Is Maintenance Therapy with Pegylated Interferon Monotherapy Ineffective or Even Harmful to Patients?

By Ronald Baker, PhD

In patients with chronic hepatitis C who do not have a favorable response to interferon-based antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.

According to a new study published in the December 4, 2008 issue of The New England Journal of Medicine (NEJM), patients who do not initially respond to standard therapy for chronic hepatitis C are unlikely to respond favorably to long-term maintenance therapy either. Standard therapy for chronic HCV infection consists of the combination of once-weekly injections of pegylated interferon alfa (Pegasys or PegIntron) plus daily weight-adjusted doses of oral ribavirin.

Many patients who do not respond to the current standard of care elect to undergo "maintenance therapy" with pegylated interferon monotherapy, hoping that long-term treatment will significantly slow or halt liver disease progression.

But this practice is "ineffective and possibly harmful," the authors of a large maintenance therapy trial wrote in the NEJM article.

Treatment with pegylated interferon plus ribavirin clears HCV from the body in about 40% of all patients, but often produces side effects like fever, debilitating fatigue, and depression.

Patients who do not respond to the initial 6-12 months of treatment (depending on HCV genotype) are sometimes advised to continue therapy using a low maintenance dose of pegylated interferon alone for an indefinite period.

The HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) study, conducted at multiple U.S. medical centers and supported by the National Institute of Diabetes and Digestive and Kidney Diseases, followed 1050 patients with advanced liver disease who had failed to respond to initial treatment with pegylated interferon plus ribavirin. Most of the participants were men, and the mean age was 51 years.

About half the patients (n = 517) were randomly assigned to receive low-dose pegylated interferon alfa-2a (Pegasys) monotherapy at a dosage of 90 mcg per week for 3.5 years, while the remainder (n = 533) received no ongoing therapy.

The patients, who were stratified according to fibrosis stage (622 with non-cirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsies at 1.5 and 3.5 years after randomization.

The primary endpoint was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or-for those with bridging fibrosis at baseline-an increase in the Ishak fibrosis score of 2 or more points.

Results

• Levels of serum aminotransferases (ALT and AST), serum HCV RNA, and histological necroinflammatory scores all decreased significantly in the treatment group (P < 0.001).

• However, there was no significant difference between the 2 groups in the rate of any primary outcomes (34.1% in the treatment group and 33.8% in the control group; P = 0.90).

• 8 patients taking pegylated interferon monotherapy died, compared with 2 untreated participants.

• The percentage of patients with at least 1 serious adverse event was 38.6% in the treatment group, compared with 31.8% in the untreated control group (P = 0.07).

In conclusion, the authors wrote, "Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin."

Discussion

In HALT-C, patients on long-term pegylated interferon fared just as poorly as non-responders who were not taking the drug, according to the researchers. About one-third of participants in each group developed serious complications of hepatitis C, like liver cancer or liver failure.

"To the extent there are still patients out there who are on this form of maintenance therapy, there is a real take-home message: It should be stopped," said HALT-C lead author Dr. Adrian DiBisceglie, professor of internal medicine and co-director of the liver center at St. Louis University School of Medicine.

Maintenance therapy failed despite the fact that it was effective at lowering the amount of virus in patients' blood and reducing conventional signs of liver damage, he added.

"This is a treatment that should not be done," said Dr. Howard Worman, professor of medicine at Columbia University College of Physicians and Surgeons, who was not involved in the study. "Patients should just sit tight and wait for new treatments or drugs to be added, which will happen within a few years."

These new drugs -- collectively referred to as "STAT-C" -- directly target various steps of the HCV lifecycle, for example, HCV protease inhibitors such as telaprevir and polymerase inhibitors such as R7128.

Dr. David Bernstein, chief of gastroenterology and hepatology at North Shore University Hospital on Long Island, said there might still be a "glimmer of hope" --though very little evidence -- that some hepatitis C patients who failed an initial course of treatment might benefit from extended maintenance treatment.

But for now, he added, "there's no reason to make someone feel sicker than they generally feel."

12/09/08

Reference
AM Di Bisceglie, ML Shiffman, GT Everson, and others (for the HALT-C Trial Investigators). Prolonged Therapy of Advanced Chronic Hepatitis C with Low-Dose Peginterferon. New England Journal of Medicine 359(23): 2429-2441. December 4, 2008.