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Sustained Virologic Response and Clinical Outcomes in Patients with Chronic Hepatitis C and Advanced Fibrosis

Bart J. Veldt, MD; E. Jenny Heathcote, MD; Heiner Wedemeyer, MD; Juerg Reichen, MD; W. Peter Hofmann, MD; Stefan Zeuzem, MD; Michael P. Manns, MD; Bettina E. Hansen, MSc; Solko W. Schalm, MD, PhD; and Harry L.A. Janssen, MD, PhD
[+] Article and Author Information

From Erasmus MC University Medical Center, Rotterdam, the Netherlands; Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Medizinische Hochschule Hannover, Hannover, Germany; Institute of Clinical Pharmacology, University of Bern, Bern, Switzerland; and Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.


Potential Financial Conflicts of Interest: Consultancies: E.J. Heathcote (Hoffmann-La Roche, Schering-Canada), S. Zeuzem (Schering-Plough, Roche, Human Genome Sciences, Novartis), H. Wedemeyer (Roche, Schering-Plough). Honoraria: E.J. Heathcote (Schering-Plough, Hoffmann-La Roche), S. Zeuzem (Schering-Plough, Roche, Human Genome Sciences, Novartis), H. Wedemeyer (Roche, Schering-Plough), H.L.A. Janssen (Schering-Plough, Roche). Grants received: B.J. Veldt (Netherlands Organisation for Health Research and Development), E.J. Heathcote (Hoffmann-La Roche, Schering-Plough), S. Zeuzem (Roche, Novartis), H.L.A. Janssen (Schering-Plough, Roche), H. Wedemeyer (Roche, Schering-Plough).

Reproducible Research Statement:Study protocol, statistical code, and data set: Available to individuals by written request.

Requests for Single Reprints: Harry L.A. Janssen, MD, PhD, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Room Ca 326a, PO Box 2040, 3000 CA Rotterdam, the Netherlands; e-mail, mailto:h.janssen@erasmusmc.nl.

Current Author Addresses: Drs. Veldt, Hansen, Schalm, and Janssen: Department of Gastroenterology & Hepatology and Epidemiology & Biostatistics, Erasmus MC University Medical Center, Room Ca 326a, PO Box 2040, 3000 CA Rotterdam, the Netherlands.

Dr. Heathcote: Toronto Western Hospital, University Health Network, 399 Bathurst Street, 6B Fell, Room 154, Toronto, Ontario M5T 2S8, Canada.

Drs. Wedemeyer and Manns: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.

Dr. Reichen: Institute of Clinical Pharmacology, University of Bern, Institute of Clinical Pharmacology, Murtenstrasse 35, 3010 Bern, Switzerland.

Drs. Hofmann and Zeuzem: Internal Medicine I, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Author Contributions: Conception and design: B.J. Veldt, H. Wedemeyer, S.W. Schalm.

Analysis and interpretation of the data: B.J. Veldt, H. Wedemeyer, S. Zeuzem, B.E. Hansen, H.L.A. Janssen.

Drafting of the article: B.J. Veldt, H. Wedemeyer, S. Zeuzem, B.E. Hansen, H.L.A. Janssen.

Critical revision of the article for important intellectual content: B.J. Veldt, E.J. Heathcote, H. Wedemeyer, J. Reichen, W.P. Hofmann, S. Zeuzem, M.P. Manns, B.E. Hansen, S.W. Schalm, H.L.A. Janssen.

Final approval of the article: B.J. Veldt, H. Wedemeyer, J. Reichen, W.P. Hofmann, S. Zeuzem, M.P. Manns, B.E. Hansen, S.W. Schalm, H.L.A. Janssen.

Provision of study materials or patients: B.J. Veldt, E.J. Heathcote, H. Wedemeyer, W.P. Hofmann, S. Zeuzem, M.P. Manns, H.L.A. Janssen.

Statistical expertise: B.J. Veldt, B.E. Hansen, H.L.A. Janssen.

Obtaining of funding: B.J. Veldt, S.W. Schalm, H.L.A. Janssen.

Administrative, technical, or logistic support: H. Wedemeyer, W.P. Hofmann, S. Zeuzem, H.L.A. Janssen.

Collection and assembly of data: B.J. Veldt, E.J. Heathcote, H. Wedemeyer, J. Reichen, W.P. Hofmann, S. Zeuzem, H.L.A. Janssen


Ann Intern Med. 2007;147(10):677-684. doi:10.7326/0003-4819-147-10-200711200-00003
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We enrolled all consecutive patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6) that was treated with an interferon-based regimen between 1990 and 2003 at 5 large hepatology units of tertiary care centers in Europe and Canada. Patients were excluded if they were co-infected with hepatitis B virus or HIV. Patients with decompensated liver disease were not eligible for treatment and were therefore not included in the study.

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Figure.
Kaplan–Meier curves showing the occurrence (95% CI) of clinical events in patients with and without sustained virologic response (SVR).
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Appendix Figure.
Relationship of overall, liver-related, and non–liver-related deaths among nonresponders.

Liver transplantation counted as liver-related death at the time of transplantation, but patients who were alive after liver transplantation were regarded as alive in the analysis of overall death.

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Regression of Cirrhosis and Clinical Outcomes in Patients with Chronic Hepatitis C and Cirrhosis
Posted on December 17, 2007
Vincent Mallet
Université Paris Descartes; APHP, Hôpital Cochin, Hépatologie; INSERM U. 567
Conflict of Interest: None Declared

The recent report by Feldt et al. confirms that sustained viral response (SVR) to antiviral treatment is associated with improved outcome in patients with chronic hepatitis C, especially in those with advanced fibrosis (Ishak 4) or cirrhosis (Ishak 5 or 6) (1-3). We have recently reported similar results in 89 consecutively treated patients with chronic hepatitis C who had compensated (Child A) biopsy-proven cirrhosis at inclusion (4) with a median 10-year follow-up period (862 patient-year) (Mallet et al, American Association for the Study of Liver Diseases. Boston, MA. 2007). Patients were stratified on the basis of the decrease of their histopathological fibrosis score on a post-therapeutic liver biopsy. Observed liver-related complications and survival rates were compared between patients with or without regression of cirrhosis, defined as a decrease from 4 to less than, or equal to, 2 METAVIR units (5), and between patients with or without sustained viral response, defined as the absence of detectable hepatitis C virus RNA, 24 weeks after the end of treatment. The median follow-up period was 119 months for patients with regression of cirrhosis (interquartile range, 92 to 134 months) and 120 months (interquartile range, 87 to 140 months) for patients without cirrhosis-reversal (P=0.63; T-test). Sustained viral response was achieved in 39 patients. During the follow-up process, 17 patients with persistent cirrhosis developed at least one cirrhosis-related complication, and among them 13 developed hepatocellular carcinoma. The incidence of liver-related complications, including hepatocellular carcinoma, was lower in patients with SVR (P=0.022 by the log-rank test) but three patients with persistent cirrhosis developed hepatocellular carcinoma despite complete response to therapy. More original and interesting was the impact of cirrhosis reversal on the outcome of patients. Regression of cirrhosis was observed in 22 patients. Twenty of them were long-term responders to therapy and two were biochemical responders (normal liver function tests, no detectable activity on liver biopsy, but persistent viremia) to anti-hepatitis C therapy. No complication occurred in the group of patients with regression of cirrhosis. During the follow-up, 15 patients without regression died (n=11) or underwent liver transplantation (n=4) while none of the 22 patients with regression did (p=0.038 by the log-rank test). Our results confirm the benefits associated with a sustained viral response in cirrhotic patients, and evidence that regression of cirrhosis is the main end-point to cancel cirrhosis-related morbidity and mortality.

1. Braks RE, Ganne-Carrie N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, et al. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin. World J Gastroenterol. 2007;13(42):5648-53.

2. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007;45(3):579-87.

3. Di Marco V, Almasio PL, Ferraro D, Calvaruso V, Alaimo G, Peralta S, et al. Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol. 2007;47(4):484-91.

4. Serpaggi J, Carnot F, Nalpas B, Canioni D, Guechot J, Lebray P, et al. Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol. 2006;37(12):1519-26.

5. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97(10):2614- 8.

Conflict of Interest:

None declared

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Summary for Patients

Sustained Virologic Response in Hepatitis C

The summary below is from the full report titled “Sustained Virologic Response and Clinical Outcomes in Patients with Chronic Hepatitis C and Advanced Fibrosis.” It is in the 20 November 2007 issue of Annals of Internal Medicine (volume 147, pages 677-684). The authors are B.J. Veldt, E.J. Heathcote, H. Wedemeyer, J. Reichen, W.P. Hofmann, S. Zeuzem, M.P. Manns, B.E. Hansen, S.W. Schalm, and H.L.A. Janssen.

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