AASLD 2013:预测肝癌恩替治疗的患者：结果从744例慢性乙

StephenW

TITLE: Prediction of Hepatocellular Carcinoma in Entecavir treated Patients: Results from 744 Chronic Hepatitis B patients in a European Multicenter Study (VIRGIL)
AUTHORS (FIRST NAME, LAST NAME): Pauline Arends1, Roeland Zoutendijk1, Ivana Carey2, Ashley S. Brown3, Massimo Fasano4, David J. Mutimer5, Katja Deterding6, Jurrien G. Reijnders1, Ye H. Oo5, Joerg Petersen7, Florian van Boemmel8, Robert J. de Knegt1, Thomas Berg8, Tania M. Welzel9, Teresa Santantonio4, Bettina E. Hansen1, 10, Heiner Wedemeyer6, Maria Buti11, Pierre Pradat12, Fabien Zoulim12, Harry L. Janssen13, 1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Gastroenterology and Hepatology, Erasmus MC university medical center, Rotterdam, Netherlands.
2. Institute of Liver Studies and Transplantation, King’s College London school of Medicine, London, London, United Kingdom.
3. Hepatology and Gastroenterology, Imperial College London, London, United Kingdom.
4. Clinic of Infectious Diseases, University of Foggia, Foggia, Italy.
5. NIHR Biomedical Research Unit and Centre for Liver Research, Queen Elizabeth Hospital, Birmingham, United Kingdom.
6. Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.
7. Liver Unit, IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany.
8. Hepatology, University Clinic Leipzig, Leipzig, Germany.
9. Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
10. Public Health, Erasmus MC university medical center, Rotterdam, Netherlands.
11. Hepatology, Hospital Vall de Hebron, Barcelona, Spain.
12. Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
13. Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada.
ABSTRACT BODY: BACKGROUND The goal of HBV treatment is to reduce disease progression to (decompensated) cirrhosis, HCC and death. Entecavir (ETV) inhibits HBV replication and reduces HCC. Recently, CU-HCC, GAG-HCC, and REACH-B HCC-risk scores showed to predict HCC in Asian ETV treated patients. The aim of this study was to investigate risk factors for development of HCC under ETV treatment.
METHODS We studied all HBV monoinfected patients treated with ETV monotherapy from 11 European referral centers within the Virgil Network. Patients with HCC at baseline or within the first 3 months of FU were excluded.
RESULTS A total of 744 patients treated with ETV were included (mean age 44±14 years; 77%male; 42%Caucasian/29%Asian/20%Black; 31%HBeAg+; HBV DNA 5.3±2.2log IU/ml; ALT 2.9xULN; 77%NA naive and 82%IFN naive; 164 patients (22%) had cirrhosis (by ultrasound or histology) at baseline. During a median FU of 167 (IQR 82-213) weeks, 14 patients were diagnosed with HCC of whom 9 (64%) had cirrhosis at baseline. Median time to development of HCC was 125 (IQR 59-188) weeks. The 5-year cumulative incidence rate of HCC was 4.4% (95% CI 1.7%–7.1%). Cumulative probability of HCC was higher in cirrhotic (p<0.001), older patients (p<0.001) and patients with lower platelet counts (p=0.02). Occurrence of HCC was not influenced by sex, HBeAg status, previous NA or IFN, baseline ALT, HBV DNA, or MELD score (p>0.11). All but one patient who developed HCC achieved virological response (VR) within 18 months of therapy. Early VR appeared protective for HCC development (HR0.63, 95%CI 0.15-2.63, p=0.52). At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with HCC. GAG-score was best in predicting HCC development. Cut-off values of 5 for the CU-HCC score and 101 for the GAG-HCC score were predictive for HCC development.(table) Hazard ratios of GAG-HCC score for development of HCC were less discriminative in Caucasians compared to Asians and Black (c-stat=0.72, 0.89 & 0.95 respectively).
CONCLUSION Cumulative incidence of HCC in ETV treated patients is low and early VR may be protective for HCC. Baseline CU-HCC and GAG-HCC, but not REACH-B scores predicted HCC in our population. Risk-scores were less discriminative in Caucasians, thus new risk-scores for this population are warranted.

                                  HR          95%CI        p-value    c-statistic
CU-HCC   continuous      1.07      1.03-1.11     0.0007    0.78
GAG-HCC continuous      1.05      1.02-1.07    <0.001    0.83
REACH-B continuous      1.003    0.90-1.11     0.955      0.66
CU-HCC   > 5                4.86      1.31-17.98    0.018     0.71
GAG-HCC > 101            4.45      1.54-12.87    0.006     0.71
REACH-B > 8               1.35       0.30-6.12      0.697    0.56

StephenW

背景乙肝治疗的目标是减少疾病进展（失代偿期）肝硬化，肝癌和死亡。恩替卡韦（ ETV ） ，抑制HBV的复制，降低肝癌。最近， CU - HCC ， GAG肝癌， REACH -B肝癌风险评分表明预测亚洲ETV治疗的患者肝癌。这项研究的目的是探讨下ETV治疗肝癌发展的危险因素。
方法我们研究了来自11个欧洲维吉尔网络内转诊中心恩替卡韦单药治疗所有HBV monoinfected患者的。在基线或FU的前3个月内的肝癌患者被排除在外。
结果共有744恩替卡韦治疗的患者（平均年龄44 ±14岁;男性占77％ ， 42％ Caucasian/29 ％黑色Asian/20 ％ ， 31％的HBeAg + HBV-DNA 5.3 ± 2.2log IU /毫升; ALT 2.9xULN ;幼稚和82 ％ 77 ％不适用干扰素天真; 164例（22％ ） ，肝硬化（通过超声或组织学）在基线中位数FU 167 （ IQR 82-213 ）周期间， 14名患者被确诊为肝癌。 ，其中9人（64％）基线肝硬化，肝癌的发展时间中位数为125 （ IQR 59-188 ）周肝癌的5年累积发病率是4.4％（ 95％CI为1.7 ％-7.1 ％ ）肝癌的累积概率较高的肝硬化（ P < 0.001 ） ，老年患者（ P < 0.001 ）和患者血小板计数较低（ P = 0.02） 。肝癌的发生无明显影响性别， HBeAg的状态，以往的NA或IFN肝癌发展，基线ALT ， HBV DNA ，或MELD评分（P > 0.11） 。所有，但一个病人谁开发肝癌治疗后18个月内取得了病毒学应答（ VR ） 。早期VR出现保护（ HR0.63 ，95％CI 0.15-2.63 ，P = 0.52） 。在基线水平，更高CU-的HCC和GAG肝癌，但不是， REACH -B分数与肝癌。 GAG比分是最好的预测HCC开发。截止值5 CU - HCC的得分和101的GAG- HCC得分预测肝癌发展。 （表） GAG - HCC得分肝癌发展的危险比在白种人相比，亚洲人和黑色（ C- STAT = 0.72 ，0.89歧视0.95元）。
结论累积在ETV治疗的患者肝癌发病率是低和早期VR可能是肝癌的保护。基线CU - HCC和GAG-肝癌，但没有达到-B评分在我国人口预测肝癌。风险比分分别为白种人歧视，从而对这个群体的新的风险分数是必要的。