Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B

BACKGROUND/AIMS: Alpha-interferon (IFN-alpha) is an effective treatment for chronic hepatitis B but only 25-40% of patients will profit from a long-te rm beneficial response to the currently recommended schedule of 3-6 MU give n 3 times a week for 6 months. Clinical trials are therefore needed to inve stigate alternative modifications of interferon therapy, including combinat ions of different antivirals or immune modulators in order to improve the t herapeutic approach to chronic hepatitis B infection. In a phase II trial w e evaluated whether a combination of natural interferon-beta (nIFN-beta) wi th strong antiviral activity plus recombinant interferon-gamma (rIFN-gamma) with a predominantly immunomodulatory activity is able to increase the res ponse rate compared to historical controls treated with IFN-alpha in a conv entional regimen. METHODOLOGY: Forty patients with chronic hepatitis B were included in this trial of combined interferon therapy at a dosage of 6 MU nIFN-beta during w eek 1 followed by 3 MU for weeks 2-4 plus rIFN-gamma at a daily subcutaneou s (s.c.) injection of 150 mu g during the entire 4 weeks of the treatment p eriod. Patients entered the trial on the basis of the following criteria: h epatitis B surface antigen (HBsAG), HBeAG and HBV-DNA positive for at least 6 months, HDV, EBV, CMV, anti-HIV negative, and chronic hepatitis proven o n biopsy taken within 4 weeks of entry as well as 6 and/or 12 months after interferon therapy. The final diagnosis and classification of chronic hepat itis has been based on guidelines according to a revised classification of chronic hepatitis (Desmet 1994). The post-treatment follow-up was 12 months . RESULTS: The combined interferon therapy achieved complete responses with s eroconversion from HBeAG to anti-HBe and st negative HBV-DNA (dot blot) tes t, as well as normalization of ALT activity in 15 patients, and partial res ponse with negativation of HBV-DNA concomitant to a decrease in aminotransf erase activity to near normal levels in 6 patients. Nineteen patients showe d no response to viral markers but showed relief of clinical symptoms as we ll as pronounced decrease of serum transaminase activity. Grading of liver biopsies demonstrated an improvement of histologic parameters after the int erferon regimen in half of the evaluable patients (n=22). Histological resp onse has been quantified by a reduction in the score of histological activi ty (HAI-index) from 12.6 before to 7.6 after interferon therapy, and in the inflammation and cellular degeneration score (ICD) from 9.9 to 5.2. Histol ogical response, however, failed to show a consistent correlation with sero logic response. This medium-dose combination of interferon-beta and interfe ron-gamma was tolerated very well by the patients, this good tolerability b eing explained by tachyphylaxis in response to daily interferon doses. No s erious side effects or decompensation of liver function were observed durin g the 4-week period of therapy or the follow-up, despite the special clinic al situation where 60% of the patients included in the study presented with histologically proven cirrhosis (35% of them with clinical manifestation o f mildly decompensated cirrhosis). CONCLUSIONS: This short-term regimen of combined nIFN-beta + rIFN-gamma the rapy in patients with chronic hepatitis B proved to be equieffective to lon g-term treatment with interferon-alpha and combines high clinical tolerabil ity with good practicability, as it can be administered on an in-patient ba sis, ensuring close patient monitoring.