The NEW ENGLAND JOURNAL Of MEDICINE ORIGINAL ARTICLE Lamivudine for patients with chronic Hepatitis b and Advanced Liver disease Yun-Fan Liaw, M.D., Joseph J.Y. Sung, M D, Wan Cheng Chow, MD Geoffrey Farrell, M.D., Cha-Ze Lee, M.D., Hon Yuen, M.D., Tawesak Tanwandee, MD Qi-Min Tao, M. D,, Kelly Shue, M.R. Pharm. S, Oliver N. Keene, M. Sc, Jonathan S Dixon, Ph. D, D. Fraser Gray, Ph. D, and Jan Sabbat, M.B.B.S for the Cirrhosis Asian Lamivudine Multicentre Study Group* ABSTRACT BACK GROUND The effectiveness of antiviral therapy in preventing disease progression in patients with From Chang Gung Memorial Hospital and chronic hepatitis B and advanced fibrosis or cirrhosis is unknown University, Taipei, Taiwan(Y-F.L); Prince of Wales Hospital, Hong Kong O.J.Y.S. METHODS ingapore General Hospital, Singapo Patients with chronic hepatitis B who had histologically confirmed cirrhosis or ad- Millennium Institute.and vanced fibrosis were randomly assigned in a 2: 1 ratio to receive lamivudine(100 mg per Sydney, Sydney,Australia((GF);National ceive lamivudine and 215 to receive placebo. The primary end point was time to disease and es wrsity e spits Taipei fc. xony progression, defined by hepatic decompensation, hepatocellular carcinoma, spontane-(HY);Siriraj Hospital,Bangkok,Thailand ous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver dis- (.T People' Hospital, Beijing (Q.M. T. laxo SmithKine, Singapore ( KS,J..) ease. An independent data and safety monitoring board monitored the progress of the and GlaxoSmithKline,Greenford study and performed interim analyses of the data. ESULTS We randomly assigned 651 patients (98 percent Asian and 85 percent male)to receive North d. Taipei 105. Taiwan, or t liw of 32. 4 months (range, 0 to 42)owing to a significant difference between treatment groups in the number of end points reached. End points were reached by 7. 8 percent of * The principal investigators participating the patients receiving lamivudine and 17.7 percent of those receiving placebo(hazard e(CALM) Study are listed in the Ap. ratio for disease progression, 0.45; P=0.001). The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo Hazard ratio, 0.45 P=0.02), whereas hepatocellular carcinoma occurred in 3.9 per- copyright o 2004 Masschusetts Medical/ Society. cent of those in the lamivudine group and 7. 4 percent of those in the placebo group (hazard ratio, 0.49; P=0.047). Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine, and the Child-pugh scorewas more likely to increase in patients with these mutations than in the other patients treated with lamin- udine(7 percent vs. <1 percent). Overall, 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious advers CONCLUSIONS Continuous treatment with lamivudine delays clinical progression in patients with chron ic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma. N EnglJ med 3575 Www.nejm.org OctobeR 7, 2004 1521 第12页n engl j med 351;15 www.nejm.org october 7, 2004 The new england journal of medicine 1521 original article Lamivudine for Patients with Chronic Hepatitis B and Advanced Liver Disease Yun-Fan Liaw, M.D., Joseph J.Y. Sung, M.D., Wan Cheng Chow, M.D., Geoffrey Farrell, M.D., Cha-Ze Lee, M.D., Hon Yuen, M.D., Tawesak Tanwandee, M.D., Qi-Min Tao, M.D., Kelly Shue, M.R.Pharm.S., Oliver N. Keene, M.Sc., Jonathan S. Dixon, Ph.D., D. Fraser Gray, Ph.D., and Jan Sabbat, M.B., B.S., for the Cirrhosis Asian Lamivudine Multicentre Study Group* From Chang Gung Memorial Hospital and University, Taipei, Taiwan (Y.-F.L.); Prince of Wales Hospital, Hong Kong (J.J.Y.S.); Singapore General Hospital, Singapore (W.C.C.); the Storr Liver Unit, Westmead Millennium Institute, and University of Sydney, Sydney, Australia (G.F.); National Taiwan University College of Medicine and University Hospital, Taipei (C.-Z.L.); Princess Margaret Hospital, Hong Kong (H.Y.); Siriraj Hospital, Bangkok, Thailand (T.T.); People’s Hospital, Beijing (Q.-M.T.); GlaxoSmithKline, Singapore (K.S., J.S.); and GlaxoSmithKline, Greenford, United Kingdom (O.N.K., J.S.D., D.F.G.). Address reprint requests to Professor Liaw at the Liver Research Unit, Chang Gung Memo￾rial Hospital and University, 199 Tung Hwa North Rd., Taipei 105, Taiwan, or at liveryfl@ so-net.net.tw. *The principal investigators participating in the Cirrhosis Asian Lamivudine Multi￾centre (CALM) Study are listed in the Ap￾pendix. N Engl J Med 2004;351:1521-31. Copyright © 2004 Massachusetts Medical Society. background The effectiveness of antiviral therapy in preventing disease progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis is unknown. methods Patients with chronic hepatitis B who had histologically confirmed cirrhosis or ad￾vanced fibrosis were randomly assigned in a 2:1 ratio to receive lamivudine (100 mg per day) or placebo for a maximum of five years. Of 651 patients, 436 were assigned to re￾ceive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontane￾ous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver dis￾ease. An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data. results We randomly assigned 651 patients (98 percent Asian and 85 percent male) to receive lamivudine or placebo. The study was terminated after a median duration of treatment of 32.4 months (range, 0 to 42) owing to a significant difference between treatment groups in the number of end points reached. End points were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo (hazard ratio for disease progression, 0.45; P=0.001). The Child–Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo (hazard ratio, 0.45; P=0.02), whereas hepatocellular carcinoma occurred in 3.9 per￾cent of those in the lamivudine group and 7.4 percent of those in the placebo group (hazard ratio, 0.49; P=0.047). Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine, and the Child–Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamiv￾udine (7 percent vs. <1 percent). Overall, 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious adverse events. conclusions Continuous treatment with lamivudine delays clinical progression in patients with chron￾ic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma. abstract 第 12 页