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FDA EXTENDS HEPATITIS C DOSING REGIMEN FOR SCHERING-PLOUGH'S INTRON A; PHYSICIANS CAN NOW TAILOR THERAPY FOR CHRONIC HEPATITIS C PATIENTS

MADISON, N.J., March 26, 1997 /PRNewswire/ -- Schering-Plough Corporation(NYSE: SGP) announced today that INTRON® A (Interferon alfa-2b, recombinant), the world's largest-selling alpha interferon, has been granted marketing clearance by the U.S. Food and Drug Administration for extension of therapy for chronic viral hepatitis C for 18-24 months. INTRON A therapy for 18-24 months has been shown to nearly double patients' sustained response rates, compared to six months of treatment (the previously indicated treatment regimen), according to studies submitted to the FDA.

"The benefits of extended therapy with interferon alfa-2b are seen in the significantly greater proportion of patients who achieved a sustained response," said Douglas T. Dieterich, M.D., Associate Professor of Medicine, New York University School of Medicine. "Early detection and immediate institution of aggressive therapy are proving to be the most effective in the treatment of hepatitis C."

Richard W. Zahn, president, Schering Laboratories, stated, "The FDA's prompt action on this extended-dosing submission now provides physicians with the opportunity to develop optimal therapy for their hepatitis C patients. Patients who are diagnosed early and treated for a duration of 18-to-24 months have a better chance of maintaining a long-term response."

The combined results from the multicenter trials demonstrated that 24 percent of all patients treated for 18-24 months achieved a durable sustained response (6 months post-therapy) compared with 12.5 percent for those treated for six months. Similarly, improvement in liver cell inflammation and death (necroinflammatory activity) -- another measure of response to treatment -- was seen in significantly more patients who received INTRON A for 18-24 months compared to those who received six months of therapy (58 percent versus 38 percent respectively).

RELATIONSHIP BETWEEN BIOCHEMICAL, VIROLOGICAL, AND HISTOLOGICAL RESPONSE DURING INTERFERON TREATMENT OF CHRONIC HEPATITIS C.

Shiffman ML; Hofmann CM; Thompson EB; Ferreira-Gonzalez A, Contos MJ; Koshy A; Luketic VA; Sanyal AJ; Mills AS; Garrett CT; Hepatology Section, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA. Hepatology, 1997 Sep, 26:3, 780-5

The present study was conducted to evaluate the relationship between biochemical, virological, and histological response during the course of interferon therapy. Ninety consecutive patients with well-documented chronic hepatitis C virus (HCV) were treated with 5 MU of interferon alfa-2b three times weekly for 6 months. Liver biopsy was performed, and serum HCV RNA titer was measured before and at the completion of interferon treatment. Normalization of serum alanine transaminase (ALT) concentration (biochemical response) was observed in 50% of patients. In these patients, Knodell score declined significantly from 9.6 +/- 0.5 to 5.0 +/- 0.5 (P < .01), and 75% became HCV RNA negative. The remaining patients (50%) were biochemical nonresponders; mean Knodell score declined from 9.6 +/- 0.5 to 7.7 +/- 0.5 (P < .01), and 11% became HCV RNA negative. For both biochemical responders and nonresponders, the decline in Knodell score was confined to the components of hepatic inflammation (piecemeal necrosis + lobular + portal inflammation); no change in fibrosis was observed. Hepatic inflammation declined by 5 points or more in 69% of biochemical responders and 48% of biochemical nonresponders, and by at least 50% from pretreatment values in 74% and 38% of biochemical responders and biochemical nonresponders, respectively. For all patients (both biochemical responders and nonresponders) who remained viremic at the conclusion of interferon therapy, the reduction in hepatic inflammation was a linear function of the decline in HCV RNA titer. We conclude that more than one third of patients who had no biochemical response after 6 months of interferon therapy achieved a similar improvement in hepatic histology as was observed in patients with biochemical response. This improvement in hepatic histology appeared to correlate with a reduction in HCV RNA titer, especially in patients who remained viremic.

INTERFERON ASSOCIATED DECREASED INCIDENCE OF HEPATOCELLULAR CARCINOMA

Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.

Nishiguchi, S., Kuroki, T., Nakatani, S., Morimoto, H., Takeda, T., Nakajima, S., Shiomi, S., Seki, S., Kobayashi, K., and Otani, S. 1995. Lancet. 346:1051-1055.

Patients with cirrhosis and chronic hepatitis C have an increased risk for the development of hepatocellular carcinoma. In this prospective study, 90 patients with chronic hepatitis C and compensated cirrhosis were randomly assigned to receive either 6,000,000 units of interferon-alpha three times a week for 12-24 weeks (n=45) or symptomatic treatment (n=45). The patients were followed for 2 to 7 years. Patients in the treatment group had lower serum alpha-fetoprotein concentrations and were more likely to have improvement on follow-up liver biopsy. Serum albumin concentrations were also greater in the treated patients. Hepatitis C viral RNA disappeared in 16% of the treated patients and none of the controls. Hepatocellular carcinoma was detected in two (4%) of patients treated with interferon-alpha and 17 (38%) of control subjects. In this study, interferon-alpha treatment of 12 to 24 weeks improved liver function in patients with compensated cirrhosis and hepatitis C. The use of interferon-alpha was also associated with a decreased incidence of hepatocellular carcinoma.

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It is thought that treatment with interferon reduces the risk of later developing liver cancer. "The low incidence of hepatocellular carcinoma in patients treated with interferon suggests that interferon may prevent the development of hepatocellular carcinoma." - "Risk Factors and the Effect of Interferon Therapy in the Development of Hepatocellular Carcinoma," Journal of Gastroenterology and Hepatology 1997 Feb;12(2):149-155

INTERFERON "BREAKTHROUGH" AND "NON-RESPONSE"

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the eatment, in spite of a complete initial response (breakthrough). Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients. - "Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection: prevalence, etiology, and management." - Hepatology Vol. 21 no. 3 pp. 645-9 1995 Mar

EFFECT OF INTERFERON THERAPY ON BILE DUCT INFLAMMATION IN HEPATITIS C.

Banner BF; Allan C; Smith L; Savas L; Bonkovsky HL; Department of Pathology, University of Massachusetts Medical Center, Worcester 01450-125, USA. Virchows Arch, 1996 Jul, 428:4-5, 253-9

Inflammation of the bile ducts was studied in liver biopsies from patients with chronic hepatitis C to determine whether the frequency of inflamed bile ducts changes with therapy and correlates with other histological variables and expression of class I and II MHC antigens on ductal epithelium. Twenty patients treated at UMMC between 1991 and 1994 underwent needle biopsies of the liver before and after therapy with interferon alpha 2B (IFN). A complete response to therapy was defined as a return to normal serum alanine aminotransferase levels occurring and persisting during therapy. The number of inflamed bile ducts/total ducts (%IBDs), presence of piecemeal necrosis and lymphoid aggregates, and grade of inflammation were assessed in each high-power field in all areas with bile ducts. The frequencies of these variables were compared in cirrhotics and non-cirrhotics and in patients with complete or incomplete responses to IFN. Frozen sections of biopsies from 5 patients were immunostained using antibodies to HLA-DR and B-2 microglobulin, and positive staining was noted on bile ducts. Before therapy, the %IBD was slightly greater in patients with cirrhosis. After IFN, both %IBD and serum alkaline phosphatase levels decreased in non-cirrhotics who responded to IFN. The change in frequency of IBD with IFN paralleled the changes in the other histological features. No correlation was noted between bile duct inflammation and expression of class I and II antigens. The conclusion is that inflammation of the bile ducts occurs frequently in chronic hepatitis C, correlates with other features of inflammation in the triads, and decreases in response to IFN therapy.

INF TREATMENT : INFLUENCE OF DURATION / DOSE

Chemello, L., Bonetti, P., Cavalletto, L., Talato, F., Donadon, V., Casarin, P., Belussi, F., Frezza, M., Noventa, F., Pontisso, P., Benvegnu, L., Casarin, C., Alberti, A., and the TriVeneto Viral Hepatitis Group. 1995. Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C. Hepatology. 22:700-706.

This paper reports another trial of different dosing schedules of alpha-interferon in the treatment of chronic hepatitis C. In this study from Italy, 174 patients with chronic hepatitis C using were randomized to three different dosing schedules: (1) 12-month treatment starting with 6 million units (MU) three times a week and decreasing the dose on the basis of serum ALT activities; (2) fixed dose of 3 MU three times a week for 12 months; (3) fixed dose of 6 MU three times a week for 6 months. Serum ALT activities became normal during therapy in between 65 % and 76 % of patients with no significant differences between groups. Twelve months after the completion of therapy, however, 49 % of the patients in the first group had normal serum ALT activities while only 31 % and 28 % respectively did in the second two groups. The majority of patients with normal serum ALT activities 12 months after treatment had no serum HCV RNA detected by the reverse transcription-polymerase chain reaction and improved liver biopsy findings at that time. Patients infected with HCV genotype 1b did worse overall but showed a better chance of having a sustained response with higher dose and longer treatment. These results, combined with the results of several other recent studies, show that sustained response to treatment with alpha-interferons in patients with chronic hepatitis C is affected by dose and duration of therapy.

IMPROVED SUSTAINED RESPONSE FOLLOWING TREATMENT OF CHRONIC HEPATITIS C BY GRADUAL REDUCTION IN THE INTERFERON DOSE

Authors: shiffman_ml, hofmann_cm, luketic_vac, sanyal_aj, contos_mj, mills_as, virginia commonwealth univ, med coll virginia, hepatol sect, box 980711, richmond, va 23298 virginia commonwealth univ, med coll virginia, div surg pathol, richmond, va 23298. Publication: HEPATOLOGY, 1996, Vol.24, No.1, pp.21-26

ABSTRACT: Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with a high rate of relapse, IFN is thought to exert its effect against HCV via direct viral inhibition and immune stimulation, We have hypothesized that relapse following termination of therapy results from the sudden withdrawal of this immune modulatory effect and that gradual reduction in the IFN dose may decrease the incidence of relapse.

One hundred six patients with chronic HCV were enrolled into this 24-month controlled, randomized prospective trial. All were treated with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who achieved biochemical response were randomized to either stop or taper IFN gradually at monthly intervals as follows; 3 mU, 2 mU, 1 mU, and 0.5 mU (all three times a week), 0.5 mU twice weekly and then once weekly.

Liver histology was assessed by Knodell index and HCV RNA was measured by a quantitative polymerase chain reaction BCR) assay, Of the 92 patients who completed the initial 6 months of IFN treatment, 47 (51%) achieved biochemical response, Twenty-one of these patients were randomized to stop IFN treatment and 25 to taper (1 drop-out), At randomization patients were well. matched with respect to age, sex, race, serum alanine transaminase (ALT), and liver histology, Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN treatment compared with only 60% who tapered (P = .04), Virological relapse occurred in 90% of patients who stopped and only 48% of persons who tapered IFN therapy. At completion of the 24-month study patients who achieved long-term sustained biochemical response had a significantly lower mean Knodell score (3.5 vs, 6.5) and a significantly greater number were HCV RNA negative in serum (85% vs, 18%) compared with relapsers.

We conclude that gradual reduction in IFN dose is associated with a significantly higher rate of sustained response and clearance of HCV RNA hom serum compared with abruptly stopping treatment, This in turn is associated with a significant improvement in hepatic histology supporting the premise that response to IFN therapy can prevent progression to cirrhosis.

DURATION OF HCV INFECTION AS A PREDICTOR OF NONRESPONSE TO INTERFERON

Author: CRAXI A, POLICLIN UNIV, DIV MED & GASTROENTEROL, MED CLIN 1, PIAZZA CLIN 2, I-90100 PALERMO, ITALY Source: DIGESTIVE DISEASES AND SCIENCES 1996 DEC;41(12):S 86-S 92

Duration of hepatitis C virus (HCV) infection is a key feature in determining responsiveness to interferon (IFN). Studies assessing its value as a predictive factor in chronic HCV infection show that a long duration of infection reduces the likelihood of a sustained response to IFN (defined as ALT normalization and clearance of serum HCV-RNA). The effect of HCV infection duration is independent of the presence of cirrhosis and level of HCV viremia. Meta-analysis of IFN trials in acute HCV infection shows an obvious effect of the drug on long-term ALT normalization and HCV-RNA clearance. Treatment of HCV infection during the acute or early chronic phase could therefore maximize therapeutic effectiveness.

A COMPARISON OF THREE INTERFERON ALFA-2b REGIMENS FOR THE LONG-TERM TREATMENT OF CHRONIC NON-A, NON-B HEPATITIS

Poynard, T., and the Multicenter Study Group. 1995. ;New England Journal of Medicine. 332:1457-1462.

In this large, prospective study from France, over 300 patients with chronic non-A, non-B hepatitis, approximately 88 % of whom were shown to be infected with the hepatitis C virus, were treated with various interferon alfa-2b regimens for 18 months. All 329 patients received the standard dose of 3,000,000 units three times a week for the first six months. For the next 12 months, approximately a third of the patients continued to receive 3,000,000 units three times a week (Group 1), another third 1,000,000 units three times a week (Group 2) and another third no interferon alfa-2b (Group 3). After a total of 18 months, 44.7 % of patients in Group 1, 26.7 % of patients in Group 2 and 30.3 % of patients in Group 3 had normal serum aminotransferase activities, respectively. At times between 19 and 42 months, 22.3 % of patients in Group 1, 9.9 % in Group 2 and 8.1 % in Group 3 had normal serum aminotransferase activities, respectively. Of patients who had follow-up liver biopsies at 18 months, a greater number in Group 1 showed improvement compared to Groups 2 and 3. These results suggest that longer treatment with interferon alfa-2b may improve the long-term response in patients with chronic hepatitis C. This study did not take into account the additional cost of longer treatment. It also is not known if the improved response at times up to 42 months will persist or prolong overall survival.

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