AASLD2018[267]综合分析的影响 治疗中间终点 Hbeag（+）慢性乙型

StephenW

267
Comprehensive Analysis for the Impact of
on-Treatment Intermediate Endpoints on
Outcomes of Hbeag (+) Chronic Hepatitis B
Jonggi Choi1, Young-Suk Lim1, Seungbong Han2, Ju Hyun
Shim3, Kang Mo Kim3, Han Chu Lee1 and Yung Sang Lee1,
(1)Department of Gastroenterology, Liver Center, Asan
Medical Center, University of Ulsan College of Medicine,
(2)Department of Applied Statistics, Gachon University, (3)
Gastroenterology, Asan Medical Center, University of Ulsan
College of Medicine
Background: Alanine aminotransferase (ALT) normalization,
virologic response (VR), and HBeAg seroclearance are
intermediate endpoints to be achieved during antiviral
treatment for patients with HBeAg-positive chronic hepatitis
B (CHB) based on current international guidelines. However,
the impact of these intermediate endpoints on the longterm
clinical outcomes remains unanswered in the era of
high potency antiviral agents. Methods: A historical cohort
of 2,630 treatment-naïve HBeAg-positive CHB patients
who initiated treatment with entecavir or tenofovir disoproxil
fumarate at a tertiary referral hospital in Korea from 2007
through 2016 were included. The risk of HCC was analyzed
by landmark analysis, and time-dependent Cox model. ALT
normalization was defined as ALT ≤25 U/L for female and
≤35 for male. VR was defined as undetectable serum HBV
DNA levels (<60 IU/mL). Results: The mean age was 45.1
years and 1,712 (65.1%) were male. Cirrhosis was present
in 1,018 (38.7%) of patients. With the median follow-up of
5.1 years, ALT normalization, VR, and HBeAg seroclearance
were achieved in 2,318 (88.1%), 2,341 (89.0%), and 1,102
(41.9%), respectively. At 1-year landmark analysis, patients
with normal ALT was significantly associated with a lower
risk of HCC (p<0.001), whereas achieving VR was not a
significant predicting factor for HCC (p=0.10). At 2-year
landmark analysis, ALT normalization remained as a
significant factor for lower risk of HCC (p<0.001), whereas VR
and HBeAg seroclearance were not significantly associated
with a lower risk of HCC (p=0.97 and p=0.13, respectively). By
multivariable analysis using time-dependent Cox model, ontreatment
ALT normalization was independently associated
with a lower risk of HCC (adjusted hazard ratio [AHR]: 0.44,
95% CI: 0.32-0.60, p<0.001). while HBeAg seroclearance
(AHR: 1.30, 95% CI: 0.96-1.75, p=0.09) was not a significant
factor for predicting HCC development, as well as VR (HR:
1.24, 95% CI: 0.85-1.81, p=0.26). Among baseline factors,
older age (AHR: 1.05, 95% CI: 1.03-1.07, p<0.001), male sex
(AHR: 2.05, 95% CI: 1.49-2.84, p<0.001), high ALT levels, x5
upper limit of normal (AHR: 0.46, 95% CI: 0.30-0.72, p<0.001),
lower albumin (AHR: 0.77, 95% CI: 0.59-0.99), p=0.049), and
cirrhosis (AHR: 2.11, 95% CI: 1.40-3.18, p<0.001) were found
to be independent predictive factors for HCC development.
Conclusion: In a large historical cohort of HBeAg-positive
CHB patients undeter treatment with entecavir or tenofovir,
on-treatment ALT normalization was a sole independent
surrogate marker for predicting HCC development, whereas
VR and HBeAg seroclearance during treatment were not
significantly associated with the development of HCC.

StephenW

267
综合分析的影响
治疗中间终点
Hbeag（+）慢性乙型肝炎的结果
Jonggi Choi1，Young-Suk Lim1，Seungbong Han2，Ju Hyun
Shim3，Kang Mo Kim3，Han Chu Lee1和Yung Sang Lee1，
（1）牙山市肝脏中心消化内科
蔚山大学医学部医学中心，
（2）Gachon大学应用统计系，（3）
蔚山大学牙山医学中心消化内科
医学院
背景：丙氨酸氨基转移酶（ALT）正常化，
病毒学应答（VR）和HBeAg血清清除率
在抗病毒治疗期间要达到的中间终点
治疗HBeAg阳性慢性肝炎患者
B（CHB）基于现行国际准则。然而，
这些中间终点对长期的影响
在这个时代，临床结果仍未得到解答
高效抗病毒药物。方法：历史队列
2630例未接受过治疗的HBeAg阳性CHB患者
谁开始用恩替卡韦或替诺福韦地索普西治疗
2007年从韩国三级转诊医院购买富马酸盐
到2016年包括在内。分析了HCC的风险
通过地标分析和时间相关的Cox模型。 ALT
归一化定义为女性和女性的ALT≤25U/ L.
男性≤35岁。 VR被定义为不可检测的血清HBV
DNA水平（<60 IU / mL）。结果：平均年龄为45.1岁
年和1,712（65.1％）是男性。肝硬化存在
在1,018名（38.7％）患者中。随着中位数的随访
5。1年，ALT正常化，VR和HBeAg血清清除
分别达到2,318（88.1％），2,341（89.0％）和1,102
（41.9％），分别。在1年的里程碑分析中，患者
与正常ALT显着相关的较低
HCC的风险（p <0.001），而实现VR则不是
HCC的显着预测因子（p = 0.10）。 2年
具有里程碑意义的分析，ALT正常化仍然存在
降低HCC风险的重要因素（p <0.001），而VR
和HBeAg血清清除率无显着相关性
HCC风险较低（分别为p = 0.97和p = 0.13）。通过
使用时间依赖的Cox模型进行多变量分析，处理
ALT标准化独立相关
HCC风险较低（校正风险比[AHR]：0.44，
95％CI：0.32-0.60，p <0.001）。同时HBeAg血清清除
（AHR：1.30,95％CI：0.96-1.75，p = 0.09）不显着
预测HCC发展的因素，以及VR（HR：
1.24,95％CI：0.85-1.81，p = 0.26）。在基线因素中，
年龄较大（AHR：1.05,95％CI：1.03-1.07，p <0.001），男性
（AHR：2.05,95％CI：1.49-2.84，p <0.001），高ALT水平，x5
正常上限（AHR：0.46,95％CI：0.30-0.72，p <0.001），
低白蛋白（AHR：0.77,95％CI：0.59-0.99），p = 0.049），和
发现肝硬化（AHR：2.11,95％CI：1.40-3.18，p <0.001）
是HCC发展的独立预测因素。
结论：在HBeAg阳性的大型历史队列中
CHB患者接受恩替卡韦或替诺福韦治疗，
治疗中ALT正常化是唯一独立的
预测HCC发展的替代标志物，而
治疗期间的VR和HBeAg血清清除率没有
与HCC的发展显着相关。