Gastroenterology

Gastroenterology

Volume 137, Issue 6, December 2009, Pages 1986-1994
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial

https://doi.org/10.1053/j.gastro.2009.08.067Get rights and content

Background & Aims

The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes.

Methods

Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 μg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child–Turcotte–Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality.

Results

During the lead-in, ≥4-log10 decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients.

Conclusions

Viral suppression by ≥4 log10 with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.

Section snippets

Patients and Study Design

The design of the HALT-C trial has been described previously.13 Briefly, 1050 subjects with bridging fibrosis or cirrhosis (Ishak fibrosis score, 3–6) who were nonresponders to prior treatment with interferon (with or without ribavirin) were re–treated with standard dose peginterferon alfa-2a and ribavirin. Subjects with detectable HCV RNA at week 20 were defined as nonresponders and randomized to receive either 90 μg/week of peginterferon alfa-2a as maintenance therapy or to stop treatment and

Patient Groups

Table 1 summarizes the clinical, biochemical, virologic, and histologic characteristics of the HALT-C trial patients included in this analysis grouped by randomization status to the maintenance therapy arm or control arm. All patients received 24 weeks of peginterferon and ribavirin during the lead-in phase, prior to randomization; 618 had detectable HCV RNA in serum at week 20 and were classified as nonresponders, and 146 had undetectable HCV RNA in serum at week 20 and entered the HALT-C

Discussion

The HALT-C trial was a prospective, randomized controlled study designed to determine whether continuing peginterferon alfa-2a at a dose of 90 μg/week over 3.5 years could reduce complications of cirrhosis, HCC, and mortality in patients with chronic hepatitis C and advanced bridging fibrosis or cirrhosis who had failed to achieve an SVR following treatment with peginterferon and ribavirin. Unfortunately, no overall reduction in any of these clinical end points was achieved.14 The results of 2

Acknowledgments

This is publication No. 41 from the HALT-C Trial Group.

The HALT-C Trial was registered with clinicaltrials.gov (No. NCT00006164).

K.L.L.'s current address is Tibotec, Yarlsey, New Jersey.

H.L.B.'s current address is Carolinas Medical Center, Charlotte, North Carolina.

References (27)

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This article has an accompanying continuing medical education activity on page 2159. Learning Objective: Upon completion of reading this article, successful learners will be able to determine the role of peginterferon alfa-2b maintenance therapy on the management of patients with chronic HCV and advanced fibrosis.

Conflicts of interest The authors disclose the following: M.L. Shiffman, G.T. Everson, A.S. Lok, and A.M. Di Bisceglie are consultants for Hoffmann-La Roche, Inc. M.L. Shiffman, J.C. Hoefs, G.T. Everson, and A.M. Di Bisceglie are on the speaker's bureau of Hoffmann-La Roche, Inc. M.L. Shiffman, W.M. Lee, G.T. Everson, A.M. Di Bisceglie, and H.L. Bonkovsky receive research support from Hoffmann-La Roche, Inc. K.L. Lindsay was a consultant and received research support during this study and is now an employee of Tibotec (a subsidiary of Johnson and Johnson), Yardsley, NJ. The remaining authors disclose no conflicts.

Funding Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers listed above), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities, and the General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, and National Institutes of Health (grant numbers are listed above). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.

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