The NEW ENGLAND JOURNAL Of MEDICINE C HRONIC HEPATITIS B IS A SERIOUs It has not been possible to devise treatment problem worldwide. Among patients with guidelines for the subgroup of patients with HBV active viral replication, cirrhosis will devel- related cirrhosis or advanced hepatic fibrosis. 27,28 op in 15 to 20 percent within five years. 2, For pa- Therefore, we conducted a prospective, random- tients with cirrhosis, acute exacerbation can occur, ized, double-blind, placebo-controlled trial to the disease may progress, and the incidence of sess the efficacy of lamivudine in terms of the clin hepatocellular carcinoma is greatly increased(70 ical progression of disease in patients with chronic occur against a backgro.epatocellular carcinoma hepatitis B and advanced fibrosis or cirrhosis.This to 90 percent of cas round of cirrhosis) .Be- study was conducted at multiple centers in coun cause of these complications, five-year survival tries in the Asian-Pacific region, where chronic hep- ates may be as low as 55 percent. Ultimately, 40 atitis B is a major cause of morbidity and mortality of either complications of cirrhosis or hepatocellu- ma is a major cause of deat R percent of Asian men with chronic hepatitis B die from cirrhosis and where hepatocellular carcino- lar carcinoma Patients with persistent seropositivity for hepa METHODS titis B e antigen(HBeAg) or an increased serum alanine aminotransferase level after HBeAg sero- STUDY DESIGN conversion have a significantly increased risk of We planned to conduct this multicenter, centrally irrhosis and hepatocellular carcinoma. -This is randomized, double-blind, placebo-controlled, par- consistent with experimental models showing im- allel group study for five years or less. Patients were portant roles for continuing hepatitis B virus(HBv) randomly assigned in a 2: 1 ratio to receive lamivu- eplication and the resultant hepatic inflammatory dine(100 mg per day) or placebo within 30 days response in hepatocarcinogenesis. 2Thus, the sup- after screening Of 651 patients, 436 were assigned pression of HBV and the reduction of necroinflam- to receive lamivudine and 215 to receive placebo matory activity in chronic hepatitis B may prevent During the double-blind phase, treatment was cirrhosis and, consequently, liver failure and hepa- stopped for patients who reached a clinically con- tocellular carcinom firmed end point (disease progression) or had Patients who have a response to interferon ther- HBeAg seroconversion. patients who reached an apy have substantially fewer life-threatening liver end point were offered open-label lamivudine for complications than those who do not have a re- one year, and patients who had HBeAg serocon sponse, 4although the evidence of theeffect ofthis version were followed up after therapy and had the therapy on the incidence of hepatocellular carcino- option to receive lamivudine as an open-label treat- ma is less conclusive. 5-7 Use of interferon is re- ment in the event of serologic relapse. If the trial stricted by cost, side effects, and, among patients was terminated according to predefined criteria, pa- with cirrhosis, the risk of liver failure during a flare tients were to be offered open-label treatment for of hepatitis. These limitations do not apply to oral one year. antiviral agents, such as lamivudine, which can pro- The data reported in this article are from the duce marked viral suppression, reduction of he- double-blind phase of the study, including follow- patic necroinflammatory activity, 8, 19 histologic up after treatment, up to the time of termination improvement of liver fibrosis, 20, and improved liver function, 22 even in patients with decompn- PATIENTS sation.23,24However, long-term therapy with lamin- Patients over 16 years of age with chronic hepati udine leads to viral breakthrough in some patients, tis B were eligible for recruitment if they had beer owing to the emergence of genotypic resistance positive for hepatitis B surface antigen(HBsAg) for tyrosine, methionine, aspartate, aspartate(ymdd) at least six months, were positive for hbeAg or mutations. 25 The possible implications of a re- negative for HBeAg with detectable HBV DNA at umption of necroinflammatory activity21 include screening, and had had a liver biopsy showing an flares of hepatitis, which may lead to liver failure Ishak fibrosis score of at least 4(where indicates and death, and a gradual erosion of hepatic func- no fibrosis and 6 indicates cirrhosis) at screening tion, which may lead to decompensation or cir- or during the previous two years. Biopsy slides were reviewed by one centrally appointed independent NENGLJMED351:15www.NEM.。RG。CTOBER7,2004 第13页n engl j med 351;15 www.nejm.org october 7, 2004 The new england journal of medicine 1522 hronic hepatitis b is a serious problem worldwide.1 Among patients with active viral replication, cirrhosis will devel￾op in 15 to 20 percent within five years.2,3 For pa￾tients with cirrhosis, acute exacerbation can occur, the disease may progress, and the incidence of hepatocellular carcinoma is greatly increased (70 to 90 percent of cases of hepatocellular carcinoma occur against a background of cirrhosis).4,5 Be￾cause of these complications, five-year survival rates may be as low as 55 percent.6 Ultimately, 40 percent of Asian men with chronic hepatitis B die of either complications of cirrhosis or hepatocellu￾lar carcinoma.7 Patients with persistent seropositivity for hepa￾titis B e antigen (HBeAg) or an increased serum alanine aminotransferase level after HBeAg sero￾conversion have a significantly increased risk of cirrhosis and hepatocellular carcinoma.8-11 This is consistent with experimental models showing im￾portant roles for continuing hepatitis B virus (HBV) replication and the resultant hepatic inflammatory response in hepatocarcinogenesis.12 Thus, the sup￾pression of HBV and the reduction of necroinflam￾matory activity in chronic hepatitis B may prevent cirrhosis and, consequently, liver failure and hepa￾tocellular carcinoma.13 Patients who have a response to interferon ther￾apy have substantially fewer life-threatening liver complications than those who do not have a re￾sponse,14 although the evidence of the effect of this therapy on the incidence of hepatocellular carcino￾ma is less conclusive.15-17 Use of interferon is re￾stricted by cost, side effects, and, among patients with cirrhosis, the risk of liver failure during a flare of hepatitis. These limitations do not apply to oral antiviral agents, such as lamivudine, which can pro￾duce marked viral suppression, reduction of he￾patic necroinflammatory activity,18,19 histologic improvement of liver fibrosis,20,21 and improved liver function,22 even in patients with decompen￾sation.23,24 However, long-term therapy with lamiv￾udine leads to viral breakthrough in some patients, owing to the emergence of genotypic resistance tyrosine, methionine, aspartate, aspartate (YMDD) mutations.25 The possible implications of a re￾sumption of necroinflammatory activity21,26 include flares of hepatitis, which may lead to liver failure and death, and a gradual erosion of hepatic func￾tion, which may lead to decompensation or cir￾rhosis. It has not been possible to devise treatment guidelines for the subgroup of patients with HBV￾related cirrhosis or advanced hepatic fibrosis.27,28 Therefore, we conducted a prospective, random￾ized, double-blind, placebo-controlled trial to as￾sess the efficacy of lamivudine in terms of the clin￾ical progression of disease in patients with chronic hepatitis B and advanced fibrosis or cirrhosis. This study was conducted at multiple centers in coun￾tries in the Asian–Pacific region, where chronic hep￾atitis B is a major cause of morbidity and mortality from cirrhosis and where hepatocellular carcino￾ma is a major cause of death. study design We planned to conduct this multicenter, centrally randomized, double-blind, placebo-controlled, par￾allel group study for five years or less. Patients were randomly assigned in a 2:1 ratio to receive lamivu￾dine (100 mg per day) or placebo within 30 days after screening. Of 651 patients, 436 were assigned to receive lamivudine and 215 to receive placebo. During the double-blind phase, treatment was stopped for patients who reached a clinically con￾firmed end point (disease progression) or had HBeAg seroconversion. Patients who reached an end point were offered open-label lamivudine for one year, and patients who had HBeAg serocon￾version were followed up after therapy and had the option to receive lamivudine as an open-label treat￾ment in the event of serologic relapse. If the trial was terminated according to predefined criteria, pa￾tients were to be offered open-label treatment for one year. The data reported in this article are from the double-blind phase of the study, including follow￾up after treatment, up to the time of termination. patients Patients over 16 years of age with chronic hepati￾tis B were eligible for recruitment if they had been positive for hepatitis B surface antigen (HBsAg) for at least six months, were positive for HBeAg or negative for HBeAg with detectable HBV DNA at screening, and had had a liver biopsy showing an Ishak fibrosis score of at least 4 (where 0 indicates no fibrosis and 6 indicates cirrhosis) at screening or during the previous two years. Biopsy slides were reviewed by one centrally appointed independent c methods 第 13 页