Altered Interferon Boosts Antiviral Response
Peginterferon alfa-2aa formulation of interferon alfa-2a covalently bound to polyethylene glycolworked significantly better than unmodified interferon alfa at controlling HCV infections, reported two studies in the Dec. 7 New England Journal of Medicine (NEJM). The benefits of peginterferon therapy came without an increase in the incidence or type of adverse effects commonly associated with standard interferon therapy, even among patients with cirrhosis.
In one large study involving mostly adults without cirrhosis, 69 percent of HCV-infected patients given subcutaneous injections of peginterferon once weekly had no detectable amount of HCV RNA in their plasma after 48 weeks of treatment. In contrast, just 28 percent of patients given unmodified interferon alfa-2a three times weekly attained this level of response. Patients who had an undetectable amount of HCV RNA in their plasma were considered to have had a virologic response to treatment.
Twenty-four weeks after treatment ended, 39 percent of the patients in the peginterferon group and 19 percent of the patients in the interferon alfa-2a group had virologic responses to treatment.
A smaller study of patients with chronic HCV infection and also cirrhosis or bridging hepatic fibrosis compared the effects of interferon alfa-2a with two dosages of peginterferon. Twenty-four weeks after treatment ended, 30 percent of the patients who self-administered the higher dosage of peginterferon and 15 percent who took the lower dosage had virologic responses. Viral RNA was undetectable in the plasma of only 8 percent of the patients treated with interferon alfa-2a.
The two research teams found that patients who mounted a strong immune response to the virus were also likely to have an improved histologic response, which was determined by examination of liver-biopsy specimens. However, 26 to 35 percent of the patients in the HCVcirrhosis study who did not eliminate the virus from their bloodstream showed histologic improvement after treatment with interferon or peginterferon. Nearly half of the patients in the larger study who did not have a virologic response showed histologic improvement at week 72, 24 weeks after the end of treatment.
Both of these clinical trials were among several conducted by the Pegasys International Study Group. Pegasys, the brand-name designation for peginterferon, is manufactured by F. HoffmannLaRoche Ltd., which funded both trials.
The company's U.S. pharmaceuticals group asked the Food and Drug Administration (FDA) in May to approve the marketing of Pegasys for the treatment of chronic HCV infection. FDA has already classified peginterferon alfa-2a as an orphan drug for the treatment of certain cancers.
Both of the studies reported in NEJM spanned 72 weeks, with 48 weeks of interferon treatment and 24 weeks of follow-up. In the larger study, patients in the peginterferon group received 180 mcg of the drug subcutaneously once a week for 48 weeks. Patients in the interferon alfa-2a group received 6 million units of the drug subcutaneously three times a week for 12 weeks, then 3 million units three times a week for 36 weeks.
The HCVcirrhosis study used a simpler treatment protocol. During the 48-week treatment phase, patients self-injected 180 or 90 mcg of peginterferon once a week or 3 million units of interferon alfa-2a three times a week.
Adjustment of the drug dosage in response to adverse events or blood abnormalities was permitted during both studies. In the larger study, 19 percent of the patients in the peginterferon group and 18 percent of the interferon alfa-2a group used a modified dosage of their assigned drug. Among patients in the HCVcirrhosis study, dosage modifications were required by 43 percent of patients taking high-dose peginterferon, 29 percent taking low-dose peginterferon, and 33 percent of interferon alfa-2a patients.
In the larger study, 7 percent of the peginterferon users and 10 percent of patients taking interferon alfa-2a withdrew from the study because of an adverse event or abnormal laboratory test results. Fourteen percent of patients taking high-dose peginterferon, 11 percent taking low-dose peginterferon, and 10 percent using interferon alfa-2a withdrew from the HCVcirrhosis study for the same reasons.
Patients in all study groups, in both studies, frequently reported having headaches, fatigue, fever, and muscle aches during treatment. One patient in the larger study died from a heroin overdose during the follow-up period. Four patients who participated in the HCVcirrhosis study died after follow-up; two died subsequent to liver failure, one had a liver neoplasm, and one patient was suspected to have taken an overdose of methadone.
The larger of the two studies was conducted between December 1997 and November 1999 at 36 medical centers outside the United States. Adults infected with hepatitis A or B or human immunodeficiency virus were not eligible to participate in this study. Other exclusion criteria included the presence of decompensated liver disease; heart, lung, or autoimmune disease; and psychiatric disorders. Although patients with cirrhosis were eligible for this study, relatively few4 percent of patients in the peginterferon group and 10 percent of those receiving interferon alfa-2ahad the condition.
A total of 531 patients, all of whom tested positive for antibodies to HCV and had at least 2,000 copies of HCV RNA per milliliter of plasma, enrolled in the study. Upon randomization, 264 patients were assigned to the interferon alfa-2a group and 267 to the peginterferon group. In all, 161 patients in the interferon alfa-2a group and 223 in the peginterferon group completed treatment.
The study of patients whose HCV infections were complicated by cirrhosis took place between September 1997 and October 1999 at 30 medical centers in the United States, Canada, Australia, and the United Kingdom. Adults with psychiatric disorders or conditionssuch as another liver disease, human immunodeficiency virus infection, cancer, or severe heart diseasewere not eligible for this study.
In this randomized trial, 87 patients were assigned to the 180-mcg peginterferon group, 96 to the 90-mcg peginterferon group, and 88 to the interferon alfa-2a group. Sixty-four patients in the interferon group, 67 in the 180-mcg peginterferon group, and 78 in the 90-mcg peginterferon group completed the treatment phase of the study.
Thirty-three percent of the patients in the larger study were women. The average age was 41 years for both study groups. Patients in the HCVcirrhosis study were, on average, 47 years old, and 26 to 30 percent of participants in the three treatment groups were women. Most patients in both of the studies were infected with variants of HCV genotype 1.
According to the studies' sponsor, the addition of polyethylene glycol to interferon alfa-2a seems to prolong the antiviral activity of the drugs interferon component. In consequence, peginterferon does not need to be administered as frequently as interferon alfa-2a, a factor that could increase patients compliance with the treatment program.
Interferon alfa-2a is often used in combination with the antiviral agent ribavirin to treat chronic HCV infection. The National Institute of Diabetes and Digestive and Kidney Diseases recommends that HCV-infected patents use interferon without the antiviral agent only if they cannot tolerate ribavirin.
Roche said it is currently conducting studies of Pegasys in combination with ribavirin.