Gastroenterology

Gastroenterology

Volume 140, Issue 2, February 2011, Pages 450-458.e1
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C

https://doi.org/10.1053/j.gastro.2010.10.047Get rights and content

Background & Aims

Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C.

Methods

HCV RNA–positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m2 body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy).

Results

SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log10 IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups.

Conclusions

The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.

Section snippets

Subjects

Subjects were enrolled by the investigators at each site from December 2004 to May 2006 at 11 US medical centers (www.ClinicalTrials.gov). The study was completed as per the original design, with 2 years of off-therapy follow-up. The last patient completed the 2-year follow-up in February 2010. Inclusion criteria included age 5 to 18 years with chronic HCV infection documented by the presence of HCV RNA in plasma on 2 occasions at least 6 months apart and chronic liver disease as indicated by

Subject Characteristics

Supplementary Figure 1 shows the number of children randomized, treated, and followed up. Baseline characteristics were similar in the 2 treatment groups (Table 1). Most children had early-stage disease; only 5 (4%) had bridging fibrosis and 1 (2%) had cirrhosis.24

Treatment Responses

The primary end point, an SVR, was met by 29 children (53%; 95% confidence interval [CI], 40%–66%) in the PEG-2a plus RV group compared with only 12 (21%; 95% CI, 10%–32%) in the PEG-2a plus placebo group (P < .001). HCV RNA levels

Discussion

This prospective, randomized, controlled trial has shown that the addition of RV to PEG alfa-2a significantly increases early as well as sustained response rates. Therapy with PEG-2a plus RV was superior to PEG-2a plus placebo regardless of age, alanine aminotransferase levels, and degree of histologic severity. The single exception to the superiority of combination therapy was in the small group of children with HCV RNA levels <600,000 IU/mL who responded well regardless of whether RV was

Acknowledgments

The authors thank the following individuals, who were instrumental in the planning, administration, or care of patients enrolled in this study from all participating institutions: Jay H. Hoofnagle, MD, director, Liver Disease Research Branch, scientific advisor, Edward Doo, MD, scientific advisor, and Rebecca Torrance, RN, administrative assistant, National Institute of Diabetes and Digestive and Kidney Diseases; Beth Garrett, RN, study coordinator, and Kathleen M. Brown PhD, study manager,

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    Conflicts of interest The authors disclose the following: Dr Schwarz is supported by Roche (grant/research support), Bristol-Myers Squibb (grant/research support), Gilead (grant/research support), and Novartis (consultant). Dr Gonzalez-Peralta is supported by Boehringer-Ingelheim (grant/research support), Roche (grant/research support), Bristol Myers-Squibb (grant/research support), and Novartis (consultant). Dr Murray is supported by Roche (grant/research support), Bristol-Myers Squibb (grant/research support), and Novartis. Dr Molleston, Dr Haber, Dr Jonas, Dr Rosenthal, Dr Smith, Dr Lobritto, and Dr Valsamakis are supported by Roche (grant/research support). Dr Mohan is supported by Roche (grant/research support) and Gilead (grant/research support). Dr Balistreri is supported by Digestive Care Inc (consultant) and Roche (grant/research support). Dr Narkewicz is supported by Novartis (consultant) and Roche (grant/research support). Dr Rossi is an employee of Roche Molecular Systems. The remaining authors disclose no conflicts.

    Funding Supported by a cooperative agreement between the National Institute of Diabetes and Digestive and Kidney Diseases and the Food and Drug Administration (contract no. 1UO1DK067767-01.CRC) and in part by National Institutes of Health/National Center for Research Resources Colorado CTSI grant no. UL1 RR025780 and the following study sites: M01-RR-00069, Children's Hospital, Aurora, CO; M01-RR-02172, Children's Hospital Boston, Boston, MA; M01-RR-01271, University of California, San Francisco, CA; 5-M01-RR-020359-01, Children's National Medical Center, Washington, DC; M01-RR-00645, Columbia University Medical Center, New York, NY; M01-RR-00082, University of Florida, Gainesville, FL; M01-RR-00037, University of Washington, Seattle, WA; 5-M01-RR-000240, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA; U01-DK-067767-02, Johns Hopkins Medical Center, Baltimore, MD; M01-RR-08084, University of Cincinnati, Cincinnati, OH; and M01-RR-00750, Indiana University, Indianapolis, IN. The contents of this report are the authors' sole responsibility and do not necessarily represent the official views of the National Institutes of Health. Additional support was provided by Hoffmann-La Roche for study medications, the data coordinating center, and central laboratory costs.

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