四年恩替卡韦治疗减少慢性乙型肝炎患者的肝细胞癌，肝硬

StephenW

Viral Hepatitis
Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients


    Tung-Hung Su1,2, Tsung-Hui Hu3, Chi-Yi Chen4, Yi-Hsiang Huang5,6, Wan-Long Chuang7, Chun-Che Lin8, Chia-Chi Wang9, Wei-Wen Su10, Ming-Yao Chen11, Cheng-Yuan Peng12, Rong-Nan Chien13, Yi-Wen Huang14, Horng-Yuan Wang15, Chih-Lin Lin16, Sheng-Shun Yang17, Tsung-Ming Chen18, Lein-Ray Mo19, Shih-Jer Hsu20, Kuo-Chih Tseng21, Tsai-Yuan Hsieh22, Fat-Moon Suk23, Chi-Tan Hu24, Ming-Jong Bair25, Cheng-Chao Liang26, Yung-Chao Lei27, Tai-Chung Tseng28, Chi-Ling Chen2, Jia-Horng Kao1,2,* andon behalf of the C-TEAM study group and the Taiwan Liver Diseases Consortium
    and on behalf of the C-TEAM study group and the Taiwan Liver Diseases Consortium

    First published: 4 October 2016Full publication history
    DOI: 10.1111/liv.13253View/save citation
    Cited by: 0 articles

    Article has an altmetric score of 2
    Funding Information

    Funding informationThis work was supported by Bristol-Myers Squibb and National Health Research Institutes (NHRI-EX103-10319PC), Taiwan.
    Handling Editor: Vincent Wong

Abstract
Background & Aims

Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients.
Methods

The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective–prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort.
Results

In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development.
Conclusions

Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.

StephenW

病毒性肝炎
四年恩替卡韦治疗减少慢性乙型肝炎患者的肝细胞癌，肝硬化事件和死亡率


    Tung-Hung Su1,2，Tsung-Hui Hu3，Chi-Yi Chen4，Yi-Hsiang Huang5,6，Wan-Long Chuang7，Chun-Che Lin8，Chia-Chi Wang9，Wei-Wen Su10，Ming-Yao Chen11，Cheng - 袁鹏12，戎南钱13，易文文14，霍金元王15，志林林16，盛顺顺17，曾明明陈18，梁雷19，谢世杰20，郭志志21 - 袁志伟22，肥月月23，志丹湖24，明榕Bair25，程超超26，永超超27，大中正28，柯志凌2，贾 - 角高Kao1,2，*代表C-TEAM研究组和台湾肝病联盟
    并代表C-TEAM研究组和台湾肝病联盟

    首次发布：2016年10月4日完整的出版历史
    DOI：10.1111 / liv.13253查看/保存引文
    引用：0文章

    文章的得分为2
    资金信息

    资助信息这项工作得到了百时美施贵宝和台湾国家健康研究所（NHRI-EX103-10319PC）的支持。
    处理编辑：Vincent Wong

抽象
背景与目的

口服抗病毒治疗可以减少慢性乙型肝炎（CHB）患者的疾病进展。我们的目的是进一步调查长期恩替卡韦治疗在减少肝细胞癌（HCC）的风险，肝硬化事件和死亡率的大型CHB相关肝硬化患者的疗效。
方法

C-TEAM（肝硬化 - 台湾EntecAvir多中心）研究是在台湾的一个全国，多中心，回顾性前瞻性队列研究。我们招收了治疗初期的CHB相关性肝硬化患者和基线HBV-DNA≥2000IU / mL接受长期恩替卡韦治疗，并将HCC，肝硬化事件和死亡率的发展与历史未治疗队列的发展进行比较。
结果

总共招募了1315名恩替卡韦治疗和503名未治疗的肝硬化患者，中位数治疗和随访时间分别为4和6年。与未治疗的队列相比，恩替卡韦治疗与60％的HCC风险降低[风险比（HR）：0.40,95％置信区间（CI）：0.28-0.57]相关。此外，治疗前年龄较大，男性，HBeAg阳性，甲胎蛋白（AFP）≥7ng / mL是HCC发展的独立预测因素。进一步分析显示恩替卡韦治疗显着降低了静脉曲张出血，自发性细菌性腹膜炎，肝脏相关性和全因死亡的风险。这些发现在倾向评分匹配队列在敏感性分析中得到证实。在恩替卡韦治疗的患者中，较大年龄，男性，HBeAg阳性，治疗前AFP水平≥7ng/ mL和1年病毒学应答预示着HCC发展。
结论

四年恩替卡韦治疗显着降低CHB相关性肝硬化患者的肝癌，肝硬化事件和死亡率的风险。

商业战士

到底有多显著？这些研究为何不能给出计量回归的拟合预测式啊。

StephenW

回复 商业战士 的帖子

Need to read the whole article.

Statistical Analysis
The continuous variables are reported as median (interquartile range) and the categorical data as a number (percentage). Differences between groups were evaluated by Student t test or the chi-square test as appropriate. The entry dates were defined as the beginning of entecavir therapy for the treatment cohort and the diagnosis date of cirrhosis for the untreated cohort. The time at risk of primary and secondary endpoints was measured from the entry date until the development of the primary or secondary endpoints, death, loss to follow-up, the beginning of antiviral therapy, or December 31, 2014. The cumulative incidence rates of the primary and secondary endpoints were estimated using Kaplan-Meier analyses and compared using the log-rank test. The risks of primary and secondary endpoints were modeled using a Cox proportional hazards regression analysis after adjustment for age, sex, entecavir treatment, platelet count, albumin, HBeAg status, AFP, and the Child-Pugh score. The baseline parameters were included in a multiple logistic regression model
to calculate patients’ propensity scores, which were used to match the entecavir and untreated cohort by the greedy algorithm [14] as a sensitivity analysis. The statistical analysis was performed using STATA (version 13.0; Stata Corp, College Station, TX, USA). All tests were two-sided and a P value < 0.05 was considered significant.
RESULTS
A total of 1315 patients were enrolled in the entecavir cohort. For the untreated cohort, 621 eligible patients with cirrhosis were screened and 118 with a baseline HBV-DNA level < 2,000 IU/mL were excluded. Finally, 503 patients were enrolled in the untreated cohort. The baseline characteristics are shown in Table 1. The sex, HBeAg status, HBV-DNA, and AFP levels were comparable between the two cohorts. Compared with the untreated cohort, the patients in the entecavir cohort were significantly older, had a significantly lower albumin and platelet count, and had significantly higher ALT, total bilirubin levels, and Child-Pugh scores, all of which indicated a more advanced disease. The median duration of treatment and follow-up was 4 years (5,255 person–years) in the entecavir cohort and 6 years (3,416 person–years) in the untreated cohort, respectively.

Entecavir therapy significantly reduces the risk of HCC, cirrhotic events, and mortality
During follow-up, 119 of 1315 (119/1315) and 121 of 503 (121/503) HCC cases occurred in the entecavir and untreated cohorts, respectively. The Kaplan-Meier survival curve shows the risk of HCC was significantly greater in the untreated cohort compared with the entecavir cohort (log-rank P < 0.0001; Figure 1). The 4-year cumulative incidence of HCC was 17.5% (95% confidence interval [CI]: 14.3%–21.3%) in the untreated cohort (average 4.4% per year) and 9.4% (95% CI: 7.8%–11.3%) in the entecavir cohort (average 2.4% per year). The results of the univariate and multivariate Cox proportional hazards regression analyses for the risk of HCC showed an older age (HR: 1.05, 95% CI: 1.04–1.06), the male sex (HR: 1.75, 95% CI: 1.26–2.42), entecavir treatment (HR: 0.40, 95% CI: 0.28–0.57), HBeAg positivity (HR: 1.63, 95% CI: 1.20–2.22), and a baseline AFP level ≥ 7 ng/mL (HR: 1.63, 95% CI: 1.18–2.26) were all predictive of HCC development (Table 2). We further evaluated the risk of cirrhotic events as well as liver-related and all-cause mortality. The Kaplan-Meier survival curve shows that the risk of variceal bleeding (log-rank P =0.0217), SBP (log-rank P =0.0097), liver-related (log-rank P <0.0001) and all-cause mortality (log-rank P <0.0001) were significantly greater in the untreated cohort compared with the entecavir cohort (Figure 1). Entecavir treatment
significantly reduced the risk of first variceal bleeding (HR: 0.38, 95% CI: 0.20–0.74), SBP (HR: 0.06, 95% CI: 0.01–0.32), liver-related mortality (HR: 0.14, 95% CI: 0.07–0.30), and all-cause mortality (HR: 0.15, 95% CI: 0.08–0.29), but not HE (Table 3). A significant improvement of the Child-Pugh score was observed after 6 months of entecavir therapy (from 5.4 to 5.1, P < 0.0001). We further conducted subgroup analyses to identify the patients who could benefit the most from entecavir treatment (Table S2). Entecavir therapy was associated with a reduced risk of HCC in all subgroups. Particularly, the beneficial effect of entecavir therapy was more pronounced for patients with Child-Pugh B (HR: 0.14, 95% CI: 0.04–0.49) compared with those with Child-Pugh A (HR: 0.44, 95% CI: 0.31–0.64).

Sensitivity analysis
Because our cohorts were not comparable in several clinical parameters, we further matched the entecavir and untreated cohorts according to propensity scores. All the parameters were comparable between the two matched cohorts (Table S3). There were 31 (1,782 person–years) and 115 (3,021 person–years) HCC cases occurred in the entecavir and untreated cohorts, respectively. Multivariate-adjusted Cox proportional hazards regression analysis again confirmed that entecavir treatment reduced the risk of HCC development (HR: 0.40, 95% CI: 0.25–0.64). (Table 4) The
Kaplan-Meier survival curve shows that the risk of HCC (log-rank P <0.0001), variceal bleeding (log-rank P =0.0324), SBP (log-rank P =0.0094), liver-related (log-rank P =0.0003) and all-cause mortality (log-rank P =0.0008) were significantly greater in the untreated cohort compared with the entecavir cohort (Figure 2).Compared with untreated patients, the patients that received entecavir therapy had significantly reduced risks of SBP, liver-related mortality (HR: 0.22, 95% CI: 0.08–0.59), and all-cause mortality (HR: 0.24, 95% CI: 0.11–0.55) by multivariate Cox proportional hazards regression analyses (Table 4).
Because the untreated patients were followed for a longer period, and there is a greater chance of finding an event in this group. We therefore truncated the treatment and follow-up durations to 4 years to minimize the difference of follow-up durations between the two cohorts. Entecavir therapy consistently reduced the risk of HCC (HR: 0.40, 95% CI: 0.28–0.58; Table S4).
Compliance and safety of 4-year entecavir therapy The 4-year sustainability of entecavir use in cirrhosis patients was high. A total of 34 patients (2.6%) discontinued entecavir treatment. Virological breakthrough (last HBV-DNA level ≥ 2,000 IU/mL) was observed in 22 patients (1.7%), and 4 (0.3%) were confirmed to have entecavir resistance. Entecavir was shifted to tenofovir in two
and adefovir had been added-on in two. None of these 22 patients developed HCC. No significant adverse reactions to entecavir were reported.
Predictive risk factors of HCC development during entecavir treatment We further investigated the risk predictors of HCC development in the entecavir cohort. The baseline characteristics are compared between HCC and non-HCC patients in Table S5. Patients who developed HCC were significantly older (61 vs. 54 years old, P < 0.0001) and had significantly lower baseline albumin (3.9 vs. 4.0 g/dL, P = 0.012) and platelet counts (109 vs. 119 K/uL, P = 0.030) compared with the non-HCC patients. The results of the Cox proportional hazards regression analysis for the risk of HCC is shown in Table 5. An older age (HR: 1.06, 95% CI: 1.04–1.08), the male sex (HR: 1.88, 95% CI: 1.20–2.96), HBeAg positivity (HR: 1.89, 95% CI: 1.23–2.92), a baseline AFP level ≥ 7 ng/mL (HR: 1.93, 95% CI: 1.30–2.88), and 1-year virological response (HR: 0.62, 95% CI: 0.40–0.98) were predictive of HCC development.

需要阅读整篇文章。

统计分析
连续变量报告为中位数（四分位数范围），分类数据报告为数字（百分比）。组间的差异通过Student t检验或卡方检验适当地评估。入组日期定义为治疗队列恩替卡韦治疗的开始和未治疗队列的肝硬化诊断日期。初始和次要终点风险的时间测量从入组日期直到主要或次要终点发生，死亡，随访失败，抗病毒治疗开始或2014年12月31日。累积发病率使用Kaplan-Meier分析估计初级和次级终点，并使用对数秩检验进行比较。在调整年龄，性别，恩替卡韦治疗，血小板计数，白蛋白，HBeAg状态，AFP和Child-Pugh评分之后，使用Cox比例风险回归分析对初级和次级终点的风险进行建模。基线参数包括在多重逻辑回归模型中
计算患者的倾向得分，用于匹配entecavir和未经治疗的队列的贪婪算法[14]作为敏感性分析。使用STATA（版本13.0; Stata Corp，College Station，TX，USA）进行统计分析。所有测试均为双侧的，P值<0.05被认为是显着的。
结果
在恩替卡韦组中总共招募了1315名患者。对于未治疗的队列，筛选了621个合格的肝硬化患者，排除了基线HBV-DNA水平<2,000 IU / mL的118个患者。最后，503名患者参加了未经治疗的队列。基线特征显示在表1中。性别，HBeAg状态，HBV-DNA和AFP水平在两个队列之间是相当的。与未治疗的队列相比，恩替卡韦组中的患者显着较大，具有显着较低的白蛋白和血小板计数，并且具有显着较高的ALT，总胆红素水平和Child-Pugh评分，所有这些都表明更晚期的疾病。恩替卡韦组中治疗和随访的中位持续时间分别为4年（5,255人 - 年）和未治疗组中的6年（3,416人 - 年）。

恩替卡韦治疗显着降低HCC，肝硬化事件和死亡的风险
在随访期间，1315（119/1315）中的119名和503名（121/503）HCC病例中的121名分别发生在恩替卡韦和未治疗的队列中。 Kaplan-Meier存活曲线显示与恩替卡韦群组相比，未治疗群组中HCC的风险显着更大（对数秩P <0.0001;图1）。未治疗队列（平均4.4％/年）和9.4％（95％CI：7.8％-11.3％）的HCC的4年累积发病率为17.5％（95％置信区间[CI]：14.3％-21.3％ ）在恩替卡韦队列（平均每年2.4％）。对于HCC风险的单变量和多变量Cox比例风险回归分析的结果显示年龄较大（HR：1.05,95％CI：1.04-1.06），男性性别（HR：1.75,95％CI：1.26-2.42 ），恩替卡韦治疗（HR：0.40,95％CI：0.28-0.57），HBeAg阳性（HR：1.63,95％CI：1.20-2.22），基线AFP水平≥7ng/ mL（HR： ％CI：1.18-2.26）都预示着HCC发展（表2）。我们进一步评估了肝硬化事件的风险以及肝脏相关性和全因死亡率。 Kaplan-Meier存活曲线显示静脉曲张出血的风险（对数秩P = 0.0217），SBP（对数秩P = 0.0097），肝相关（对数秩P <0.0001）和全因死亡率-rank P <0.0001）在未治疗组中显着大于恩替卡韦组（图1）。恩替卡韦治疗
显着降低首次静脉曲张出血的风险（HR：0.38,95％CI：0.20-0.74），SBP（HR：0.06,95％CI：0.01-0.32），肝脏相关死亡率（HR：0.14,95％CI： 0.07-0.30）和全因死亡率（HR：0.15,95％CI：0.08-0.29），但不是HE（表3）。在恩替卡韦治疗6个月后观察到Child-Pugh评分的显着改善（从5.4至5.1，P <0.0001）。我们进一步进行亚组分析，以确定能最有利于恩替卡韦治疗的患者（表S2）。恩替卡韦治疗与所有亚组的HCC风险降低相关。特别地，与具有Child-Pugh A的患者相比，恩替卡韦治疗的有益效果对于具有Child-Pugh B的患者（HR：0.14,95％CI：0.04-0.49）更加明显：HR：0.44,95％CI： 0.64）。

敏感性分析
因为我们的队列在几个临床参数不可比，我们进一步匹配恩替卡韦和未经治疗的队列根据倾向得分。所有参数在两个匹配的队列之间是可比的（表S3）。在恩替卡韦和未治疗的队列中分别有31（1,782人 - 年）和115（3,021人 - 年）HCC病例。多变量校正的Cox比例风险回归分析再次证实，恩替卡韦治疗降低了HCC发生的风险（HR：0.40，95％CI：0.25-0.64）。 （表4）
Kaplan-Meier存活曲线显示，HCC（对数秩P <0.0001），静脉曲张出血（对数秩P = 0.0324），SBP（对数秩P = 0.0094），肝相关（对数秩P = 0.0003）和全因死亡率（log-rank P = 0.0008）在未治疗组中明显高于恩替卡韦组（图2）。与未治疗的患者相比，接受恩替卡韦治疗的患者SBP的风险显着降低，多因素Cox比例风险回归分析（表4）显示肝脏相关死亡率（HR：0.22,95％CI：0.08-0.59）和全因死亡率（HR：0.24,95％CI：0.11-0.55）。
因为未治疗的患者被跟踪更长的时间，并且在该组中找到事件的可能性更大。因此，我们将治疗和随访持续时间缩短到4年，以最小化两个队列之间随访持续时间的差异。恩替卡韦治疗始终降低HCC的风险（HR：0.40,95％CI：0.28-0.58;表S4）。
4年恩替卡韦治疗的依从性和安全性肝硬化患者恩替卡韦使用的4年可持续性很高。共有34名患者（2.6％）停用恩替卡韦治疗。在22名患者（1.7％）中观察到病毒学突破（最后HBV-DNA水平≥2,000IU/ mL），确认4名（0.3％）具有恩替卡韦抗性。恩替卡韦两次转为替诺福韦
和阿德福韦加入了两个。这22个患者中没有一个发展成HCC。没有报道对恩替卡韦显着的不良反应。
恩替卡韦治疗期间HCC发展的预测危险因素我们进一步调查了恩替卡韦组中HCC发展的风险预测因子。在表S5中比较HCC和非HCC患者的基线特征。发展HCC的患者显着较大（61对54岁，P <0.0001），并具有显着较低的基线白蛋白（3.9对4.0g / dL，P = 0.012）和血小板计数（109对119K / P = 0.030）。年龄（HR：1.06,95％CI：1.04-1.08），男性性别（HR：1.88,95％CI：1.20） -2.96），HBeAg阳性（HR：1.89,95％CI：1.23-2.92），基线AFP水平≥7ng/ mL（HR：1.93,95％CI：1.30-2.88）和1年病毒学应答HR：0.62,95％CI：0.40-0.98）预测HCC发展。

商业战士

未治疗队列（平均4.4％/年）和9.4％（95％CI：7.8％-11.3％）的HCC的4年累积发病率为17.5％（95％置信区间[CI]：14.3％-21.3％ ）在恩替卡韦队列（平均每年2.4％）。--------------癌变率下降50%？