Comment Evidence-based medicine in China In recent decades, evidence-based medicine has been Medical associations in every discipline have built propagated rapidly in China, not only to doctors but clinical guidelines for common diseases according to to nurses and other health-care professionals. the evidence to inform clinical decision making and Chinese Journal of Evidence-Based Medicine, the teaching. Evidence-based medicine has also engaged Journal of Evidence-Based Medicine, and the Chinese with traditional Chinese medicine. Research teams in Journal of Evidence-Based Pediatrics were launched in traditional Chinese medicine have been established and 2001-06. Several organisations developed programmes the rigour of traditional medicine has been gradually to strengthen a national culture of evidence-based raised. The Chinese clinical trial registry was established medicine, including the clinical epidemiology committee in 2007 and the number of clinical trials registered in of the Chinese Medical Association(established in 1993) China is increasing(figure) working with the Chinese Clinical Epidemiology Network There are, however, several concerns about the devel (ChinaCLEN; registered as part of the International opment of evidence- based medicine in China. First, Clinical Epidemiology Network in 1989),the Chinese access to scientific evidence is not equal in all regions Cochrane Centre(which became the 14th centre of Doctors from developed areas and large cities, such as the International Cochrane Collaboration in 1999), Shanghai and Beijing, can search the literature for free the Ministry of Educations virtual research centre of at their university via databases such as Medline. But evidence-based medicine founded in 2004, and the doctors in remote areas might not be able to access China Medical Doctor Association,'s evidence-based the best information resources, which, together with a medicine committee organised in 2003.3 limited knowledge of English, could prevent use of the The board members of these organisations are located best evidence in their practice seminate Second most of the world 's clinical evidence does knowledge of evidence-based medicine throughout the not come from China. Few results from China have country Programmes(usually 1-3 months)organised been included in systematic reviews or clinical by the Ministry of Education, continuing education practice guidelines. I calculated that from 1999 to programmes, and online education programmes are 2008, 1880 clinical research articles were published available. Clinical epidemiology and evidence-based in The New England Journal of Medicine, The Lancet, medicine have become compulsory curricula for medical and JAMA. However, only 0-21% of these were from students and clinical postgraduates in all universities. mainland China. Wu and colleagues analysed randomised trials on 20 common diseases published in Chinas natural knowledge infrastructure database from 1994 to 2005, and found that only 7% of them met methodological criteria(according to Cochrane review criteria). Frequent errors in statistical analyses are also found in Chinese medical journals, which reduces the credibility of the evidence Third, because of a lack of funding for investigator-led trials are pharmaceutical premarketing trials sponsored by drug companies. Such research is more likely to have could result in publication bias. Finally, although the Chinese government has made research into traditional 2006 0072008 medicine a priority area and randomised trials have shown effcacy for some nal therapies, because We searched clinical Trials. go on June 15, 2009, with the term "lead principal investigator/sponsor=China ity of trials and selective 第10页 www.thelancet.comVol375February13,2010
Comment 532 www.thelancet.com Vol 375 February 13, 2010 Evidence-based medicine in China In recent decades, evidence-based medicine has been propagated rapidly in China, not only to doctors but also to nurses and other health-care professionals. The Chinese Journal of Evidence-Based Medicine, the Journal of Evidence-Based Medicine, and the Chinese Journal of Evidence-Based Pediatrics were launched in 2001–06. Several organisations developed programmes to strengthen a national culture of evidence-based medicine, including the clinical epidemiology committee of the Chinese Medical Association (established in 1993) working with the Chinese Clinical Epidemiology Network (ChinaCLEN; registered as part of the International Clinical Epidemiology Network in 1989),1 the Chinese Cochrane Centre (which became the 14th centre of the International Cochrane Collaboration in 1999),2 the Ministry of Education’s virtual research centre of evidence-based medicine founded in 2004, and the China Medical Doctor Association’s evidence-based medicine committee organised in 2003.3 The board members of these organisations are located all around China, and have sought to disseminate knowledge of evidence-based medicine throughout the country. Programmes (usually 1–3 months) organised by the Ministry of Education, continuing education programmes, and online education programmes are available. Clinical epidemiology and evidence-based medicine have become compulsory curricula for medical students and clinical postgraduates in all universities. Medical associations in every discipline have built clinical guidelines for common diseases according to the evidence to inform clinical decision making and teaching. Evidence-based medicine has also engaged with traditional Chinese medicine. Research teams in traditional Chinese medicine have been established and the rigour of traditional medicine has been gradually raised. The Chinese clinical trial registry4 was established in 2007 and the number of clinical trials registered in China is increasing (fi gure).5 There are, however, several concerns about the develop ment of evidence-based medicine in China. First, access to scientifi c evidence is not equal in all regions. Doctors from developed areas and large cities, such as Shanghai and Beijing, can search the literature for free at their university via databases such as Medline. But doctors in remote areas might not be able to access the best information resources, which, together with a limited knowledge of English, could prevent use of the best evidence in their practice. Second, most of the world’s clinical evidence does not come from China. Few results from China have been included in systematic reviews6 or clinical practice guidelines. I calculated that from 1999 to 2008, 1880 clinical research articles were published in The New England Journal of Medicine, The Lancet, and JAMA. However, only 0·21% of these were from mainland China.7 Wu and colleagues8 analysed randomised trials on 20 common diseases published in China’s natural knowledge infrastructure database from 1994 to 2005, and found that only 7% of them met methodological criteria (according to Cochrane review criteria). Frequent errors in statistical analyses are also found in Chinese medical journals,9 which reduces the credibility of the evidence. Third, because of a lack of funding for investigator-led randomised trials, most good-quality Chinese clinical trials are pharmaceutical premarketing trials sponsored by drug companies. Such research is more likely to have outcomes that favour the sponsor’s product, which could result in publication bias.10 Finally, although the Chinese Government has made research into traditional medicine a priority area and randomised trials have shown effi cacy for some traditional therapies, because of the low methodological quality of trials and selective 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year 50 100 150 200 250 Numbers 300 350 400 450 500 Phase 1/2 Phase 3 Phase 4 Randomised trials Observational studies Total Figure: Growth in clinical trials in China We searched ClinicalTrials.gov5 on June 15, 2009, with the term “lead principal investigator/sponsor=China”. 第 10 页
Comment publication of positive results, the effcacy of most Jiyao Wang traditional therapies is uncertain. Department of Internal Medicine, Zhongshan He Several factors might contribute to this situation. University, Shanghai200032, China Most active clinical researchers and physicians have wang jiyao@zs-hospitalshcn little formal training in research methods. "Even the the chinese Medical Association; vice chair of the Society of Evidence-Based do not know or ignore reporting criteria, such as of Education's virtual research centre of evidence-based medicine; anda try editors and peer reviewers of Chinese medical journals Medicine, Chinese Medical Doctor Association a board member of the Mini he Board of Trustees, INCLEN. I thank Xue-juan Jin for collecting CONSORT STROBE. STARD and PRISMA 13 Preclinical information to make the figure. trial registration has not been essential for publication, 1ChinadinicalEpidemiologyNetwork.httpc//www.chinaclen.org.cn ccessed Dec 13, 2009) eventhoughregistrationresultsintrialsthataremore2chineseCochraneCentrehttp:/www.hxyx.com/cochrane_new(accessed rigoroUs, effciently conducted, and ethically sound Oct 12, 2009)(in Chinese) 3ChineseMedicalDoctorAssociationhttp://www.cmdagov.cn(accessed To counter these problems, I have several suggestion Oct 12, 2009)(in Chinese). Clinical researchers in China should be formally trained andaccreditedinclinicaltrialmethodologyReporting5clinicaLtrialsgov.http://www.clinicaltrials.gow(accesSedJune15,2009). guidelines have been translated into Chinese and pub- Straus SE, Richardson WS, Glasziou P, Haynes RB Evidence-based medicine. lished partly in Chinese, 5 and are now available online. 77 Wang )Y Follow international reporina(Commentary ) e the quality of searchers need to improve study design by adopting the advice in relevant reporting guidelines to reduce 8 WuT, LiY, Bian Z, Liu G, Moher D Randomized trials published in some how many are randomized? Trials 2009: 10: bias. National level platforms need to be established for 9 He, jinz, Yu D Statistical reporting in Chinese biomedical joumal consultation and administration of multicentre clinical trials. journal editors must require documentation of f 10 Lexchin Bero JA, Djubegovic B, Clark. Pharmaceutical industry ethics approval and clinical trial registration before BM20x261670 Journals in China that are 372:1938-40. members of the ICMJE should obey international criteria 12 Schulz KF, Grimes DA. The Lancet handbook of essential concepts in dinical for publication. Finally, the Chinese Government should 13 EQUATOR Network Enhancin increaseitssupportofclinicalresearchintheformofresearchhttp://www.equator-networkorg(accessedDec13,2009) clinical research grants for physicians, the creation of YiJie He Xue Bao 2007: 5: 234-42(in Chinese) national repositories of clinical cases and samples of 15 Gluud C, eds Evidence based medicine and clinical practice, endix 3 and 5. Beijing, China: Science Publishe serum and tissues, and financial support for universities in remote areas to buy literature databases There is a long way to go before the words of a Lancet Dec13,2009) Editorial-"China has the opportunity to lead the world The Lancet. Reforming research in China. Lancet 2007: 369: 880. not only in research quantity, but also in quality"are fulfilled Fomenting a prevention revolution for Hiv 2010 heralds the year set by the UN to achieve universal stay, and residence in some 57 countries. M About access to HIV prevention, treatment, care, and support 10 million people are currently denied access Despite major achievements and heroic efforts over saving treatment the past decades by people living with HIv to assert Despite or perhaps because of, its success, the AIDS their rights for treatment equity, to end stigma and response has itself come under attack. Coalitions of discrimination, and to ensure more inclusive approaches social conservatives have orchestrated a global campaign to governing the response, much remains to be against condom promotion and supported legislation done. 80 countries still criminalise homosexuality? criminalising same-sex relations. Such actions increase People living with Hiv face restrictions on entry, stigma and isolate people most at risk of Hiv at a 第11页 www.thelancet.comVol375February13,2010
Comment www.thelancet.com Vol 375 February 13, 2010 533 Fomenting a prevention revolution for HIV 2010 heralds the year set by the UN to achieve universal access to HIV prevention, treatment, care, and support.1 Despite major achievements and heroic eff orts over the past decades by people living with HIV to assert their rights for treatment equity, to end stigma and discrimination, and to ensure more inclusive approaches to governing the response, much remains to be done. 80 countries still criminalise homosexuality.2 People living with HIV face restrictions on entry, stay, and residence in some 57 countries.3,4 About 10 million people are currently denied access to lifesaving treatment. Despite, or perhaps because of, its success, the AIDS response has itself come under attack.5,6 Coalitions of social conservatives have orchestrated a global campaign against condom promotion and supported legislation criminalising same-sex relations.7 Such actions increase stigma and isolate people most at risk of HIV at a publication of positive results, the effi cacy of most traditional therapies is uncertain.11 Several factors might contribute to this situation. Most active clinical researchers and physicians have little formal training in research methods.12 Even the editors and peer reviewers of Chinese medical journals do not know or ignore reporting criteria, such as CONSORT, STROBE, STARD, and PRISMA.13 Preclinical trial registration has not been essential for publication, even though registration results in trials that are more rigorous, effi ciently conducted, and ethically sound.14 To counter these problems, I have several suggestions. Clinical researchers in China should be formally trained and accredited in clinical trial methodology. Reporting guidelines have been translated into Chinese and published partly in Chinese,15 and are now available online.1,7 Researchers need to improve study design by adopting the advice in relevant reporting guidelines to reduce bias. National level platforms need to be established for consultation and administration of multicentre clinical trials. Journal editors must require documentation of ethics approval and clinical trial registration before manuscript acceptance. Journals in China that are members of the ICMJE16 should obey international criteria for publication. Finally, the Chinese Government should increase its support of clinical research, in the form of clinical research grants for physicians, the creation of national repositories of clinical cases and samples of serum and tissues, and fi nancial support for universities in remote areas to buy literature databases. There is a long way to go before the words of a Lancet Editorial—“China has the opportunity to lead the world not only in research quantity, but also in quality”17—are fulfi lled. Jiyao Wang Department of Internal Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China wang.jiyao@zs-hospital.sh.cn I am: president of ChinaCLEN; chair of the Clinical Epidemiology Committee of the Chinese Medical Association; vice chair of the Society of Evidence-Based Medicine, Chinese Medical Doctor Association; a board member of the Ministry of Education’s virtual research centre of evidence-based medicine; and a member of the Board of Trustees, INCLEN. I thank Xue-juan Jin for collecting information to make the fi gure. 1 China Clinical Epidemiology Network. http://www.chinaclen.org.cn (accessed Dec 13, 2009). 2 Chinese Cochrane Centre. http://www.hxyx.com/cochrane_new (accessed Oct 12, 2009) (in Chinese). 3 Chinese Medical Doctor Association. http://www.cmda.gov.cn (accessed Oct 12, 2009) (in Chinese). 4 The Chinese Clinical Trial Register. http://www.chictr.org (accessed Dec 14, 2009). 5 ClinicalTrials.gov. http://www.clinicalTrials.gov (accessed June 15, 2009). 6 Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-based medicine: therapy, 3rd edn. London, UK: Elsevier, 2005. 7 Wang JY. Follow international reporting guidelines to raise the quality of articles about clinical research in China (Commentary). Chung Hua Hsiao Hua Tsa Chih 2010; 30: 1 (in Chinese). 8 Wu T, Li Y, Bian Z, Liu G, Moher D. Randomized trials published in some Chinese journals: how many are randomized? Trials 2009; 10: 46. 9 He J, Jin Z, Yu D. Statistical reporting in Chinese biomedical journals. Lancet 2009; 373: 2091–93. 10 Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. 11 Tang J-L, Liu B-Y, Ma K-W. Traditional Chinese medicine. Lancet 2008; 372: 1938–40. 12 Schulz KF, Grimes DA. The Lancet handbook of essential concepts in clinical research. Philadelphia, PA, USA: Elsevier, 2006. 13 EQUATOR Network. Enhancing the quality and transparency of health research. http://www.equator-network.org (accessed Dec 13, 2009). 14 Yu H, Liu JP. A review of international clinical trial registration. Zhong Xi Yi Jie He Xue Bao 2007; 5: 234–42 (in Chinese). 15 Wang J, Gluud C, eds. Evidence based medicine and clinical practice, 2nd edn. Appendix 3 and 5. Beijing, China: Science Publisher, 2006: 383–87. 16 International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. http://www.icmje.org (accessed Dec 13, 2009). 17 The Lancet. Reforming research in China. Lancet 2007; 369: 880. 第 11 页
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 Memorial 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 Multicentre (CALM) Study are listed in the Appendix. 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 advanced 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 receive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. 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 percent 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 lamivudine (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 chronic 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
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 develop in 15 to 20 percent within five years.2,3 For patients 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 Because 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 hepatocellular carcinoma.7 Patients with persistent seropositivity for hepatitis B e antigen (HBeAg) or an increased serum alanine aminotransferase level after HBeAg seroconversion have a significantly increased risk of cirrhosis and hepatocellular carcinoma.8-11 This is consistent with experimental models showing important roles for continuing hepatitis B virus (HBV) replication and the resultant hepatic inflammatory response in hepatocarcinogenesis.12 Thus, the suppression of HBV and the reduction of necroinflammatory activity in chronic hepatitis B may prevent cirrhosis and, consequently, liver failure and hepatocellular carcinoma.13 Patients who have a response to interferon therapy have substantially fewer life-threatening liver complications than those who do not have a response,14 although the evidence of the effect of this therapy on the incidence of hepatocellular carcinoma is less conclusive.15-17 Use of interferon is restricted 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 produce marked viral suppression, reduction of hepatic necroinflammatory activity,18,19 histologic improvement of liver fibrosis,20,21 and improved liver function,22 even in patients with decompensation.23,24 However, long-term therapy with lamivudine 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 resumption of necroinflammatory activity21,26 include flares of hepatitis, which may lead to liver failure and death, and a gradual erosion of hepatic function, which may lead to decompensation or cirrhosis. It has not been possible to devise treatment guidelines for the subgroup of patients with HBVrelated cirrhosis or advanced hepatic fibrosis.27,28 Therefore, we conducted a prospective, randomized, double-blind, placebo-controlled trial to assess the efficacy of lamivudine in terms of the clinical progression of disease in patients with chronic hepatitis B and advanced fibrosis or cirrhosis. This study was conducted at multiple centers in countries in the Asian–Pacific region, where chronic hepatitis B is a major cause of morbidity and mortality from cirrhosis and where hepatocellular carcinoma is a major cause of death. study design We planned to conduct this multicenter, centrally randomized, double-blind, placebo-controlled, parallel group study for five years or less. Patients were randomly assigned in a 2:1 ratio to receive lamivudine (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 confirmed 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 seroconversion were followed up after therapy and had the option to receive lamivudine as an open-label treatment in the event of serologic relapse. If the trial was terminated according to predefined criteria, patients 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 followup after treatment, up to the time of termination. patients Patients over 16 years of age with chronic hepatitis 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
LAMIVUDINE FOR CHRONIC HEPATITIS B AND ADVANCED LIVER DISEASE histopathologist who was blinded to the treatment Bayer Diagnostics, with a lower limit of detection assignments of 0.7 mEq per milliliter). Results were unavail- Patients were excluded if they had any of the fol- able to the investigators until after the completion lowing: evidence of hepatocellular carcinoma(sus- of the study, and serum HBV DNA assays were not picious foci on hepatic ultrasonography at screen- permitted at the investigators'sites during double ing or a rising serum level of alpha-fetoprotein), blind therapy but were allowed after confirmed a serum alanine aminotransferase level more than HBeAg seroconversion or during open -label lamin 10 times the upper limit of normal, any evidence of udine therapy. Samples collected at baseline, at an hepatic decompensation(as defined by the study nual visits, and at the completion of treatment protocol), autoimmune hepatitis, coinfection with were also analyzed for the presence of ymDd mu- hepatitis C or D virus or human immunodeficiency tations by polymerase-chain-reaction assay and virus, other serious concurrent illness(e.g, alco- restriction-fragment-length polymorphism assay holism, uncontrolled diabetes, or cancer), pancre- Samples collected at all scheduled visits from pa- atic amylase or lipase levels more than two times tients with clinical end points were also tested for the upper limit of normal, an elevated serum creat- YMDD mutations inine level, a hemoglobin level of less than 8 g per deciliter, a white-cell count below 1500 per cubic END POINTS millimeter, a platelet count 50,000 percubic mil- The primary end point was time to disease pro- limeter or less, treatment with immunomodulate- gression, as defined by the first occurrence of an ry or chronic antiviral therapy within the 6 months of the following: an increase of at least 2 points in before screening, treatment with any investigation- the Child-Pugh score(an assessment of the severi- al drug within the 30 days before the study began, ty of liver disease [range, 5 to 15, where 5 indicates or any previous treatment with lamivudine. Wom- good liver function and 15 indicates poor liver func- en who were pregnant were also excluded tion] calculated on the basis of the serum bilirubin and albumin levels, the prothrombin time, and the ASSESSMENTS presence and degree of ascites or encephalopathy), Patients were assessed at baseline, at the end of spontaneous bacterial peritonitis with proven sep- months 1 and 3, and at every three months thereat- sis, renal insufficiency, bleeding gastric or esoph ter for clinical evidence of hepatic decompensation ageal varices, the development of hepatocellular or other complications. They were also questioned carcinoma, ordeath related to liver disease Patients about adverse events, concurrent medications, and with a first clinical end pointwere followed for sub- study drug accountability; blood was taken for he- sequent end points. Any increase in the Child-Pugh matology and biochemistry profiles; serum sam- score due solely to laboratory parameters was con- ples were tested for HBeAg, hepatitis B e antibody, firmed on two consecutive visits at least one month and alpha-fetoprotein; and the prothrombin time apart. For patients with albumin levels below 35 was measured. At baseline and every six months per liter or bilirubin levels greater than 34.2 umol thereafter, serum was assayed for HBsAg and hep- per liter(2 mg per deciliter)at baseline, confirma- atitis B surface antibody, and liver ultrasonogra- tory tests were conducted one week after the first phy was performed. HBeAg seroconversion was test. Renal insufficiency was defined as a decrease considered confirmed if two consecutive samples in creatinine clearance to 50 ml per minute(0.8 ml taken at least a month apart were positive for hepa- per second)or less that was confirmed two times, titis B e antibody and negative for HBeAg Hepatic at least one week apart. Hepatocellular carcinoma ultrasonography and liver biopsy or fine-needle was diagnosed on the basis of results of ultraso- aspiration were performed as clinically indicated nography, selective arteriography, imaging ofhe- to investigate or confirm a diagnosis of hepato- patic tumors during the vascular phase, serum cellular carcinoma levels of alpha-fetoprotein, or by cytologic or his erum samples were collected at baseline and tologic evaluation. The evidence for each end point at months 1, 12, 24, 36, 48, and 60 and analyzed was reviewed and confirmed by a blinded clinical for HBV DNA levels at a central laboratory. HBV end-points committee composed of three interna- dNA was determined by a branched-chain hybridi- tionally recognized hepatologists zation assay (Versant HBV DNA Quantitative Assay, NEnglJMed351715www.nejm.orgocTober7,2004 1523 第14页
n engl j med 351;15 www.nejm.org october 7, 2004 lamivudine for chronic hepatitis b and advanced liver disease 1523 histopathologist who was blinded to the treatment assignments. Patients were excluded if they had any of the following: evidence of hepatocellular carcinoma (suspicious foci on hepatic ultrasonography at screening or a rising serum level of alpha-fetoprotein), a serum alanine aminotransferase level more than 10 times the upper limit of normal, any evidence of hepatic decompensation (as defined by the study protocol), autoimmune hepatitis, coinfection with hepatitis C or D virus or human immunodeficiency virus, other serious concurrent illness (e.g., alcoholism, uncontrolled diabetes, or cancer), pancreatic amylase or lipase levels more than two times the upper limit of normal, an elevated serum creatinine level, a hemoglobin level of less than 8 g per deciliter, a white-cell count below 1500 per cubic millimeter, a platelet count of 50,000 per cubic millimeter or less, treatment with immunomodulatory or chronic antiviral therapy within the 6 months before screening, treatment with any investigational drug within the 30 days before the study began, or any previous treatment with lamivudine. Women who were pregnant were also excluded. assessments Patients were assessed at baseline, at the end of months 1 and 3, and at every three months thereafter for clinical evidence of hepatic decompensation or other complications. They were also questioned about adverse events, concurrent medications, and study drug accountability; blood was taken for hematology and biochemistry profiles; serum samples were tested for HBeAg, hepatitis B e antibody, and alpha-fetoprotein; and the prothrombin time was measured. At baseline and every six months thereafter, serum was assayed for HBsAg and hepatitis B surface antibody, and liver ultrasonography was performed. HBeAg seroconversion was considered confirmed if two consecutive samples taken at least a month apart were positive for hepatitis B e antibody and negative for HBeAg. Hepatic ultrasonography and liver biopsy or fine-needle aspiration were performed as clinically indicated to investigate or confirm a diagnosis of hepatocellular carcinoma. Serum samples were collected at baseline and at months 1, 12, 24, 36, 48, and 60 and analyzed for HBV DNA levels at a central laboratory. HBV DNA was determined by a branched-chain hybridization assay (Versant HBV DNA Quantitative Assay, Bayer Diagnostics, with a lower limit of detection of 0.7 mEq per milliliter). Results were unavailable to the investigators until after the completion of the study, and serum HBV DNA assays were not permitted at the investigators’ sites during doubleblind therapy but were allowed after confirmed HBeAg seroconversion or during open-label lamivudine therapy. Samples collected at baseline, at annual visits, and at the completion of treatment were also analyzed for the presence of YMDD mutations by polymerase-chain-reaction assay and restriction-fragment–length polymorphism assay. Samples collected at all scheduled visits from patients with clinical end points were also tested for YMDD mutations. end points The primary end point was time to disease progression, as defined by the first occurrence of any of the following: an increase of at least 2 points in the Child–Pugh score (an assessment of the severity of liver disease [range, 5 to 15, where 5 indicates good liver function and 15 indicates poor liver function] calculated on the basis of the serum bilirubin and albumin levels, the prothrombin time, and the presence and degree of ascites or encephalopathy), spontaneous bacterial peritonitis with proven sepsis, renal insufficiency, bleeding gastric or esophageal varices, the development of hepatocellular carcinoma, or death related to liver disease. Patients with a first clinical end point were followed for subsequent end points. Any increase in the Child–Pugh score due solely to laboratory parameters was confirmed on two consecutive visits at least one month apart. For patients with albumin levels below 35 g per liter or bilirubin levels greater than 34.2 µmol per liter (2 mg per deciliter) at baseline, confirmatory tests were conducted one week after the first test. Renal insufficiency was defined as a decrease in creatinine clearance to 50 ml per minute (0.8 ml per second) or less that was confirmed two times, at least one week apart. Hepatocellular carcinoma was diagnosed on the basis of results of ultrasonography, selective arteriography, imaging of hepatic tumors during the vascular phase, serum levels of alpha-fetoprotein, or by cytologic or histologic evaluation. The evidence for each end point was reviewed and confirmed by a blinded clinical end-points committee composed of three internationally recognized hepatologists. 第 14 页
The NEW ENGLAND JOURNAL Of MEDICINE Table 1 Baseline Characteristics of the Patients Lamivudine Group Placebo Grou Characteristic Range 17-74 341(78) 156(73) 75(17) 41(19) 20(5) 18(8) Ishak fibrosis score (%) 127(29) 55(26) (31) V DNA 11.7 21.5 <0.7-109800 HBV DNA 20.7 mEq/ml-no(9)5 345(79) 174(81) 252(58) 124(58) Alpha-fetoprotein -ug/liter 0.7-600 Alanine aminotransferase-U/liter Median 338(78) 171(80) viewing interim analyses. The board was empow All adverse events, regardless of their possible as- ered to recommend termination of the study on the sociation with the disease or study treatment, were basis of safety concerns or as soon as sufficient ev recorded. Adverse events were considered to be se- idence indicated that lamivudine was statistically rious if the investigator determined that they jeop- superior to placebo or that lamivudine did not pro- ardized the patient, were life-threatening, or would vide a significant advantage over placebo esult in hospitalization, disability, or death. STATISTICAL ANALYSES DATA AND SAFETY MONITORING BOARD Sample size was determined on the basis of the pri- The data and safety monitoring board consisted mary analysis of time to disease progression. To es- of three independent hepatologists, who were not timate power, the annual rate of disease progres- members of the end-points committee, and an in- sion was assumed to be 20 percent for the placebo dependent statistician. The board protected the group, 9,29 whereas a reduction in this rate of one ethical interests and safety of the patients by re- third(to 13. 3 percent) for the lamivudine group 524 N englj Med 35715 Www.nejm.org OctobeR 7, 2004 第15页
n engl j med 351;15 www.nejm.org october 7, 2004 The new england journal of medicine 1524 safety All adverse events, regardless of their possible association with the disease or study treatment, were recorded. Adverse events were considered to be serious if the investigator determined that they jeopardized the patient, were life-threatening, or would result in hospitalization, disability, or death. data and safety monitoring board The data and safety monitoring board consisted of three independent hepatologists, who were not members of the end-points committee, and an independent statistician. The board protected the ethical interests and safety of the patients by reviewing interim analyses. The board was empowered to recommend termination of the study on the basis of safety concerns or as soon as sufficient evidence indicated that lamivudine was statistically superior to placebo or that lamivudine did not provide a significant advantage over placebo. statistical analyses Sample size was determined on the basis of the primary analysis of time to disease progression. To estimate power, the annual rate of disease progression was assumed to be 20 percent for the placebo group,8,9,29 whereas a reduction in this rate of one third (to 13.3 percent) for the lamivudine group Table 1. Baseline Characteristics of the Patients.* Characteristic Lamivudine Group (N=436) Placebo Group (N=215) Male sex — no. (%) 370 (85) 182 (85) Asian — no. (%) 426 (98) 210 (98) Age — yr Median 43 44 Range 17–74 22–71 Child–Pugh score — no. (%)† 5 341 (78) 156 (73) 6 75 (17) 41 (19) ≥7 20 (5) 18 (8) Ishak fibrosis score — no. (%)‡ 4 176 (40) 76 (35)‡ 5 127 (29) 55 (26) 6 133 (31) 84 (39) HBV DNA — mEq/ml Median 11.7 21.5 Range 1 time the upper limit of normal — no. (%) 338 (78) 171 (80) 第 15 页
AMIVUDINE FOR CHRONIC HEPATITIS B AND ADVANCED LIVER DISEASE Table 1.(Continued. Characteristic Aspartate aminotransferase-U/liter Bilirubin 13.7 Range 3.0-50.0 1.7-58.1 Range 35-173 35-135 H 14.7 14.6 Range 8.4-19.0 92-17.8 Median 14,000-401,000 Prothrombin time 12.5 80-23.8 9.8-27.6 White-cell count per mm3 Median 5330 1980-1,600 2200-11,500 ☆ There were no he two treatment groups. The patients' race was recorded by the investi- ations of the patients indicates good liver function and 15 poor liver function ) is a measure of the severity of liver disease f The ishak fibrosis score(range, 0 to 6)is a measure of the degree of fibrosis i topsy specimens. Scores of o to 4 indi- S All patients had detectable HBV DNA at screening: 0. 7 meq per milliliter equals approximately 7x105 copies per milliliter I To convert values for bilirubin to milligrams per deciliter, divide by 17.1. I To convert values for creatinine to milligrams per deciliter, divide by 88.4 was considered to be a clinically relevant treatment ping boundaries. At each inspection, the"Christ- effect. This difference corresponds to a hazard ra- mas tree"correction was applied to the contin cent at the 5 percent level of significance, with a ra- number and timing ofinterim analyste predictable tio of0.64. For the study to have a power of 90 per- uous boundaries to account for the ur tio of 2: 1 for the random assignment of patients The first interim analysis was scheduled for to lamivudine or placebo, 240 end points would months after the completion of patient recruit need to be observed. o Assuming a dropout rate ment, and subsequent interim analyses were to be of 25 percent during a five-year period, the num- performed between 6 and 12 months after the first ber of patients required overall was estimated to interim analysis; the aim was to have approximate- ly 35 events between interim analyses. The inten We used a sequential, asymmetric trial with the tion-to treat analysis included all patients who were triangular test to monitor the primary efficacy randomly assigned to receive either lamivudine or end point of time to clinical disease progression. placebo. Treatments were compared with the use At each interim analysis, the test statistics were of a Cox proportional-hazards model, 32 with each calculated and compared with straight-line stop- analysis allowing for the covariates of country, sex, NEnglJMed351715www.nejm.orgocTober7,2004 1525 第16页
n engl j med 351;15 www.nejm.org october 7, 2004 lamivudine for chronic hepatitis b and advanced liver disease 1525 was considered to be a clinically relevant treatment effect. This difference corresponds to a hazard ratio of 0.64. For the study to have a power of 90 percent at the 5 percent level of significance, with a ratio of 2:1 for the random assignment of patients to lamivudine or placebo, 240 end points would need to be observed.30 Assuming a dropout rate of 25 percent during a five-year period, the number of patients required overall was estimated to be 600. We used a sequential, asymmetric trial with the triangular test31 to monitor the primary efficacy end point of time to clinical disease progression. At each interim analysis, the test statistics were calculated and compared with straight-line stopping boundaries. At each inspection, the “Christmas tree” correction31 was applied to the continuous boundaries to account for the unpredictable number and timing of interim analyses. The first interim analysis was scheduled for 18 months after the completion of patient recruitment, and subsequent interim analyses were to be performed between 6 and 12 months after the first interim analysis; the aim was to have approximately 35 events between interim analyses. The intention-to-treat analysis included all patients who were randomly assigned to receive either lamivudine or placebo. Treatments were compared with the use of a Cox proportional-hazards model,32 with each analysis allowing for the covariates of country, sex, * There were no significant differences between the two treatment groups. The patients’ race was recorded by the investigators, on the basis of the interviews and evaluations of the patients. † The Child–Pugh score (range, 5 to 15, where 5 indicates good liver function and 15 poor liver function) is a measure of the severity of liver disease. ‡ The Ishak fibrosis score (range, 0 to 6) is a measure of the degree of fibrosis in liver-biopsy specimens. Scores of 0 to 4 indicate no or moderate fibrosis, and 5 or 6 severe fibrosis or cirrhosis. § All patients had detectable HBV DNA at screening; 0.7 meq per milliliter equals approximately 7¬105 copies per milliliter. ¶To convert values for bilirubin to milligrams per deciliter, divide by 17.1. ¿ To convert values for creatinine to milligrams per deciliter, divide by 88.4. Table 1. (Continued.) Characteristic Lamivudine Group (N=436) Placebo Group (N=215) Aspartate aminotransferase — U/liter Median 52 54 Range 14–686 17–367 Bilirubin — µmol/liter¶ Median 13.7 13.7 Range 3.0–50.0 1.7–58.1 Creatinine — µmol/liter¿ Median 88 88 Range 35–173 35–135 Hemoglobin — g/dl Median 14.7 14.6 Range 8.4–19.0 9.2–17.8 Platelet count per mm3 Median 145,000 131,000 Range 14,000–401,000 41,000–360,000 Prothrombin time — sec Median 12.5 12.8 Range 8.0–23.8 9.8–27.6 White-cell count per mm3 Median 5330 5300 Range 1980–11,600 2200–11,500 第 16 页
The NEW ENGLAND JOURNAL Of MEDICINE baseline alanine aminotransferase levels, and base- bers vouch for the validity and completeness of line Child-Pugh and fibrosis scores. The data from the data and the veracity of the data analysis patients withoutend points were censored as ofthe date that treatment was stopped (if the data and RESULTS safety monitoring board terminated the trial)or at the last date of available follow-up after treatment CHARACTERISTICS OF THE PATIENTS (if the trial was terminated for other reasons). Be- The intention-to-treat population consisted of 651 cause the study was stopped at the second interim patients who were randomly assigned to treatment alysis with strict stopping criteria applied at the at 41 sites across Australia, China, Hong Ko first interim analysis, adjustments that had to be laysia, New Zealand, the Philippines, Singapore, Tai- made to the final P values and estimates were neg- wan, and Thailand; 436 patients were assigned to ligible(an increase in the P value of <0.001 and an receive lamivudine and 215 to receive placebo. In y o The study was conducted in accordance with were male and 98 percent were Asian. The treat- rease of <0.002 for the hazard ratio ach treatment group, 85 percent of the patients good clinical practice and all applicable regula- ment groups were also well matched in terms of tions, including the Declaration of Helsinki(mod- age, laboratory results at baseline, and Ishak fibro- ified in 1996). Each investigator ensured that the sis scores (Table 1). The median Child-Pugh score protocol was reviewed and approved by the local at baseline was 5(range, 5 to 9), and no patient had ethics committee. Written informed consent was evidence of hepatocellular carcinoma, renal insuf. obtained from each patient before enrollment in ficiency, bleeding varices, or spontaneous bacterial dy entry. The study was designed by the academic inves- tigators in conjunction with medical staff from STUDY TERMINATION AND END POINTS GlaxoSmithKline. The data were collected by the At the recommendation of the data and safety investigators and analyzed by glaxoSmithKline. monitoring board, the double-blind phase of the Each author had access to the data. This article study was terminated at the second interim analy was written by a committee consisting of seven sis, because results had crossed the predefined authors(Drs. Liaw, Sung, Chow, and Farrell; and boundary for showing efficacy. At this time, 67 pa Mrs Shue, Mr. Keene, and Dr. Dixon, who are tients had achieved HBeAg seroconversion, 52 had GlaxoSmithKlineemployees) The committee mem- stopped therapy for other reasons, and 68 end Table 2. Disease Progression during Double-Blind Treatment and Follow-up after Treatment. Lamivudine Placebo P Variable (N=215 c noof patients(%) Overall disease progression 34(7.8) 045(0.28-0.73 0.001 Increase in Child-Pugh score 15(34) 19(8.8) 045(022-0.90 Hepatocellular car 17 16(74) 049(025-0.99) Bleeding varices Spontaneous bacterial peritonitis Liver-related death atient reached an end point during follow-up before the termination of the study. Dashes denote not gh score, and Ishak fibrosis score. Cl de fidencountry, sex, baseline alanine aminotransferase level, Child- When five cases of hepatocellul ed during the first cluded the hazard ratio was 0.47 (95 percent confidence interval, 0. 22 to 1.00; P-0.052) N englj Med 35715 Www.nejm.org OctobeR 7, 2004 第17页
n engl j med 351;15 www.nejm.org october 7, 2004 The new england journal of medicine 1526 baseline alanine aminotransferase levels, and baseline Child–Pugh and fibrosis scores. The data from patients without end points were censored as of the date that treatment was stopped (if the data and safety monitoring board terminated the trial) or at the last date of available follow-up after treatment (if the trial was terminated for other reasons). Because the study was stopped at the second interim analysis with strict stopping criteria applied at the first interim analysis, adjustments that had to be made to the final P values and estimates were negligible (an increase in the P value of <0.001 and an increase of <0.002 for the hazard ratio). The study was conducted in accordance with good clinical practice and all applicable regulations, including the Declaration of Helsinki (modified in 1996). Each investigator ensured that the protocol was reviewed and approved by the local ethics committee. Written informed consent was obtained from each patient before enrollment in the study. The study was designed by the academic investigators in conjunction with medical staff from GlaxoSmithKline. The data were collected by the investigators and analyzed by GlaxoSmithKline. Each author had access to the data. This article was written by a committee consisting of seven authors (Drs. Liaw, Sung, Chow, and Farrell; and Mrs. Shue, Mr. Keene, and Dr. Dixon, who are GlaxoSmithKline employees). The committee members vouch for the validity and completeness of the data and the veracity of the data analysis. characteristics of the patients The intention-to-treat population consisted of 651 patients who were randomly assigned to treatment at 41 sites across Australia, China, Hong Kong, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, and Thailand; 436 patients were assigned to receive lamivudine and 215 to receive placebo. In each treatment group, 85 percent of the patients were male and 98 percent were Asian. The treatment groups were also well matched in terms of age, laboratory results at baseline, and Ishak fibrosis scores (Table 1). The median Child–Pugh score at baseline was 5 (range, 5 to 9), and no patient had evidence of hepatocellular carcinoma, renal insufficiency, bleeding varices, or spontaneous bacterial peritonitis at study entry. study termination and end points At the recommendation of the data and safety monitoring board, the double-blind phase of the study was terminated at the second interim analysis, because results had crossed the predefined boundary for showing efficacy. At this time, 67 patients had achieved HBeAg seroconversion, 52 had stopped therapy for other reasons, and 68 end results * Only one patient reached an end point during follow-up before the termination of the study. Dashes denote not applicable. † Hazard ratios were derived from a Cox model adjusted for country, sex, baseline alanine aminotransferase level, Child– Pugh score, and Ishak fibrosis score. CI denotes confidence interval, unadjusted for interim analyses. ‡ Two patients fulfilled two criteria simultaneously at end-point confirmation. § When five cases of hepatocellular carcinoma diagnosed during the first year were excluded, the hazard ratio was 0.47 (95 percent confidence interval, 0.22 to 1.00; P=0.052). Table 2. Disease Progression during Double-Blind Treatment and Follow-up after Treatment.* Variable Lamivudine Group (N=436) Placebo Group (N=215) Hazard Ratio (95% CI)† P Value no. of patients (%) Overall disease progression 34 (7.8)‡ 38 (17.7) 0.45 (0.28–0.73) 0.001 Increase in Child–Pugh score 15 (3.4) 19 (8.8) 0.45 (0.22–0.90) 0.02 Hepatocellular carcinoma§ 17 (3.9) 16 (7.4) 0.49 (0.25–0.99) 0.047 Renal insufficiency 2 (0.5) 0 — — Bleeding varices 2 (0.5) 3 (1.4) — — Spontaneous bacterial peritonitis 0 0 — — Liver-related death 0 0 — — 第 17 页
