crossover arms. SVR was associated with early virologic response and on-treatment duration of undetectable HCV RNA (more than 36 weeks). Resistant variants were frequently noted in nonresponders (49%), patients with on-treatment viral breakthrough (82%), and those experiencing posttreatment relapse (58%).
      • Schiff E.
      • Poordad F.
      • Jacobson I.
      • et al.
      Boceprevir (NS3 protease inhibitor) combination therapy in non responders: phase II dose finding study.
      This early experience with boceprevir underscored concerns that nonresponders may be particularly susceptible to the emergence of resistant variants because of their proven refractoriness to IFN alfa therapy. It is of note that none of the treatment groups in this dose ranging study initially received the regimen that was implemented subsequently during the course of the study.
      In light of concerns that a single STAT-C agent combined with standard of care in previous nonresponders would be akin to “functional monotherapy,” results from a report of a phase 2 trial of telaprevir in nonresponders and relapsers to PEG-IFN and RBV have garnered attention.
      • McHutchison J.G.
      • Shiffman M.L.
      • Terrault N.
      • et al.
      A phase 2b study of telaprevir with peginterferon-alfa-2a and ribavirin in hepatitis C genotype 1 null and partial responders and relapsers following a prior course of peginterferon-alfa-2a/b and ribavirin therapy: PROVE3 interim results.
      This study included 4 treatment arms: PEG-IFN alfa 2a (180 μg/week) plus RBV (1000–1200 mg/day) for 48 weeks (control arm); telaprevir (750 mg, 3 times daily) plus PEG-IFN alfa-2a plus RBV for 12 weeks, then PEG-IFN alfa-2a plus RBV for 12 weeks; telaprevir plus PEG-IFN alfa-2a plus RBV for 24 weeks, then PEG-IFN alfa-2a plus RBV for 24 weeks; telaprevir plus PEG-IFN alfa-2a for 24 weeks. Interim data reported recently indicated that HCV RNA was undetectable at week 12 of follow-up (SVR-12) in 41% of the prior nonresponders who received 24 weeks of total treatment versus only 11% of those in the RBV-free arm.
      • McHutchison J.G.
      • Shiffman M.L.
      • Terrault N.
      • et al.
      A phase 2b study of telaprevir with peginterferon-alfa-2a and ribavirin in hepatitis C genotype 1 null and partial responders and relapsers following a prior course of peginterferon-alfa-2a/b and ribavirin therapy: PROVE3 interim results.
      Prior relapsers had SVR-12 rates of 72% and 36%, respectively. Data from the 48-week treatment arms are pending. In this study, retrospective stratification of the population by degree of prior viral load reduction in the nonresponders was not possible. Additional preliminary insights have been provided from another open-label study of telaprevir plus PEG-IFN alfa-2a and RBV in patients who failed treatment in the phase 2 development program, in whom data on degree of prior viral load reduction were available.
      • Shiffman M.L.
      • Berg T.
      • Poordad F.F.
      • et al.
      A study of telaprevir combined with peginterferon-alfa-2a and ribavirin in subjects with well-documented non-response or relapse after previous peginterferon-alfa-2a and ribavirin treatment: interim analysis.
      Null responders, who had <1 log reduction of HCV RNA at week 4 or <2 log at week 12, attained undetectable HCV RNA in 40%, 61%, and 43% at 4, 12, and 24 weeks, respectively. Response was more frequent in partial responders and relapsers. Prior null responders had higher rates of breakthrough relapse at the interim analysis.
      • Shiffman M.L.
      • Berg T.
      • Poordad F.F.
      • et al.
      A study of telaprevir combined with peginterferon-alfa-2a and ribavirin in subjects with well-documented non-response or relapse after previous peginterferon-alfa-2a and ribavirin treatment: interim analysis.
      The provocative data from these 2 studies will doubtless lead to much additional investigation of STAT-C agents in nonresponder populations.

      Conclusions

      Although advances in chronic hepatitis C therapy have improved SVR rates significantly in the past decade, nonresponders continue to constitute a significant proportion of HCV-infected patients. Retreatment with PEG-IFN alfa plus RBV may be beneficial in some patients who did not respond to earlier conventional IFN alfa monotherapy or conventional IFN alfa plus RBV combination therapy. SVR rates are higher among those who previously experienced relapse than in those who were nonresponders. Patients not responding to PEG-IFN alfa plus RBV are difficult to retreat successfully. The merits of switching from one PEG-IFN alfa to another remain unclear, but at best switching benefits a small subset of patients, and SVR rates attained using CIFN-based regimens are lower than initially reported. Accordingly, a watchful waiting approach to most nonresponders to PEG-IFN plus ribavirin appears appropriate. Retreatment might be considered when there has been a substantial lapse in adherence or premature discontinuation of prior therapy, and in patients with advanced fibrosis. When nonresponders to PEG-IFN and RBV are retreated, extended duration of therapy in those who become HCV RNA negative may decrease the chance of relapse. Retreatment of relapsers has been associated with higher success rates, even with 48 weeks of retreatment, as shown in the EPIC3 trial, but extended treatment duration in these patients should be strongly considered as well. Finally, the benefit of long-term PEG-IFN alfa maintenance therapy in slowing disease progression has been cast into sufficient doubt by recent data from multicenter maintenance therapy studies to discourage its use in routine practice. Novel approaches to treatment, such as viral-specific enzyme inhibitors, have shown promising results in early clinical trials and may prove valuable for retreating patients who have not responded to PEG-IFN alfa–based antiviral therapy.

      Acknowledgments

      Editorial assistance was provided by Maribeth Bogush, PhD, and Tim Ibbotson, PhD. This assistance was funded by Schering-Plough.

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