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1. Author response

   • Donald M. Jensen, M.D.
   • Patrick Marcellin

   University of Chicago
   We thank Professor Poynard for his interest in our article and for pointing out some differences between the non-comparative EPIC3 trial(1) and the randomized international REPEAT trial.(2) We agree that differences in the proportion of patients with advanced fibrosis are noteworthy; however, this is not necessarily the most important difference between the two studies. EPIC3 recruited patients who did not achieve a sustained virologic response (SVR) after at least 12 weeks of treatment with any type of interferon plus ribavirin, regardless of the nature of the previous virologic response.(1) Thus, the study population was a heterogenous mixture of primarily non-responders and relapsers to conventional interferon plus ribavirin and to pegylated interferon plus ribavirin. This heterogenous patient population is reflected in the heterogenous results: among patients most likely to have an SVR (those who relapsed after treatment with conventional interferon plus ribavirin) the cure rate was 43%; among those least likely to have an SVR (non-responders to pegylated interferon plus ribavirin) the cure rate was 6% — a 7-fold difference.(1) The inclusion criteria for REPEAT were more stringent.(2) Only patients with detectable HCV RNA documented at every post-baseline assessment during at least a 12-week course of treatment with pegylated interferon alfa-2b plus ribavirin were eligible. When this strict definition of non-response is superimposed on the baseline characteristics of the 2293 patients enrolled in the EPIC3 program, 476 patients (21%) meet the eligibility criteria for REPEAT. SVR rates reported by fibrosis stage in EPIC3 are the pooled results for “all comers” (previous relapsers, non-responders and “treatment failures”) and thus are not comparable to those obtained in non-responders to pegylated interferon plus ribavirin in REPEAT. For this reason it is not possible to compare results by fibrosis stage between the two studies. Although important, this discussion of inclusion criteria and study populations obscures the most fundamental difference between REPEAT and EPIC3. REPEAT showed a significant two-fold increase in sustained response rates in nonresponders who were re-treated with peginterferon alfa-2a plus ribavirin for 72 weeks compared with 48 weeks. Regardless of their fibrosis stage, non-responders to the standard of care who are willing should be retreated for 12 weeks. Those with detectable HCV RNA at week 12 should stop treatment because they are unlikely to have an SVR;(1-3) those with undetectable HCV RNA should continue treatment for 72 weeks with peginterferon alfa-2a plus ribavirin because it offers the best chance of a cure. References (1) Poynard T, Colombo M, Bruix J, Schiff E, Terg R, Flamm S et al. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. Gastroenterology. 2009;136:1618-28. (2) Jensen DM, Marcellin P, Freilich B, Andreone P, Di BA, Brandao-Mello CE et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med. 2009;150:528-40. (3) Moucari R, Ripault MP, Oules V, Martinot-Peignoux M, Asselah T, Boyer N 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. J Hepatol. 2007;46:596-604.

   Conflict of Interest:

   Roche investigator and consultant

   Submit response
   Published June 9, 2009
2. REPEAT confirms EPIC

   • Thierry Poynard, Prof

   UPMC lLiver Center

   To the Editor:

   In their manuscript Jensen and colleagues (1) make a comparison of their study to the EPIC3 non-responder trial (2). As the principal investigator of the EPIC3 non-responder trial, I would like to clarify some key differences and similarities between the two trials. The EPIC3 program was designed to assess the benefit of re-treatment in patients with advanced fibrosis and cirrhosis, while the REPEAT trial assesses retreatment in all comers. Indeed, EPIC3 had 42% cirrhotic patients and 29% with bridging fibrosis (71% combined); and all subjects had at least F2 fibrosis on the METAVIR scale. This constitutes the largest trial of HCV treatment of cirrhotics. In contrast, the REPEAT study had only 25-30% bridging fibrosis and cirrhosis combined, less than half that seen in the EPIC3 trial. This is a key point, as both studies demonstrate incrementally higher levels of SVR with lower levels of fibrosis. If one only considers subjects treated for 48 weeks, the SVR rates seen in patients with bridging fibrosis or cirrhosis is nearly identical in the two studies.

   Additionally, in the primary publication for the EPIC3 study we reported our response rates by level of fibrosis, and by combinations of genotype and fibrosis. This detailed reporting has obvious clinical utility. Such detailed analysis of the REPEAT would also be of great clinical interest. In particular, it would important to confirm the stepwise response rate by fibrosis level as was seen in EPIC3. REPEAT was able to reproduce one important finding from EPIC3: “(the) most practical finding is that complete viral suppression at week 12 can be used as an on-treatment milestone to limit continued treatment exposure to patients who are unlikely to achieve SVR.” This observation was reported in abstracts presented based upon the EPIC3 non-responder trial at the EASL(3) and DDW(4) meetings in 2005 and more conclusively at the AASLD(5) meeting in 2006, prior to full publication this year (2). It is reassuring that the REPEAT study was able to confirm some of the major findings of the EPIC3 trial.

   References

   (1) Jensen DM, Marcellin P, Freilich B, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med, 2009 Apr 21;150(8):528-40.

   (2) 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. Gastroenterology, 2009 May;136(5):1618-28.

   (3) Poynard T, Schiff E, Terg R et al. Sustained virologic response (SVR) in the EPIC3 trial: week twelve virology predicts SVR in previous interferon/ribavirin treatment failures receiving peg-intron/rebetol (PR) weight based dosing (WBD). J. Hepatol., (40th ann. Mtg. Eur. Assoc. Study Liver, EASL, Paris, France, Apr. 13-17, 2005), vol. 42, no. 2, suppl., abstr. No. 96.

   (4) Poynard T, Schiff E, Terg R, et al. Sustained virologic response (SVR) with peg-interferon-alfa 2b/ribavirin weight based dosing in previous interferon/ribavirin HCV treatment failures; week 12 virology as a predictor of SVR in the EPIC3 trials. Gastroenterology, (Dig. Dis. Wk., (DDW), Chicago, Il, USA, May 14-19, 2005), vol. 128, no. 4, suppl. 2, April, 2005, abstr. No. 5.

   (5) Poynard T, Schiff E, Terg R, et al. HCV RNA negativity after 12 weeks of therapy is the best predictor of sustained viral response (SVR) in the re-treatment of previous interferon-a/ribavirin non-responders (NR): results from the EPIC3 program. Hepatology, (57th Ann. Mtg. Am. Assoc. Study Liver Dis., AASLD, Boston, MA, USA, Oct. 27-31, 2006), Vol. 44, No. 4, Suppl. 1, Oct. 2006, P. 606A, Abstr. No. 1123.

   Conflict of Interest:

   Bureau Speaker of Schering Plough. Investigator for Schering, Roche, Vertex, Gilead.

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   Published May 15, 2009