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ARTICLE

Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan

Haruhiko Yoshida, MD; Yasushi Shiratori, MD; Mitsuhiko Moriyama, MD; Yasuyuki Arakawa, MD; Tatsuya Ide, MD; Michio Sata, MD; Osami Inoue, MD; Michitami Yano, MD; Motohiko Tanaka, MD; Shigetoshi Fujiyama, MD; Shuhei Nishiguchi, MD; Tetsuo Kuroki, MD; Fumio Imazeki, MD; Osamu Yokosuka, MD; Shingo Kinoyama, MD; Gotaro Yamada, MD; Masao Omata, MD, for the IHIT Study Group

3 August 1999 | Volume 131 Issue 3 | Pages 174-181

Background: Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma.

Objective: To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis.

Design: Retrospective cohort study.

Setting: Seven university hospitals and one regional core hospital in Japan.

Patients: 2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490were untreated.

Measurements: The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional-hazards regression.

Results: Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis(P = 0.0128) and for those with stage F3 fibrosis(P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% CI, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [CI, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [CI, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [CI, 0.206 to 0.622]).

Conclusions: Interferon therapy significantly reduces the risk for hepatocellular carcinoma, especially among virologic or biochemical responders.

Author and Article Information

From University of Tokyo and Nihon University, Tokyo, Japan; Kurume University, Fukuoka, Japan; Nagasaki Chuo Hospital, Nagasaki, Japan; Kumamoto University, Kumamoto, Japan; Osaka City University, Osaka, Japan; Chiba University, Chiba, Japan; and Kawasaki Medical School, Okayama, Japan.

Acknowledgments: The authors thank Tadao Kakizoe, MD, for general support and Yasuo Ohashi, PhD, for advice on biostatistics.

Grant Support: By the Ministry of Health and Welfare of Japan as one of the Comprehensive 10-Year Strategy for Cancer Control Projects (Field 4, Theme 2).

Requests for Reprints: Haruhiko Yoshida, MD, Department of Gastroenterology, University of Tokyo, Hongo 7-3-1,Bunkyo, Tokyo 113-8655, Japan; e-mail, yoshida-2im{at}h.u-tokyo.ac.jp.

Current Author Addresses: Drs.Yoshida, Shiratori, and Omata: Department of Gastroenterology, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113, Japan.

Drs. Moriyama and Arakawa: Third Department of Internal Medicine, Nihon University, Oyaguchi-Kamicho 30-1, Itabashi, Tokyo173, Japan.

Drs. Ide and Sata: Second Department of Internal Medicine, Kurume University, Asahicho 67, Kurume, Fukuoka 830, Japan.

Drs. Inoue and Yano: Department of Clinical Research, Nagasaki Chuo Hospital, Kuhara 2-1001, Ohmura, Nagasaki 856,Japan.

Drs. Tanaka and Fujiyama: Third Department of Internal Medicine, Kumamoto University, Honjo 1-1-1, Kumamoto, Kumamoto 860,Japan.

Drs. Nishiguchi and Kuroki: Third Department of Internal Medicine, Osaka City University, Asahicho 1-5-7, Abeno, Osaka 545,Japan.

Drs. Imazeki and Yokosuka: First Department of Internal Medicine, Chiba University, Inohana 1-8-1, Chuo, Chiba 260, Japan.

Drs. Kinoyama and Yamada: Liver Center, Kawasaki Medical School, Nakayamashita 2-1-80, Okayama, Okayama 700, Japan.

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