恩替卡韦治疗5年后慢性乙型肝炎患者肝细胞癌的发生率和预

StephenW

Hepatol Int. 2020 Apr 21. doi: 10.1007/s12072-020-10031-3. [Epub ahead of print]
Incidence and predictors of hepatocellular carcinoma beyond year 5 of entecavir therapy in chronic hepatitis B patients.
Sou FM1, Hu TH1, Hung CH1, Lai HC2, Wang JH1, Lu SN1, Peng CY3,4, Chen CH5.
Author information

1
    Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
2
    Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.
3
    Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan. [email protected].
4
    School of Medicine, China Medical University, Taichung, Taiwan. [email protected].
5
    Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan. [email protected].

Abstract
BACKGROUND:

PURPOSE: The study compared the incidence and predictors of hepatocellular carcinoma (HCC) within and beyond year 5 of entecavir (ETV) therapy.
METHODS:

The study enrolled 1397 CHB patients who were naïve to nucleos(t)ide analogue (NA) treatment and had received ETV monotherapy for more than 12 months.
RESULTS:

The cumulative incidences of HCC at 3, 5, and 10 years of ETV treatment were 4%, 9.1%, and 15.8%, respectively. In the entire cohort, the annual incidence rates of HCC were 2.28% within the first 5 years and 1.34% within 5-10 years of therapy. The incidences of HCC did not differ significantly within and beyond 5 years of ETV therapy (p = 0.53), including patients with cirrhosis (p = 0.85) and without cirrhosis (p = 0.47). At year 5 of treatment, the multivariate analysis showed that the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) levels were independent risk factors for HCC development beyond year 5. The 10-year cumulative incidences of HCC beyond year 5 in the high-risk group (FIB-4 > 2.20 and AFP > 3.21 ng/mL) and low-risk group (FIB-4 ≤ 2.20 and AFP ≤ 3.21 ng/mL) were 48.7% and 0%, respectively. APA-B score at 12 months and year 5 had a higher C-index for the prediction of HCC beyond year 5 than the PAGE-B at baseline and year 5 (p = 0.003 and p = 0.039, respectively) CONCLUSIONS: The HCC incidence tended to decrease but did not change significantly within and beyond 5 years of ETV therapy. The FIB-4 index and AFP levels at year 5 were predictive of HCC development beyond year 5 of ETV therapy.
KEYWORDS:

APA-B score; Alpha-fetoprotein; C-index; Cirrhosis; Entecavir; Fibrosis-4; Hepatitis B virus; Hepatocellular carcinoma; Nucleos(t)ide analogue; PAGE-B score

PMID:
    32319045
DOI:
    10.1007/s12072-020-10031-3

StephenW

Hepatol Int。 2020 Apr 21. doi：10.1007 / s12072-020-10031-3。 [Epub提前发行]
恩替卡韦治疗5年后慢性乙型肝炎患者肝细胞癌的发生率和预测指标。
Sou FM1，Hu TH1，Hung CH1，Lai HC2，Wang JH1，Lu SN1，Peng CY3,4，Chen CH5。
作者信息

1个
    台湾高雄大北路123号高雄长庚纪念医院及长庚大学医学院内科肝消化病科。
2
    台湾台中市40447育德路2号中国医科大学附属医院内科肝消化肠内科。
3
    台湾台中市40447育德路2号中国医科大学附属医院内科肝消化肠内科。 [email protected]。
4
    中国医科大学医学院，台湾台中。 [email protected]。
5
    台湾高雄大北路123号高雄长庚纪念医院和长庚大学医学院内科肝消化病科。 [email protected]。

抽象
背景：

目的：本研究比较了恩替卡韦（ETV）治疗第5年内及以后肝细胞癌（HCC）的发生率和预测指标。
方法：

该研究招募了1397名未接受过核苷酸类似物（NA）治疗且已接受ETV单药治疗超过12个月的CHB患者。
结果：

ETV治疗3年，5年和10年时HCC的累积发生率分别为4％，9.1％和15.8％。在整个队列中，HCC的年发病率在治疗的前5年为2.28％，在5-10年内为1.34％。在ETV治疗的5年内及以后，肝癌的发生率无显着差异（p = 0.53），包括肝硬化（p = 0.85）和无肝硬化（p（= 0.47）的患者。在治疗的第5年，多因素分析表明，纤维化4（FIB-4）指数和甲胎蛋白（AFP）水平是第5年以后肝癌发展的独立危险因素。第10年以后HCC的10年累积发生率高危组（FIB-4≥2.20和AFP> 3.21 ng / mL）和低危组（FIB-4≤2.20和AFP≤3.21 ng / mL）中的5分别为48.7％和0％。结论：在HCC发生率方面，在12年和5年级时，APA-B评分在第5年以后的HCC预测中的C指数高于PAGE-B在基线时和第5年时的C-指数（分别为p = 0.003和p = 0.039）。在接受ETV治疗的5年内及以后，其趋势趋于下降，但没有明显变化。第5年的FIB-4指数和AFP水平可预测ETV治疗5年后的肝癌发展。
关键字：

APA-B分数；甲胎蛋白C指数肝硬化；恩替卡韦;纤维化4;乙型肝炎病毒;肝细胞癌；核苷类似物; PAGE-B分数

PMID：
    32319045
DOI：
    10.1007 / s12072-020-10031-3

疯一点好

这种风险预测也太苛刻了吧，AFP3.21  就属于高风险了，看了很担心，我的AFP经常在3左右摆动，经常达到3.21的，有点惶恐，史提芬你的看法呢？谢谢！

StephenW

回复 疯一点好 的帖子

我个人的看法是：
1. 这是许多研究中的一项，所有研究都有不同的结果;
2. 在这项研究中, FIB-4≥2.20和AFP> 3.21 ng / mL, 表示HCC风险高. FIB-4> 2.20代表明显的纤维化.
2. 如果接受ETV治疗时且AFP显着增加，则应去看医生


Discussion
One recent study demonstrated that the HCC risk decreased
beyond year 5 of ETV/TDF therapy in Caucasian CHB
patients [annual HCC incidence rates: 1.22% vs. 0.73%
within and beyond 5 years (p = 0.05)], particularly in those
with compensated cirrhosis (3.22% vs. 1.57%, p = 0.039) [9].
Similarly, a recent study from Korea showed that the annual
HCC incidence rates significantly decreased after 4 years
of therapy with ETV/TDF compared to the first 4 years of
therapy (0.3% vs. 1.9%; p < 0.001) [19]. However, another
study from Korea showed that the incidence rates of HCC
in patients with CHB did not differ significantly within and
beyond 5 years of ETV therapy, including the non-cirrhotic
subgroup (0.31% vs. 0.43%, p = 0.739) and cirrhotic subgroup
(4.16% vs. 2.83%, p = 0.155) [10]. In our study, the
incidence of HCC tended to decrease but did not differ
significantly within and beyond 5 years of ETV therapy in
the non-cirrhotic patients (0.63% vs. 0.14%, p = 0.47) and
cirrhotic patients (4.5% vs. 2.3%, p = 0.85). Our results are
consistent with one of the Korean studies [10].
So far, two studies on Caucasian and Korean patients
reported that the HCC risk decreased after the first 5 years
of ETV/TDF therapy [9, 19]. In contrast, the incidence
rate of HCC in CHB patients did not change significantly
before and after the first 5 years of ETV therapy in the other
Korean study [10] and the present study. Compared with
the first two studies [9, 19] the other Korean study [10]

and the present study had several different clinical characteristics,
including a focus on only ETV therapy (no TDF
therapy), the enrolment of only NA-naïve patients, and the
exclusion of patients who developed HCC within the first
year of enrollment. These different clinical characteristics of
patients might lead to different results of HCC risks within
and beyond 5 years of NA therapy. In addition, it is possible
that the relatively small number of patients included in our
study and the Korean study [10] might result in the statistically
insignificant decreases in the incidence of HCC.
In recent years, several risk factors of HCC have been
identified among patients within 5 years of beginning NA
therapy. Old age, male sex, cirrhosis, platelet count, AFP,
and DM at baseline or 12 months of treatment have also
been reported [14, 16, 17, 20]. HCC risk factors measured
beyond 5 years of NA therapy have rarely been reported.
Papatheodoridis et al. showed that old age, low platelet
count at baseline or year 5, and liver stiffness ≥ 12 kPa at
year 5 were independently associated with HCC development
beyond year 5 of ETV/TDF therapy [9]. Kim et al. also
showed that old age and low platelet count at baseline were
independent risk factors for HCC occurrence beyond year 5
[10]. In the present study, old age, FIB-4 and AFP levels at
year 1 or 5, and genotype C were independent risk factors
for HCC occurrence beyond year 5.
The use of FIB-4 could predict HCC occurrence in both
NA-treated and untreated CHB patients [21]. Higher FIB-4
values at year 5 of NA therapy correlated with a higher
degree of fibrosis or cirrhosis despite long-term HBV suppression.
Thus, the FIB-4 index at year 5 of NA therapy is
useful to predict HCC occurrence beyond year 5 in both
non-cirrhotic and cirrhotic patients.
AFP has also been shown to be a predictor of HCC in
CHB patients receiving ETV therapy [22, 23]. We found
that AFP levels at year 1 or 5 of treatment were an independent
factor of HCC beyond year 5, particularly in cirrhotic
patients. Our findings revealed that an AFP cutoff value of
3.21 ng/mL at year 5 of treatment was optimal for predicting
HCC beyond year 5. Therefore, patients who cannot achieve
low AFP levels after long-term HBV suppression require
HCC surveillance.
Our study showed that a combination of FIB-4 and AFP
levels at year 5 of ETV could predict the risk of HCC occurrence
beyond year 5. The 10-year cumulative incidences of
HCC in the high-risk group and low-risk group were 48.7%
and 0%, respectively. Thus, a combination of FIB-4 and AFP
levels at year 5 was an useful marker to predict HCC beyond
year 5 of treatment.
Our study also investigated whether the APA-B and
PAGE-B scores [16, 17] could predict HCC development
beyond year 5. We found that higher APA-B and PAGE-B
scores at baseline (PAGE-B) and 1 year (APA-B) could predict
HCC occurrence before and beyond year 5, and APA-B
and PAGE-B scores at 5 years could predict HCC occurrence
beyond year 5. Furthermore, the APA-B model yielded
a higher C-statistic than the PAGE-B model. The APA-B
score can be considered as a supplementary tool for the prediction
of HCC before and beyond year 5 among NA-naïve
Asian patients receiving ETV therapy.
There are several limitations to this study. The first limitation
is the retrospective design. Second, cirrhosis was
mostly diagnosed via ultrasonography and clinical features,
which means that patients with early cirrhosis might have
been underdiagnosed. Third, our study included only Asian
patients (among which genotypes B and C are predominant)
[15] and patients who were treated with ETV. It is unclear
whether the same predictors are applicable to other HBV
genotypes and to those receiving TDF therapy.
In conclusion, the HCC incidence tended to decrease but
did not change significantly within and beyond 5 years of
ETV therapy. The FIB-4 index and AFP levels at both year
1 and year 5 were risk factors for HCC development beyond
5 years of ETV therapy. Therefore, continued HCC surveillance
is required for those who receive long-term ETV
therapy and do not develop HCC by year 5.
讨论区
最近的一项研究表明，HCC风险降低了
高加索CHB接受ETV / TDF治疗5年后
患者[每年HCC发生率：1.22％对0.73％
5年以内（p = 0.05）]，特别是在那些
合并肝硬化的患者（3.22％对1.57％，p = 0.039）[9]。
同样，韩国最近的一项研究表明，
4年后HCC发生率显着下降
与前4年相比，使用ETV / TDF进行治疗的比例
治疗（0.3％vs. 1.9％; p <0.001）[19]。但是，另一个
韩国的一项研究表明，肝癌的发生率
CHB患者中和
超过5年的ETV治疗，包括非肝硬化
亚组（0.31％vs.0.43％，p = 0.739）和肝硬化亚组
（4.16％对2.83％，p = 0.155）[10]。在我们的研究中
肝癌发生率呈下降趋势，但无差异
在ETV治疗的5年内及以后
非肝硬化患者（0.63％vs. 0.14％，p = 0.47）和
肝硬化患者（4.5％比2.3％，p = 0.85）。我们的结果是
与韩国的一项研究一致[10]。
到目前为止，两项针对高加索人和韩国人的研究
报告说头5年后HCC风险降低
ETV / TDF治疗[9，19]。相反，发生率
CHB患者的HCC发生率没有明显变化
在另一个ETV治疗的前5年前后
韩国研究[10]和本研究。和....相比
前两个研究[9，19]其他韩国研究[10]

并且本研究具有几种不同的临床特征，
仅关注ETV治疗（不包括TDF）
疗法），仅接受NA初次接受治疗的患者以及
排除在第一个内发生HCC的患者
入学年份。这些不同的临床特点
患者可能导致不同的HCC风险结果
以及超过5年的NA治疗。另外，有可能
包括在我们中的患者相对较少
研究和韩国研究[10]可能会导致
HCC发生率的下降不明显。
近年来，肝癌的几个危险因素已经
在开始使用NA后的5年内在患者中识别出NA
治疗。老年，男性，肝硬化，血小板计数，AFP，
以及基线或治疗12个月时的糖尿病
据报道[14、16、17、20]。肝癌危险因素
超过5年的NA治疗的报道很少。
Papatheodoridis等。表明年纪大，血小板低
在基线或第5年计数，并且肝硬度≥12 kPa
第5年与HCC的发展独立相关
ETV / TDF治疗超过5年[9]。 Kim等。也
显示基线时的老年和低血小板计数
五年后发生肝癌的独立危险因素
[10]。在本研究中，老年人，FIB-4和AFP的水平
第1年或第5年，基因型C是独立的危险因素
对于超过5年的HCC发生。
FIB-4的使用可以预测两种肝癌的发生
NA治疗和未治疗的CHB患者[21]。更高的FIB-4
NA治疗第5年的数值与较高
尽管长期抑制了HBV，但纤维化或肝硬化的程度。
因此，NA治疗第5年的FIB-4指数为
有助于预测5年后HCC的发生率
非肝硬化和肝硬化患者。
AFP还被证明是HCC的预测因子
CHB患者接受ETV治疗[22，23]。我们找到
在治疗的第1年或第5年，AFP水平是独立的
5年后肝癌的危险因素，尤其是肝硬化
耐心。我们的发现表明，AFP的临界值为
第5年治疗时的3.21 ng / mL最适合预测
超过5年的HCC。因此，无法达到目标的患者
长期抑制HBV后AFP水平低
HCC监视。
我们的研究表明FIB-4和AFP的组合
ETV第5年的水平可以预测发生HCC的风险
超过5年。
高危组和低危组的肝癌为48.7％
和0％。因此，FIB-4和AFP的组合
第5年的水平是预测HCC超过
治疗的第5年。
我们的研究还调查了APA-B和
PAGE-B评分[16，17]可以预测肝癌的发展
超过第5年。我们发现较高的APA-B和PAGE-B
基线（PAGE-B）和1年（APA-B）得分可以预测
第5年及以后的HCC发生以及APA-B
和PAGE-B评分在5年时可以预测HCC的发生
超过第5年。此外，APA-B模型产生了
C统计量高于PAGE-B模型。 APA-B
分数可被视为预测的补充工具
天真的5年之前和之后的H​​CC人数
亚洲患者接受ETV治疗。
这项研究有几个局限性。 第一个限制
是追溯设计。 二是肝硬化
主要是通过超声检查和临床特征诊断出来的，
这意味着早期肝硬化患者可能会
未被充分诊断。 第三，我们的研究仅包括亚洲人
患者（其中以B和C基因型为主）
[15]以及接受ETV治疗的患者。 尚不清楚
相同的预测因子是否适用于其他乙肝病毒
基因型和接受TDF治疗的患者。
总之，肝癌的发病率呈下降趋势，但
在5年内及之后没有明显变化
ETV疗法。 两年的FIB-4指数和AFP水平
第1年和第5年是超过
5年的ETV治疗。 因此，继续进行HCC监测
那些接受长期ETV的人是必需的
疗法，到5年不发展HCC。

疯一点好

我过去（近10年里检查都在3左右，平均下来大概在2.9ug/ml），最近一次检查AFP是3.42，这么说是属于高风险人群咯