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Re-treatment of Patients With Chronic Hepatitis C Who Do Not Respond to Peginterferon-α2b: A Randomized Trial

Donald M. Jensen, MD; Patrick Marcellin, MD; Bradley Freilich, MD; Pietro Andreone, MD; Adrian Di Bisceglie, MD; Carlos E. Brandão-Mello, MD, PhD; K. Rajender Reddy, MD; Antonio Craxi, MD; Antonio Olveira Martin, MD; Gerlinde Teuber, MD; Diethelm Messinger, MS; James A. Thommes, MD; and Andreas Tietz, MD
[+] Article and Author Information

ClinicalTrials.gov registration number: NCT00087646.


From the Center for Liver Diseases, University of Chicago Hospitals, Chicago, Illinois; Centre de Recherche Biologique Bichat-Beaujon CRB3, Hôpital Beaujon, Clichy, France; Liver and Pancreas Institute of Kansas City, Kansas City, Missouri; University of Bologna, Bologna, Italy; Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri; University of Rio de Janeiro, Rio de Janeiro, Brazil; University of Pennsylvania, Philadelphia, Pennsylvania; University of Palermo, Palermo, Italy; Hospital La Paz, Madrid, Spain; J.W. Goethe University Hospital, Frankfurt, Germany; IST, Mannheim, Germany; Roche, Nutley, New Jersey; and Roche, Basel, Switzerland.


Note: Drs. Jensen and Marcellin contributed equally to this work.

Acknowledgment: The authors thank all of the patients who volunteered to participate in this study and all of the investigators and other health care professionals who ensured the successful completion of the study. They also thank Blair Jarvis for providing editorial assistance.

Grant Support: By Roche, Basel, Switzerland.

Potential Financial Conflicts of Interest:Employment: D. Messinger (IST [provides various services for sponsor]), J.A. Thommes (Roche), A. Tietz (Roche). Consultancies: D.M. Jensen (Roche, Abbott, Boehringer Ingelheim, Vertex, Novartis, AstraZeneca, HGS), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche, Schering), K.R. Reddy (Roche, Gilead, Idenix, Vertex), D. Messinger (Roche). Honoraria: P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Idenix-Novartis), K.R. Reddy (Roche, Gilead, Idenix, Vertex), G. Teuber (Roche). Grants received: D.M. Jensen (Roche, Vertex, Boehringer Ingelheim), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche), K.R. Reddy (Roche, Schering, Human Genomics, Novartis). Grants pending: K.R. Reddy (Boehringer Ingelheim, Pharmasset).

Reproducible Research Statement:Study protocol: Available at http://www.roche-trials.com/patient/trials/trial120.html. Statistical code: Not available. Data set: Available at http://www.roche-trials.com/patient/trialresults/stur124.html.

Requests for Single Reprints: Donald M. Jensen, MD, Center for Liver Diseases, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637; e-mail, djensen@medicine.bsd.uchicago.edu.

Current Author Addresses: Dr. Jensen: Center for Liver Diseases, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637.

Dr. Marcellin: Service d'Hepatologie and Centre de Recherches Biologiques Bichat Beaujon (INSERM CRB3), Hôpital Beaujon, Clichy 92110, France.

Dr. Freilich: Liver and Pancreas Institute of Kansas City, 6675 Holmes, Suite 425, Kansas City, MO 64131.

Dr. Andreone: Department of Internal Medicine, Cardiology, and Hepatology, Ospedale S. Orsola-Malpighi, Universita di Bologna, Via Massarenti 9-40138, Bologna, Italy.

Dr. Di Bisceglie: Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Boulevard, Saint Louis, MO 63110-0250.

Dr. Brandão-Mello: University of Rio de Janeiro Medical School, Internal Medicine Department, Liver and Gastroenterology Unit, Gaffree e Guinle University Hospital, Rua Mariz e Barros 775, 20270-004 Rio de Janeiro, Brazil.

Dr. Reddy: Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Craxi: Instituto Di Clinica Medica Policlinico, Divisione Di Gastroenterologia, Piazzale Delle Cliniche 2, Palermo 90127, Italy.

Dr. Olveira Martin: Digestive Diseases (Servicio Aparato Digestivo), Hospital La Paz, Paseo de la Castellana 261, Madrid 28046, Spain.

Dr. Teuber: J.W. Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

Mr. Messinger: IST GmbH, Soldnerstrasse 1, 68219 Mannheim, Germany.

Dr. Thommes: Roche Pharmaceuticals, 340 Kingsland Street, Nutley, NJ 07110.

Dr. Tietz: Pharmaceuticals Division, F. Hoffmann-La Roche, Building 074/3O.202, CH-4070 Basel, Switzerland.

Author Contributions: Conception and design: P. Marcellin, K.R. Reddy, D. Messinger, J.A. Thommes, A. Tietz.

Analysis and interpretation of the data: D.M. Jensen, P. Marcellin, A. Di Bisceglie, K.R. Reddy, A. Craxi, D. Messinger, J.A. Thommes, A. Tietz.

Drafting of the article: D.M. Jensen, P. Marcellin, A. Di Bisceglie, K.R. Reddy, J.A. Thommes, A. Tietz.

Critical revision of the article for important intellectual content: D.M. Jensen, P. Marcellin, P. Andreone, A. Di Bisceglie, C.E. Brandão-Mello, K.R. Reddy, A. Craxi, G. Teuber, D. Messinger, J.A. Thommes, A. Tietz.

Final approval of the article: D.M. Jensen, P. Marcellin, B. Freilich, P. Andreone, A. Di Bisceglie, C.E. Brandão-Mello, K.R. Reddy, A. Craxi, A. Olveira Martin, G. Teuber, J.A. Thommes, A. Tietz.

Provision of study materials or patients: D.M. Jensen, P. Marcellin, P. Andreone, A. Di Bisceglie, K.R. Reddy, A. Craxi, A. Olveira Martin, G. Teuber.

Statistical expertise: A. Craxi, D. Messinger.

Collection and assembly of data: D.M. Jensen, C.E. Brandão-Mello.


Ann Intern Med. 2009;150(8):528-540. doi:10.7326/0003-4819-150-8-200904210-00007
Text Size: A A A

Background: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin.

Objective: To evaluate use of peginterferon-α2a plus ribavirin to re-treat nonresponders to peginterferon-α2b plus ribavirin.

Design: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis.

Setting: 106 international centers.

Patients: 950 nonresponders to 12 or more weeks of therapy with peginterferon-α2b plus ribavirin.

Intervention: Peginterferon-α2a, 360 µg/wk, for 12 weeks, then 180 µg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-α2a, 180 µg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d.

Measurements: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment.

Results: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively.

Limitation: Nonresponders to peginterferon-α2a plus ribavirin were not evaluated.

Conclusion: Re-treating nonresponders to therapy with peginterferon-α2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12.

Primary Funding Source: Roche.

Figures

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Figure 1.
Study design.

* Only in groups B and D.

† Only in groups A and C.

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Figure 2.
Study flow diagram.

AE = adverse event.

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Appendix Figure.
Study design, showing time of withdrawal.

AE = adverse event; IR = insufficient therapeutic response; LFU = lost to follow-up.

* Only in groups B and D.

† Only in groups A and C.

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Figure 3.
Sustained virologic response rates, by baseline prognostic factors.

Histologic diagnosis was not reported in 4 patients, and HCV RNA level was not reported in 37 patients. HCV = hepatitis C virus.

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Figure 4.
Virologic response at week 12 and sustained virologic response.

We excluded 66 patients with missing HCV RNA results at week 12 from these calculations; of these, only 3 had achieved a sustained virologic response (1 each in groups A, B, and C). HCV = hepatitis C virus. A. Patients with virologic response at week 12, defined as undetectable HCV RNA levels (<50 IU/mL) or ≥2-log10 decrease (if detectable). B. Patients with complete viral suppression at week 12, defined as undetectable HCV RNA levels. C. Sustained virologic response in patients with virologic response at week 12. D. Sustained virologic response in patients with complete viral suppression at week 12.

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REPEAT confirms EPIC
Posted on May 15, 2009
Thierry Poynard
UPMC lLiver Center
Conflict of Interest: None Declared

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.

Author response
Posted on June 8, 2009
Donald M. Jensen
University of Chicago
Conflict of Interest: None Declared
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

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Summary for Patients

Re-treating Patients With Chronic Hepatitis C Who Have Not Responded to Peginterferon-α2b

The summary below is from the full report titled “Re-treatment of Patients With Chronic Hepatitis C Who Do Not Respond to Peginterferon-α2b. A Randomized Trial.” It is in the 21 April 2009 issue of Annals of Internal Medicine (volume 150, pages 528-540). The authors are D.M. Jensen,P. Marcellin, B. Freilich, P. Andreone, A. Di Bisceglie, C.E. Brandão-Mello, K.R. Reddy, A. Craxi, A. Olveira Martin, G. Teuber, D. Messinger,J.A. Thommes, and A. Tietz.

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