HALT-C Trial Shows Minimal Long-term Benefit of Pegylated Interferon Alfa-2a (Pegasys) Maintenance Therapy in Patients with Chronic Hepatitis C
Combination therapy with pegylated interferon plus ribavirin produces
sustained hepatitis C virus (HCV) suppression in about half of all patients
(less for HCV genotype 1, more for genotypes 2 or 3).
Over time, chronic HCV infection can progress to advanced liver fibrosis,
cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, and
death due to liver failure. Since interferon-based therapy does not always
eradicate the virus, researchers have explored various strategies for
reducing or reversing liver disease progression even in the absence of
sustained virological response (SVR).
The large HALT-C (Hepatitis C Antiviral Long-term Treatment against
Cirrhosis) study aimed to determine whether extended maintenance with
pegylated interferon monotherapy could prevent progressive liver disease
among hepatitis C patients who did not respond to combination therapy.
Results were presented in a late-breaker session at the recent 58th Annual
Meeting of the American Association for the Study of Liver Diseases (AASLD)
Researchers from multiple U.S. centers conducted a randomized controlled
trial in which 1050 patients with chronic hepatitis C and advanced fibrosis
who were non-responders to prior therapy with pegylated interferon plus
ribavirin were randomly assigned to received either 90 mcg once-weekly
pegylated interferon alfa-2a (Pegasys) for 3.5 years or no further
treatment. For comparison, the usual Pegasys dose in combination therapy is
180 mcg once-weekly for 24 (genotypes 2/3) or 48 (genotype 1) weeks.
Participants eligible for enrollment had an Ishak fibrosis score of > 3 on
liver biopsy, a Child-Turcotte-Pugh score of >6, no history of ascites,
encephalopathy, or bleeding varices, and no other identifiable cause of
liver disease. Participants were stratified according to their stage of
fibrosis: Ishak stage 3 or 4 (622 with fibrosis) vs 5 or 6 (428 with
Participants were seen at 3-month intervals, underwent liver biopsies at 1.5
and 3.5 years after randomization, and were monitored for the occurrence of
death, HCC, hepatic decompensation (variceal hemorrhage, ascites,
spontaneous bacterial peritonitis, encephalopathy, or a Child-Turcotte-Pugh
score of = 7), and -- for those with pre-cirrhotic fibrosis at baseline --
an increase in fibrosis score of = 2 points.
By the end of the study, 34.1% of patients in the pegylated interferon maintenance arm and 33.8% of the control group had reached one of the study endpoints (hazard ratio 1.01; P = 0.91; not a significant difference).
Although mean serum ALT and HCV RNA levels decreased significantly with treatment (both P < 0.0001), as did necroinflammatory changes on liver biopsy (P < 0.0001), there was no significant difference observed in rates of any of the primary outcomes:
Death: 6.6% in the treatment group vs 4.6% in the control group;
The rate of serious adverse events was similar in both groups: 284
events among 175 treated patients and 283 events among 155 control subjects.
Hepatic decompensation: 14.3% vs 13.2%, respectively;
HCC: 2.8% vs 3.2%;
Increased fibrosis: 28.2% vs 31.9%.
Among treated patients, 17% stopped pegylated interferon maintenance by
1.5 years and 30% discontinued by 3.5 years.
“Long-term therapy with peginterferon did not reduce the rate of disease
progression,” the investigator concluded. “These findings do not support
maintenance therapy with peginterferon in patients with chronic hepatitis C
and advanced hepatic fibrosis who are non-responders to a course of
Previously presented interim results from HALT-C looked promising, since
pegylated interferon maintenance therapy led to improvements in ALT level,
HCV viral load, and necroinflammation -- surrogate markers that are often
assumed to predict liver disease progression. However, while these results
held, they ultimately did not translate into a lower likelihood of fibrosis
progression, liver cancer, liver failure, or death.
This is supported by data from a similar study of pegylated interferon
alfa-2b (PegIntron) maintenance monotherapy presented at the same
conference, which showed improvements in necroinflammation and fibrosis
scores, but no reduction the rate of serious liver complications including
decompensation and HCC.
Saint Louis University School of Medicine, St. Louis, MO; Virginia
Commonwealth University Medical Center, Richmond, VA; University of Colorado
School of Medicine, Denver, CO; Keck School of Medicine, University of
Southern California, Los Angeles, CA; National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Department of
Health and Human Services, Bethesda, MD; University of Texas Southwestern
Medical Center, Dallas, TX; University of Michigan Medical Center, Ann
Arbor, MI; University of Connecticut Health Center, Farmington, CT;
University of California, Irvine and VA Long Beach Healthcare System,
Irvine, CA; Massachusetts General Hospital and Harvard Medical School,
Boston, MA; University of Washington, Seattle, WA; New England Research
Institutes, Watertown, MA.
AM Di Bisceglie, ML Shiffman, GT Everson, and others. Prolonged Antiviral
Therapy With Peginterferon to Prevent Complications of Advanced Liver
Disease Associated With Hepatitis C: Results of the Hepatitis C Antiviral
Long-term Treatment against Cirrhosis (HALT-C) Trial. 58th Annual Meeting of
the American Association for the Study of Liver Diseases. Boston. November
2-6, 2007. Abstract (oral) LB1.