• Progression of Liver Disease as Indicated by Death, Hepatic Decompensation, Hepatocellular Carcinoma, or for Patients With Noncirrhotic Fibrosis at Baseline, an Increase in the Ishak Hepatic Fibrosis Score of 2 or More Points [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Increase in Ishak Fibrosis Score by 2 Points or More at 2 or 4 Year Biopsies [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Death From Any Cause [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: Yes ]
• Development of Hepatocellular Carcinoma (HCC) [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Child-Turcotte-Pugh (CTP) Score of 7 or Higher at Two Consecutive Study Visits [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Variceal Hemorrhage [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Ascites [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Spontaneous Bacterial Peritonitis [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Hepatic Encephalopathy [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]

• Increase in Ishak fibrosis score by 2 points or more at 2 or 4 year biopsies
• Death from any cause
• Development of HCC
• CTP score of 7 or higher at two consecutive study visits
• Variceal hemorrhage
• Ascites
• Spontaneous bacterial peritonitis
• Hepatic encephalopathy

• Serious Adverse Events [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: Yes ]
• Events Requiring Dose Reductions (in Both Treatment Groups). [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: Yes ]
• Changes in Fibrosis From Baseline at Year 2 or Year 4 Biopsy. [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Presumed Hepatocellular Carcinoma (HCC) [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]
• Quality of Life [ Time Frame: 1400 days (3.85 years) post randomization ] [ Designated as safety issue: No ]

• Quality of life,
• Serious adverse events, and
• Events requiring dose reductions (in both treatment groups).
• Changes in fibrosis from baseline at year 2 or year 4 biopsy.
• Presumed Hepatocellular Carcinoma

The HALT-C Trial is a National Institute of Diabetes and Digestive and Kidney Diseases sponsored, randomized clinical trial of long-term use of Peginterferon alfa-2a (pegylated interferon) in patients who failed to respond to prior interferon treatment. All patients who enter the trial will be treated for 6 months with Peginterferon alfa-2a and Ribavirin. Patients who respond to this 6 month treatment will continue to be treated for an additional 6 months.

Patients who do not respond to this treatment will be eligible for the long-term maintenance phase of this study where patients will be randomly selected to be treated with Peginterferon alfa-2a or to discontinue treatment for 3.5 years. Patients in both arms of this study will be followed closely with quarterly study visits.

The combination of peginterferon plus ribavirin has recently been approved by the FDA for treatment of chronic HCV. Patients who remain HCV-RNA positive after being treated for at least 6 months with peginterferon and ribavirin outside of this study may be eligible to directly enter the randomized portion of the HALT-C Trial.

The HALT-C study is designed to determine if continuing interferon long-term over several years will suppress Hepatitis C virus, prevent progression to cirrhosis, prevent liver cancer and reduce the need for liver transplantation.

• Chronic Hepatitis C
• Cirrhosis, Liver
• Fibrosis, Liver
• Hepatic Cirrhosis

• Drug: Peginterferon alfa-2a + Ribavirin
• Drug: Peginterferon alfa-2a

• Experimental: Peg-interferon alfa-2a 90 mcg/week
• Active Comparator: Standard of care followup

• Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL; HALT-C Trial Investigators. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med. 2008 Dec 4;359(23):2429-41.
• Lee WM, Dienstag JL, Lindsay KL, Lok AS, Bonkovsky HL, Shiffman ML, Everson GT, Di Bisceglie AM, Morgan TR, Ghany MG, Morishima C, Wright EC, Everhart JE; HALT-C Trial Group. Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders. Control Clin Trials. 2004 Oct;25(5):472-92.
• Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, Lee WM, Lok AS, Di Bisceglie AM, Bonkovsky HL, Hoefs JC, Dienstag JL, Morishima C, Abnet CC, Sinha R; HALT-C Trial Group. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009 Nov;50(5):1360-9.
• Everhart JE, Lok AS, Kim HY, Morgan TR, Lindsay KL, Chung RT, Bonkovsky HL, Ghany MG; HALT-C Trial Group. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology. 2009 Aug;137(2):549-57. Epub 2009 May 13.
• Lok AS, Everhart JE, Chung RT, Kim HY, Everson GT, Hoefs JC, Greenson JK, Sterling RK, Lindsay KL, Lee WM, Di Bisceglie AM, Bonkovsky HL, Ghany MG, Morishima C; HALT-C Trial Group. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2009 Jun;49(6):1828-37.
• Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman ZD; HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009 Jan;136(1):138-48. Epub 2008 Sep 18.
• Lindsay KL, Morishima C, Wright EC, Dienstag JL, Shiffman ML, Everson GT, Lok AS, Bonkovsky HL, Lee WM, Morgan TR, Ghany MG; HALT-C Trial. Blunted cytopenias and weight loss: new correlates of virologic null response to re-treatment of chronic hepatitis C. Clin Gastroenterol Hepatol. 2008 Feb;6(2):234-41.

Inclusion Criteria:

• Age at entry at least 18 years.
• Positive for Hepatitis C.
• Previous treatment with any interferon or interferon and ribavirin for at least 3 months.
• Documented non-response to treatment with interferon.
• A liver biopsy demonstrating significant liver scarring.

Exclusion Criteria:

• No other liver disease.
• No unstable major medical diseases or conditions.
• No major complications of cirrhosis.
• No recent abuse of alcohol or illicit drugs.

• National Institute of Allergy and Infectious Diseases (NIAID)
• National Center on Minority Health and Health Disparities (NCMHD)
• National Cancer Institute (NCI)
• Hoffmann-La Roche