More HCV Patients Have Long-Term Response to Lymphoblastoid Interferon in Multicenter Trial

A new type of interferon has been proven to be effective for more hepatitis C patients in a long-term response than the standard drug therapy.

Thirty-two percent of the patients who responded to lymphoblastoid interferon alpha n-1 saw their liver function tests return to normal and remain that way six months after stopping therapy, as compared with 20% treated with interferon alpha 2-b, the standard therapy.

Eighty-three percent of the patients with a sustained response using the lymphoblastoid therapy showed no trace of the hepatitis C viral RNA (ribonucleic acid), the genetic messenger whose presence indicates the virus is reproducing itself.

"We are encouraged from these trial results that lymphoblastoid interferon may be useful as an alternative therapy for chronic hepatitis C virus (HCV) infection," said Bruce R. Bacon, M.D., one of the investigators treating 1,071 patients at 63 centers here and abroad. Dr. Bacon is also Professor of Medicine and Director of Gastroenterology and Hepatology at Saint Louis University School of Medicine and Chairman of the American Liver Foundation Patient and Professional Education Committee.

Even though most of the patients with a sustained response because of the lymphoblastoid therapy were HCV RNA negative does not mean that the virus is not still in their bodies.

"Even if there has been clearance of blood-borne virus...HCV can still be sequestered in the liver and elsewhere," Mickey S. Urdea, M.D., of the Chiron Corp., told a meeting of the American Association for the Study of Liver Diseases a year ago. "It is not uncommon for HCV RNA negative patients to relapse based on ALT (alanine aminotransferase, a liver enzyme) and/or RNA elevation."

Why patients respond to interferon alpha, one of three types produced by the body in response to viral infections, is thought by researchers to be associated with the degree of liver disease, concentration of the virus (viral load) and the viral genetic type, as well as other factors in the body which are not completely understood.

"In general, IFN (interferon) is likely to be more effective when at the same time the immune mechanisms involved in viral clearance are already activated and the replicative drive of the virus is failing," Antonio Craxi, M.D., Silvio Magrin, M.D., and Christina Linea, M.D., reported at a recent conference in Barcelona on treatments in hepatology, organized by Juan Rodes, M.D., Jaime Bosch, M.D., and Vincente Aroyo, M.D.

The lymphoblastoid trial showed that patients infected with genotype 2 of the virus had a higher response with lymphoblastoid interferon compared with genotypes 1a, 1b, 1a/1b and 3a. There are at least 21 different genetic forms of the hepatitis C virus around the world. Most patients in the U.S. are infected with either 1a or 1b. The "viral load" for patients in both groups at the start of the trial was the same. Patients treated with lymphoblastoid interferon had side effects similar to interferon alpha 2-b, the most common of which mimic the flu.

"The kind of genotype you have is actually strongly associated with the response to interferon," said Teresa Wright, M.D., Chief of Gastroenterology at the Veterans Administration Medical Center, San Francisco, and an investigator in the lymphoblastoid trial. "Indeed, when we looked at these more than 1,000 patients, the single strongest predictor of response was if you did not have type I. Type I is what unfortunately affects 70% of patients in the U.S.," she told a "Meet The Researchers" program of the San Francisco Bay Chapter of the American Liver Foundation recently.

Viral genotypes 2 and 3, compared to 1b, also showed a greater sustained response to interferon alpha 2-a in an Italian study of chronic hepatitis C patients reported in Hepatology.

Overall 19 of 44 patients (49%) saw their liver enzymes remain normal, with most not having the virus detected in their blood 12 months after they stopped treatment. The treatment was six million units three times a week, with the dose being modified according to the fluctuations of liver enzymes over a period of 12 months. Fourteen of the 19 responders at this dosage were either genotype 2 or 3, with five being type 1b.

Overall 46 of 139 patients had a "sustained response." Fourteen of 47 patients responded to three million units three times a week for a year. Thirteen of 48 responded to six million units three times a week for six months.

Interferon alphas manufactured in the laboratory interfere with the virus reproducing itself in the infected liver cell and stimulate the immune system to reduce the number of infected cells.

The stage of liver disease in the patient is also thought by interferon researchers to be a factor in the complex chemistry between the patient, the drug and the virus. Patients with no cirrhosis and low fibrous tissue in the liver respond better to the drug.

Other host factors that are thought to influence response to interferon alpha are gender (females do better), age (the young do better) and body weight (the leaner the better).

The authors of the Italian study also cautioned about the favorable response rate at six million units because the patients were relatively young, with a recent diagnosis of hepatitis C and a low rate of cirrhosis.

Those with a high concentration of iron also do not respond well. "It is not clear whether increased hepatic iron is an independent factor or if it is a mere reflection of older age, inflammation, presence of cirrhosis or concominant alcohol use," Anna S.F. Lok, M.D., of the University of Michigan, reported at a recent meeting at the University of Texas Southwestern Medical Center.

A second multicenter trial, which tested the results of consensus interferon (a combination of alpha and beta interferons) has also been completed, but the results have not been published.

At one center 50 patients with chronic hepatitis C were placed on five different doses of consensus interferon. Half of the 10 patients on the highest dosage (15 million units) still had normal liver enzymes and were negative for HCV RNA two years after stopping the six month therapy. The long term response rate for the other groups were 30% (12 million units), 10% (9 million and 6 million units) and 0% for three million units.

Beta interferon was used to treat 34 hepatitis C patients in a French and U.S. study for six months at two different doses. Twelve months after therapy was halted, four (23%) of the 21 patients who had never been treated before saw their liver enzymes return to normal and tested negative for HCV RNA. In a second group, two (15%) of 13 patients who did not respond previously to interferon alpha 2-b had the same sustained response as the other group a year after a halt of therapy. The first group was treated at a lower dosage than the second group.

Another multicenter trial, scheduled to begin in 1996, will test a combination therapy of ribavirin, an anti-viral drug, with interferon alpha 2-b. In a small Italian trial, reported two years ago, half the 10 patients had normal liver enzyme levels and a loss of HCV RNA six months after completing the six month course of therapy. (Progress, Fall, 1993). The 10 patients either had relapsed previously in taking interferon alone or had not responded to interferon.

In another small trial, conducted by the National Institutes of Health, the five patients taking ribavirin for two years showed "improvements" in their liver function tests, but no loss of HCV RNA.

Thymosin alpha 1, an immune modulating drug, and interferon alpha 2-b were used in another combined trial in Italy reported recently. Six months after a 12 month course of therapy 7 of 15 patients, including four with cirrhosis, were HCV RNA negative with "normal or near normal" liver function tests. A multicenter trial with this combined therapy, involving over 100 patients, is underway in the U.S.

Source: ALF's Progress; Vol 17 No. 2, Fall-Winter 1996

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