Final results are in for a landmark study of long-term peginterferon for patients with chronic hepatitis C that isn't responsive to therapy.
It doesn't work, according to Adrian Di Bisceglie, M.D., of Saint Louis University School of Medicine and colleagues.
In the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis study -- or HALT-C -- low-dose peginterferon alfa-2a had no impact on disease progression, Dr. Di Bisceglie and colleagues reported in the Dec. 4 issue of the New England Journal of Medicine.
In the wake of that report, Dr. Di Bisceglie said, many doctors who had been treating patients empirically with peginterferon stopped doing so. "With the publication of the paper, I would hope and imagine that any remaining patients on maintenance therapy would have their therapy stopped," he said.
The researchers randomized 1,050 patients with chronic disease and advanced fibrosis to get either 90 micrograms of peginterferon a week for 3.5 years or no treatment. They were looking for differences in disease progression, indicated by death, hepatocellular carcinoma, hepatic decompensation, or -- for patients who started the trial with bridging fibrosis -- an increase in the Ishak fibrosis score of at least two. Instead, the researchers found, 34.1% of patients treated with peginterferon progressed, compared with 33.8% in the control group, for a nonsignificant hazard ratio of 1.01.
Although there were no overall differences in any of the components of the primary endpoint, Dr. Di Bisceglie pointed out that analysis found one subgroup for which the treatment appeared to worsen outcomes.
Among treated patients with non-cirrhotic fibrosis, 5% died, compared with 1.9% of control patients, a difference that was significant at P=0.04. There was no difference in mortality among cirrhotic patients.
"Not only did it not work, in this little subgroup it looked as if it might have made things worse," he said.
All the patients had previously failed standard therapy with peginterferon and ribavirin, which leads to a sustained virological response in about 50% of patients.
Because earlier studies had shown interferon can suppress hepatitis C RNA levels, decrease serum aminotransferase levels, and improve liver histologic findings, even if the virus is not eradicated, the researchers thought extended treatment might be indicated.
Indeed, in the HALT-C trial, they found that those getting peginterferon had significant changes in all those surrogate markers, compared with the control patients. Specifically:
At 3.5 years, serum alanine aminotransferase levels had declined by
0.47 times the upper limit of the normal range among treated patients, compared with 0.19 times among control patients, a difference that was significant at P<0.001.
At baseline, 17.0% of all patients had normal serum alanine aminotransferase levels, but at 3.5 years, 35.1% of treated patients and 22.6% of control patients had normal levels. Again, the difference was significant at P<0.001.
At the 3.5-year mark, serum hepatitis C RNA levels had fallen by 0.71 log10 IU per milliliter in the treatment group and 0.12 log10 IU per milliliter in the control group, a difference that was again significant at P<0.001.
Both cirrhotic and non-cirrhotic patients in the treatment group had significant declines, on average, in the necroinflammatory score, compared with those in the control group (at P<0.001 for both comparisons).
In the treatment group, there were 3,991 adverse events among 486 patients, compared with 3,129 among 492 patients in the control group. Infections, mainly bacterial, were the most frequent adverse events.
All told, 330 patients had at least one serious adverse event, with a higher proportion in the treatment arm (38.6% versus 31.8%), although the difference did not reach significance.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, the National Institute on Alcohol Abuse and Alcoholism, and by Hoffmann-La Roche.
Dr. Di Bisceglie reported financial links with Hoffmann-La Roche, Idenix Pharmaceuticals, Novartis, Vertex Pharmaceuticals, Bristol-Myers Squibb, Clinical Care Options, Abbott, Schering-Plough, Anadys, GlobeImmune, Pharmasset, Gilead, Geneva Foundation, and SciClone Pharmaceuticals.
Primary source: New England Journal of Medicine
Source reference: Di Bisceglie AM, et al "Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon." N Engl J Med 2008; 359: 2429-41.
Medpagetoday.com
Extended Drug Therapy for Hepatitis Is Challenged
Patients who do not initially respond to standard drug therapy for treatment of hepatitis C are unlikely to respond to long-term maintenance therapy as well, according to a new study.
Yet many patients who do not at first respond to drugs are placed on maintenance therapy, which is expensive and can be both physically and psychologically grueling, in hopes that long-term treatment will keep the disease in check. The practice is ineffective and possibly harmful, the study’s authors said.
“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 the lead author, Dr. Adrian M. Di Bisceglie, professor of internal medicine and co-director of the liver center at St. Louis University School of Medicine.
The 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, Dr. Di Bisceglie said.
The report appears in Thursday’s issue of The New England Journal of Medicine.
The standard treatment for hepatitis C is a regimen of two potent drugs, peginterferon and ribavirin, that can produce side effects like fever, debilitating fatigue and depression. But the treatment clears the virus from the body in about half of all patients.
Those who do not respond to the initial one-two punch in six months to a year are often advised to continue with a lower, maintenance dose of peginterferon alone for an indefinite period.
The new study, conducted at multiple medical centers and supported by the National Institute of Diabetes and Digestive and Kidney Diseases, followed 1,050 patients with advanced liver disease who had failed to respond to initial treatment for three and a half years. Most of the subjects were men, and their mean age was 51. About half received low doses of peginterferon, while half received no therapy.
Patients on long-term peginterferon fared just as poorly as nonresponders who were not taking the drug, the investigators found.
About a third in each group developed serious complications of hepatitis C, like liver cancer and liver failure.
Eight patients on peginterferon died, compared with two who were not taking the drug, a statistically significant difference, researchers said.
“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.”
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 the initial course of treatment might benefit from extended maintenance treatment.
But for now, Dr. Bernstein added, “there’s no reason to make someone feel sicker than they generally feel.”
New York Times By Roni Caryn Rabin
