C MAINTENANCE THERAPY STUDIES
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.
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
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.
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.
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)..
C Antiviral Long Term Treatment Against Cirrhosis
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.
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.
SITES LISTED BELOW.
Peg Intron Long Term Therapy
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.
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.
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.
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.
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
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.
(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
College of Virginia Commonwealth University (physicians call) Mitchell L.
Shiffman, MD 804-828-4060
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
Nezam Afdhal, MD (Beth Israel Deaconess Medical Center)
David Nunes, MD (Boston Med Ctr)
N.Y. Presbyterian (Bob Brown, MD)
New York, NY
North Shore University Hospital
Div. of GI
Sam Moskowitz, MD
Forest Hills, NY
New York, NY
Edward Lebovics, MD (NY Medical College)
Murray Ehrinpreis, MD (Haper Hosp)
Viktor Eysselein, MD (Harbor-UCLA Med Ctr)
Robert Gish, MD
San Francisco, CA
John Goff, MD
Rajeev Jain, MD
Paul Lebovitz, MD
Pierre Nader, MD
George Nikias, MD (Hackensack University Med Ctr)
Eddie Chueng, MD
Mitchell Davis, MD
West Palm Beach, FL
Mark Swaim, MD (Duke Univ Med Ctr)
John Venetos, MD
Paul Thuluvath, MD (Johns Hopkins Hosp)
Ira Jacobson, MD
Cornell Hospital, Chief of GI
New York, NY