Hepatitis C MAINTENANCE THERAPY STUDIES

Recent research has suggested that maintenance therapy of interferon may delay histology or hepatitis disease progression. Histological improvement is observed in some nonresponders to interferon or interferon/ribavirin therapy. This observation has given impetus to begin two large studies to test the concept of low dose interferon maintenace therapy.

Mitch Shiffman conducted a small randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in a subset of nonresponders (Gastroenterology  1999;117:1164-1172). Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months.  Abstract reported--Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 15.6), log HCV-RNA titer (5.85 0.15 copies/mL), histology score (9.5 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions (P < 0.05) in serum ALT level (62.6   9.6), log HCV-RNA titer (4.79 0.13 copies/mL), and hepatic inflammation (4.0 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement (P < 0.03). Discontinuation of interferon was associated with an increase in

mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients (P < 0.01). Shiffman concluded that these data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic.

I think there are some doubters that maintenance therapy will prove for all non-responders to be significantly meaningful, particularly enough to suffer the rigors of ongoing long-term therapy. But these two studies will hopefully answer this question. One concern that has been raised is that complete non-responders or individuals with less virological response than others may not benefit much if at all from long-term low-dose interferon maintenace therapy.

THE TWO STUDIES

There are two main differences between these two studies. In one study, a person receives the Hoffman-LaRoche Pegasys pegylated interferon, and if not virologically responsive is randomized to low dose maintenance Pegasys interferon or no therapy at all. In the other study, a participant receives low dose Schering-Plough Peg-Intron pegylated interferon, and if not responsive virologically is randomized to low dose maintenance Peg-Intron interferon or colchecine (described below)..

HALT-C  Hepatitis C Antiviral Long Term Treatment Against Cirrhosis

This study is being conducted by the NIH (National Institutes of Health) and will be available at 10 sites listed below. The study size is targeted for 1300 people. Essentially, the study is for people with cirrhosis or more advanced disease who might progress to cirrhosis. The goal of the study is to see if a progression from fibrosis to cirrhosis can be prevented or delayed, and to see if progression from cirrhosis to decompensation can be delayed or prevented. You can enter the study with frank cirrhosis. Eligibility criteria -- for individuals with detectable HCV viral load and previously treated with at least 12 weeks with any form of interferon or interferon/ribavirin; a person will need a fibrosis score of 3 (Ishak Fibrosis Scoring System - range 0-6). Study participants will receive 5 months of full dose Pegasys 180 ug/ml once weekly subcutaneous injection (Roche pegylated interferon) + ribavirin. After 5 months of treatment, if a person has detectable viral load they will be randomized to low dose interferon alone (90 ug/ml once weekly subc. injection) or no treatment at all. Participants will receive 90 ug/ml for 3.5 years. Biopsies will be performed at baseline and at 2 and 4 years into the study.

A biopsy performed within 12 months prior to start of study is acceptable. A full battery of bloodwork will be performed at baseline and throughout the study including monitoring histology changes, and regular bloodwork monitoring including ALT and HIV-RNA. Individuals with HIV or hepatitis B are not eligible for the study. Additional eligibility criteria: hemoglobin 11 g/dL; neutrophil count>1,500/mm3; platelets >75,000/mm3.

STUDY SITES LISTED BELOW.

COPILOT Study--Colchecine Peg Intron Long Term Therapy

This is a study of maintenance Schering-Plough's Pegylated Intron therapy at a dose of 0.5 mcg/kg (once weekly subcutaneous injection). There will be 100 study sites, and 17 sites are up and running now. About 1000 participants are planned for enrollment. Participants will be randomized to either colchecine (0.6 mg twice daily), which is a pill, or Peg Intron. The study will look to see if long term Peg-Intron will prevent the clinical progression of disease and fibrosis in patients with advanced fibrosis or cirrhosis secondary to hepatitis C, who are virological non-responders to interferon/ribavirin. More specifically, the study will evaluate the effect of colchecine and Peg-Intron on the slowing or preventing of fibrosis progression, progression to decompensation, and progression to liver cancer. The study is 4 years in length. The hope for maintenance therapy is that individuals who are complete non-responders, partial responders or relapsers to prior HCV therapy will be able to slow or prevent fibrosis progression and HCV disease. The goal is to keep people alive and healthy enough to receive additional treatments for HCV which are in early stages of  research and development.

This study is designed for individuals who have severe fibrosis or cirrhosis and have tried more than one attempt at therapy and were unable to achieve undetectable HCV-RNA. Colchecine is an anti-fibrotic drug. In alcoholic hepattis and cirrhosis, colchicine has shown a survival benefit.

In alcoholic hepatitis interferon, therapy is not indicated because interferon is an antiviral, and in alcoholic hepatitis fibrosis is due to damage from alcohol. The efficacy of colchecine is unknown in HCV. There will baseline evaluation by biopsy, serum fibrosis markers, liver cancer markers, ultrasound to look for tumors in the liver, and alpha-fetoprotein (marker for cancer). For patients with cirrhosis the study protocol calls for clinical follow-up during the study for cancer by ultrasound examination and alpha-feotprotein measurement. The study will evaluate if treatment for individuals who are expected to progress to liver cancer or decompensation with 2-5 years can delay or prevent progression. Certainly, preventing progression is a main goal, but reducing progression rates would permit a person to avail themselves of new treatment developments that may emerge in the future. Compliance will be assessed and monitored by study coordinators, monthly phone calls and at regular visits.

If you think you might be intertested in this study please make sure your doctor checks the protocol to make sure it's appropriate for you. The use of herbal/alternative treatments except those listed below will be strongly discouraged: multivitamins without iron, thiamine, vitamin E, and folic acid.

People with liver failure and decompensation, or HIV are excluded. But individuals with advanced fibrosis and cirrhosis are eligible for the study. Other inclusion criteria include: hemoglobin 11 g/dL in males or 10 in females; neutrophil count>1,500/mm3; platelets >70,000/mm3; fasting blood sugar 115 mg/dl or within 20% of the upper limit of normal for non-diabetics; alpha-fetprotein within the normal range or < 100 ng/ml with normal ultrasound; ultrasound with no evidence of suggested hepatoma.

The Principal Investigator for this study is Nezam Afdhal, MD. He is Associate Prefessor of Medicine at Harvard University School of Medicine, Chief of Hepatology, Beth-Israel Deaconess Medical Center.

SITES FOR TWO STUDIES

HALT-C (physicians call requested)

University of Massachusetts in Worcester
Herbert Bonkovsky, MD  508-856-3068

St. Louis University in Missouri
Adrian Di Bisceglie, MD  314-577-8762

Massachusetts General Hospital in Boston
Jules Dienstag, MD  617-726-7450

University of Colorado Health Sciences Center in Denver  Gregory T.Everson, MD  303-372-8862

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Disease Section

Marc Ghany, MD 301-402-5115

University of California at Irvine in Orange, California
John Hoefs, MD 714-456-7518

University of Texas Southwestern Medical Center in Dallas
William M. Lee, MD 214-648-3323

University of Southern California in Los Angeles
Karen L. Lindsay, MD 323-442-5550

University of Michigan in Ann Arbor
Anna Lok, MD 877-452-4813

Medical College of Virginia Commonwealth University (physicians call) Mitchell L. Shiffman, MD  804-828-4060

COPILOT

Since there will be 100 sites the list is too long to reproduce here. You can call the main study site: Jocelyn Leone, the study coordinator and nurse practitioner for a site in your area (617 632-1071). There are sites in all major cities.  Below are sites in some major cities.   The list is  in no particular order.

Nezam Afdhal, MD (Beth Israel Deaconess Medical Center)
Boston, MA
617 632-1071

David Nunes, MD (Boston Med Ctr)
Boston, MA
617 638-8221

N.Y. Presbyterian (Bob Brown, MD)
New York, NY
212 305-0662

North Shore University Hospital
Div. of GI
Manhasset, NY
516 562-4281

Sam Moskowitz, MD
Forest Hills, NY
718 520-0857

Doug Dieterich
New York, NY
212 995-6930

Edward Lebovics, MD (NY Medical College)
Valhalla, NY
914 493-7337

Murray Ehrinpreis, MD (Haper Hosp)
Detroit, MI
313 745-8601

Viktor Eysselein, MD (Harbor-UCLA Med Ctr)
Torrance, CA
310 222-2474

Robert Gish, MD
San Francisco, CA
415 202-1530

John Goff, MD
Denver, CO
303 573-9951

Rajeev Jain, MD
Dallas, TX
214 979-0883

Paul Lebovitz, MD
Pittsburgh, PA
412 359-6950

Pierre Nader, MD
Seattle, WA
206-243-4940

George Nikias, MD (Hackensack University Med Ctr)
Hackensack, NJ
201 996-3196

Eddie Chueng, MD
Oakland, CA
510 654-5555

Mitchell Davis, MD
West Palm Beach, FL
561 845-6228

Mark Swaim, MD (Duke Univ  Med Ctr)
Durham, NC
919 403-5228

John Venetos, MD
Chicago, Ill
773 489-6262

Paul Thuluvath, MD (Johns Hopkins Hosp)
Baltimore, MD
410 614-5389

Ira Jacobson, MD
Cornell Hospital, Chief of GI
New York, NY
212 746-2115