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Retreatment of Hepatitis C in Nonresponders and Relapsers

for Health Care Providers

Retreatment of Hepatitis C in Nonresponders and Relapsers

What are the options for patients who have been treated for hepatitis C but had a nonresponse or a relapse?

Introduction

Nonresponders and relapsers make up a large population of patients with hepatitis C virus (HCV) infection in the United States. When reviewing the literature on retreatment of patients for whom a prior course of therapy did not result in a sustained virologic response (SVR), it is important to recognize that this is a heterogeneous group of patients with a variety of prior treatment regimens. In discussing the research on retreatment, we need to carefully note the characteristics of the patients in each study and their prior treatment history, as the study population can differ significantly from one trial to another.

Any patient who completes a course of treatment that did not result in an SVR can be described as one who had a "failed" treatment. However, there are different patterns of response even among these patients. The prior patterns of response may significantly differentiate patients and their likelihood of achieving an SVR if re-treated.

Patterns of Treatment Responsiveness

Patient TypeTreatment Response
"nonresponder"No significant virologic response occurs, and patient never becomes virus negative at any point during treatment
"slow responder"Virologic response does not begin until after 24 weeks of treatment
"partial responder"Virologic response occurs before 24 weeks of treatment, but is not maintained at the end of treatment
"relapser"Virologic response is HCV RNA negative and is maintained through the end of treatment, but relapse occurs before 6 months posttreatment

The patterns of prior response are as important as the prior treatment regimens, and "prior treatment" can involve any of the following hepatitis C antiviral regimens:

  • standard interferon (IFN) monotherapy
  • standard IFN combination treatment with ribavirin (RBV)
  • pegylated IFN alfa-2a monotherapy
  • pegylated IFN alfa-2b monotherapy
  • pegylated IFN alfa-2a combination therapy with RBV
  • pegylated IFN alfa-2b combination therapy with RBV

When considering the prior treatment history for a patient or a group in a study, it is also important to note that the treatments may have differed in terms of the IFN dosage, the RBV dosage, and the duration of the course.

Finally, retreatment may be initiated with a different medication regimen, different dosages, a different duration, or the addition of growth factors or other ancillary treatments to help sustain a complete treatment course.

Currently, there are many data on retreatment of patients who experienced failure of standard IFN-based regimens, but far fewer data are available on retreatment of patients who experienced treatment failure with pegylated IFN + RBV.

The data for retreatment show variability in regimens used, patients studied, and outcomes observed.

Retreatment after Prior Standard IFN + RBV

  • Among patients with a prior nonresponse to standard IFN with or without RBV, retreatment with pegylated IFN alfa-2a + RBV for 48 weeks resulted in SVR in 18-20%.(1,2)
  • Among patients with a prior nonresponse to standard IFN + RBV, retreatment with pegylated IFN alfa-2b + RBV for 48 weeks resulted in SVR in 8%.(3)
  • Among patients with a prior relapse to standard IFN + RBV, retreatment with pegylated IFN alfa-2b + RBV for 48 weeks resulted in SVR in 42%.(3)
  • Among patients with a prior nonresponse to standard IFN + RBV, retreatment with consensus IFN (CIFN) + RBV resulted in SVR in 22%.(4)
  • Trials examining high-dose induction CIFN therapy in standard IFN + RBV nonresponders showed no benefit from induction doses.(4)

Retreatment after Prior Pegylated IFN + RBV

  • Among patients who did not achieve a 12-week "early virologic response" (EVR) on pegylated IFN + RBV and were subsequently switched to CIFN + RBV for 48 weeks, SVR was achieved in 37%.(5)
  • In a trial examining nonresponse to pegylated IFN alfa-2b + RBV, patients are being re-treated with pegylated IFN alfa-2a + RBV, with half of them receiving high-dose pegylated IFN alfa-2a induction. The trial is ongoing.(6)
  • In a multicenter prospective trial (the DIRECT trial), patients with a prior nonresponse to pegylated IFN + RBV are being re-treated with CIFN at 9 or 15 mcg/day plus RBV. The trial is ongoing.(7)

Table 1. Favorable and Unfavorable Factors for Retreatment of Hepatitis C

FactorFavorableUnfavorable
Adapted from Darling et al.(8)
Previous treatment regimenIFN monotherapyIFN + RBV
Previous response to therapyRelapse, partial responseNull response
Genotype2 or 31
Serum HCV RNALowHigh
RaceCaucasian, Hispanic, AsianAfrican American
Stage of fibrosisMinimalAdvanced or cirrhosis
Prior treatment adherencePoor (if reversible factors)Complete
Patient motivationHighLow

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Retreatment Principles

  • Consider retreatment if significant dosage reductions were necessary during the initial treatment.
  • Consider retreatment if compliance was poor during the initial therapy.
  • Consider retreatment if the duration of the initial therapy was shortened or inadequate.
  • Treat for 48 weeks regardless of genotype.
  • Do not stop treatment if an EVR is not achieved. Consider treating until 24 weeks before deciding whether to stop therapy.
  • Consider high-dose induction therapy.

Conclusions

  • Some patients who have failed prior therapy can achieve an SVR with retreatment.
  • There is a significant benefit to retreatment of patients who were nonresponders or relapsers to a course of standard IFN + RBV using pegylated IFN alfa-2a + RBV.
  • There are marginal potential benefits to retreatment of patients who were nonresponders to standard IFN + RBV using pegylated IFN alfa-2b + RBV.
  • There are moderate potential benefits to retreatment of relapsers to standard IFN + RBV with pegylated IFN alfa-2a + RBV.
  • Retreatment for patients who experienced treatment failure with standard IFN + RBV using pegylated IFN + RBV has been studied with pegylated IFN alfa-2a and pegylated IFN alfa-2b but these have never been compared in any head-to-head trial.
  • There is a slim benefit to retreatment of patients who were nonresponders or relapsers to a prior course of pegylated IFN + RBV.
  • Decisions regarding retreatment for any patient need to be made on an individualized basis between patient and doctor.
  • Important factors to consider for retreatment include an assessment of whether the retreatment course can be optimized through the use of growth factors or additional approaches to side effect management in order to avoid dosage reductions or shortened treatment courses.
  • For patients with advanced fibrosis or cirrhosis, offering a longer duration of treatment or an extended course of low-dose pegylated IFN monotherapy may result in sustained periods of virologic response.
  • Currently, no therapy has been approved by the U.S. Food and Drug Administration for retreatment of patients who have experienced treatment failure with pegylated IFN + RBV.

References

  1. Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatmentLink will take you outside the VA website.. Gastroenterology. 2004 Apr;126(4):1015-23; discussion 947.
  2. Taliani G, Gemignani G, Ferrari C, et al. Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patientsLink will take you outside the VA website.. Gastroenterology. 2006 Apr;130(4):1098-106.
  3. Jacobson IM, Gonzalez SA, Ahmed F, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis CLink will take you outside the VA website.. Am J Gastroenterol. 2005 Nov;100(11):2453-62.
  4. 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 studyLink will take you outside the VA website.. J Hepatol. 2006 Feb;44(2):291-301.
  5. Leevy C, Chalmers C, Blatt LM. Predictive model and sustained virologic response for PEG IFN-alfa-2 + weight-based ribavirin nonresponders re-treated with IFN alfacon-1 + weight-based ribavirin. Presented at: Digestive Diseases Week 2005; May 14-19, 2005; Chicago. Abstract, Poster #S1538.
  6. Jensen DM, Marcellin P. Rationale and design of the REPEAT study: a phase III, randomized, clinical trial of peginterferon alfa-2a (40 kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12 kDa) plus ribavirinLink will take you outside the VA website.. Eur J Gastroenterol Hepatol. 2005 Sep;17(9):899-904.
  7. Bacon B, Regev A, Ghalib R, et al. Use of daily interferon alfacon-1 (Infergen, CIFN) plus ribavirin in patients infected with hepatitis C virus (HCV) who are nonresponders to previous pegylated interferon plus ribavirin therapy: 24-week data from the DIRECT trial. Hepatology. 2006 Oct;44(4), Suppl 1: 698A.
  8. Darling JM, Fried MW. Optimizing treatment regimens in hepatitis CLink will take you outside the VA website.. Clin Liver Dis. 2006 Nov;10(4):835-50. Review.