HBsAg损失的HBV携带者的临床特征

StephenW

Discussion

We summarize here five important key findings regarding HBsAg seroclearance in Korean HBV carriers from a new perspective. First, HBsAg-SCR, HBeAg, HBV DNA and CLD are factors associated with the time interval from a given carrier state to HBsAg seroclearance. Second, the start of a decrease in HBsAg-SCR usually indicates the gradual loss of HBsAg quantity. Third, asymptomatic, inactive LC is present in approximately 30% of carriers with HBsAg seroclearance. Fourth, HCC can develop after HBsAg loss. Fifth, in addition to LC, risk factors for HCC may include excessive drinking and a family history of HBV infection.

The HBsAg clearance rate seems to be lower in Korea than in other countries. The clearance rate was determined to be 0.76% in Korea, while other studies have reported rates of 1.15%-1.6% in Taiwan[6,18], 1.14% in Kawerau of New Zealand[19], 1%-1.9% in Caucasian carriers[5,17], 2.5% in the Goto Islands of Japan[20], and 3.08% in China[21]. Compared with data from Taiwan[18], HBsAg seroclearance in Korea was significantly reduced in all age groups as follows: 0.55% vs 0.77% in the 20-30 year, 0.45% vs 1.07% in the 30-40 year, 0.92% vs 1.65% in the 40-50 year, and 0.89% vs 1.83% in the 50 and over age groups. This variability may be due to various factors, such as geographic differences in genotypes, age, gender, viral loading and fibrosis at enrollment. For instance, almost all Korean carriers are known to be infected with genotype C, whereas 60% and 34% of Taiwanese carriers are infected with genotypes B and C, respectively[6,22].

Carriers with an initial HBeAg-positive result show the gradual negative conversion of HBeAg and HBV DNA before the loss of HBsAg[14]. In carriers with an initial HBeAg-negative result, HBV DNA is cleared from the serum before HBsAg-NC, although low HBV DNA titers are persistently detected in some patients[23]. These results are inter-related in that the HBsAg loss is usually preceded by a long period of inactive disease[17].

The time period from entry to HBsAg loss in our study is similar to that reported in a previous six-year study conducted in China[21]. Notably, no significant differences in this time interval were observed according to age, the HBeAg status or the HBV DNA titer at the time of enrollment. Two opposite conclusions have been made regarding the role of HBV DNA in HBsAg seroclearance. One is that HBV DNA is not a dependent factor for HBsAg-NC[6,19], while the other suggests that lower viral loads are predictive of HBsAg seroclearance[24]. In our study, the HBV DNA titer was associated with the relative period of time from detection of viral activity to HBsAg seroclearance, and this period was at least 1.5 times longer in the carriers with HBV DNA levels ≥ 2000 IU/mL than in those with levels < 20 IU/mL 40s. However 50s, HBeAg exhibited this effect only in the 40s and 50s age groups, indicating its age-dependent role in predicting HBsAg loss, in contrast with the HBV DNA titer.

The baseline HBsAg level is known to be a better predictor of HBsAg seroclearance than other factors[6,16,19,21,24-26]. This statement applies to inactive carrier, in whom a lower HBsAg level is more predictive of HBsAg seroclearance. Reportedly, the optimum cut-off baseline HBsAg level has varied among studies, for example, studies have reported levels of < 10 IU/mL[6,21], < 100 IU/mL[19,24], < 200 IU/mL[25,26], and < 751 IU/mL[16]. In addition, it has been reported that the predictive capacity of the HBsAg level can be improved by considering it in combination with other factors, such as a normal platelet count[21], old age[19], an undetectable HBV DNA level[24], the HBV DNA level at 12 mo after HBeAg seroconversion[27], and a yearly ≥ 0.5 log IU/mL reduction[25,26].

Because the quantitative HBsAg test is expensive, we analyzed the utility of the HBsAg-SCR in predicting HBsAg seroclearance. A good linear correlation was observed between an HBsAg-SCR < 1000 and HBsAg-QNT < 200 IU/mL. In addition, a prozone effect on the HBsAg-SCR caused by excess antigen was observed among the carriers with excessive HBsAg titers of > 10000 IU/mL, most of whom had a very high serum HBV DNA level of > 7 log10 IU/mL. With the exception of those carriers with highly replicative infections, the HBsAg-SCR was significantly reduced in the HBeAg-negative carriers compared with the HBeAg-positive carriers. Moreover, the period of time from a given viral state to HBsAg loss tended to be shorter, as shown in Figure 2. A gradual decrease in the repeated tests during follow-up usually indicated HBsAg loss within five years. These results suggest that sequential HBsAg-SCR data are very useful for predicting HBsAg seroclearance.

The rate of LC at entry of 31.1% for the carriers with HBsAg seroclearance is similar to that reported previously[14]. These results indicate that LC is present in an appreciably high rate of carriers with HBsAg seroclearance. On the other hand, significant fibrosis has been reported to be more prevalent in patients with HBsAg seroclearance who are > 50 years of age compared with those who are < 50 years of age[19,28]. In our study, the prevalence of LC was significantly increased among the males who were approximately forty years of age. In addition, the carriers in whom LC/CLD was detected on US exhibited a longer time interval from entry to HBsAg seroclearance than those with normal US results. These results suggest that the correlation between age and HBsAg loss is meaningful when it is considered together with gender and LC. In addition, the frequency of HBsAg loss was higher in the carriers over the age of 40 than in the younger carriers, and this trend is similar to trends reported in Taiwan[18], Japan[20], and New Zealand[29]. These results might be associated with a high rate of HBsAg seroclearance during long-term follow-up, as reported in Chu and Liaw’s study[18].

Inactive carriers generally have a good prognosis. Indeed, none of the patients developed HCC following HBsAg loss (median follow-up of 72 mo) in a community study conducted in Kawerau, New Zealand[19], or in a study of Caucasians[5]. In contrast, in studies performed in Hong Kong and the United States, 1.4%-2.4% of the patients developed HCC after HBsAg seroclearance[7,14,28]. In our study, 4.82% of the carriers with HBsAg seroclearance developed HCC after HBsAg loss, indicating that HBsAg seroclearance does not guarantee patient safety out of HCC.

In one study, HBsAg seroclearance in individuals < 50 years of age has been shown to be associated with a lower risk of the development of HCC[28]. In another study, a low baseline level of albumin and family histories of HBsAg positivity and HCC have been demonstrated to be associated with a high risk of development of HCC, even in individuals who are < 50 years of age at the time of HBsAg clearance[14]. In our study, HCC developed in one patient over 50 years of age and in three patients over 60 years of age after HBsAg seroclearance. All patients had asymptomatic LC at registration and no evidence of deterioration of liver function during follow-up. In addition, none of these patients had a family history of HCC. Three men were excessive drinkers, and one woman had a vertical HBV infection.

In conclusion, HBsAg seroclearance does not indicate safety out of HCC, particularly in patients with LC. Spontaneous HBsAg loss might occur in a large proportion of cryptogenic LC and HCC cases in Korea, and surveillance should be continued after HBsAg loss in the same manner as for HBsAg-positive patients. Sequential HBsAg-SCR data measured with the conventional test are very useful for the long-term management of carriers, similar to HBsAg levels.

StephenW

讨论

我们从这个角度总结了韩国HBV携带者HBsAg血清清除的五个重要的关键发现。首先，HBsAg-SCR，HBeAg，HBV DNA和CLD是与从给定载体状态到HBsAg血清清除的时间间隔相关的因素。第二，HBsAg-SCR减少的开始通常表明HBsAg量逐渐减少。第三，无症状，无活性LC存在于约30％的具有HBsAg血清清除的载体中。第四，HCC可以在HBsAg消失后发展。第五，除了LC之外，HCC的风险因素可包括过度饮酒和HBV感染的家族史。

韩国的HBsAg清除率似乎低于其他国家。在韩国，清除率确定为0.76％，而其他研究报告在台湾为1.15％-1.6％[6,18]，新西兰Kawerau [19]为1.14％，白种人为1％-1.9％载体[5,17]，日本Goto群岛的2.5％，中国的3.08％[21]。与来自台湾的数据[18]相比，韩国的HBsAg血清清除率在所有年龄组中显着降低，如下：在20-30年中为0.55％对0.77％，在30-40年中为0.45％，而在1.0-40％中为0.92％在40-50岁时为1.65％，在50岁及以上年龄组为0.89％与1.83％。这种变异性可能是由于各种因素，例如在登记时基因型，年龄，性别，病毒载量和纤维化的地理差异。例如，几乎所有的韩国运营商都知道感染基因型C，而60％和34％的台湾运营商分别感染基因型B和C [6,22]。

具有初始HBeAg阳性结果的携带者显示在HBsAg缺失之前HBeAg和HBV DNA的逐渐负转化[14]。在具有初始HBeAg阴性结果的载体中，HBV DNA在HBsAg-NC之前从血清中清除，尽管在一些患者中持续检测到低HBV DNA滴度[23]。这些结果是相互关联的，因为HBsAg缺失通常在长时间的非活动性疾病之前[17]。

在我们的研究中，从进入HBsAg消失的时间段与在中国进行的前六年研究中报道的相似[21]。值得注意的是，在登记时，根据年龄，HBeAg状态或HBV DNA滴度未观察到该时间间隔的显着差异。有关HBV DNA在HBsAg血清清除中的作用的两个相反的结论。一个是HBV DNA不是HBsAg-NC的依赖因子[6,19]，而另一个表明较低的病毒载量是HBsAg血清清除的预测[24]。在我们的研究中，HBV DNA滴度与从检测病毒活性到HBsAg血清清除的相对时间段相关，并且在HBV DNA水平≥2000IU/ mL的载体中，该时间至少为1.5倍，水平<20 IU / mL 40s。然而50年代，HBeAg只在40和50岁年龄组中表现出这种作用，表明其与HBV DNA滴度相反，在预测HBsAg丧失中的年龄依赖性作用。

已知基线HBsAg水平是比其他因子更好的HBsAg血清清除预测因子[6,16,19,21,24-26]。这种说法适用于非活动载体，其中较低的HBsAg水平更可预测HBsAg血清清除。据报道，研究中最佳截断基线HBsAg水平不同，例如，研究报告的水平<​​10 IU / mL [6,21]，<100 IU / mL [19,24]，<200 IU / mL [25,26]和<751 IU / mL [16]。此外，据报道，通过将其与其它因素如正常血小板计数[21]，老年人[19]，不可检测的HBV DNA水平[24]联系起来，可以提高HBsAg水平的预测能力]，HBeAg血清学转换后12 mo的HBV DNA水平[27]，每年≥0.5 log IU / mL减少[25,26]。

因为定量HBsAg测试是昂贵的，我们分析了HBsAg-SCR在预测HBsAg血清清除率中的效用。在HBsAg-SCR <1000和HBsAg-QNT <200IU / mL之间观察到良好的线性相关性。此外，在具有> 10000IU / mL的过量HBsAg效价的载体中观察到由过量抗原引起的对HBsAg-SCR的前带效应，其中大多数具有> 7log 10 IU / mL的非常高的血清HBV DNA水平。除了那些具有高复制性感染的载体外，与HBeAg阳性携带者相比，HBsAg-SCR在HBeAg阴性载体中显着减少。此外，从给定的病毒状态到HBsAg损失的时间段倾向于更短，如图2所示。在随访期间重复测试的逐渐减少通常表明在5年内HBsAg丧失。这些结果表明顺序HBsAg-SCR数据对于预测HBsAg血清清除非常有用。

HBsAg血清清除载体进入时的LC率为31.1％，与之前报道的类似[14]。这些结果表明LC以相当高的速率存在具有HBsAg血清清除的载体。另一方面，据报道，与50岁以下的患者相比，显着的纤维化在≥50岁的HBsAg血清清除患者中更为普遍[19,28]。在我们的研究中，LC的流行率在大约四十岁的男性中显着增加。此外，在美国检测到LC / CLD的载体从进入HBsAg血清学清除的时间间隔比具有正常美国结果的载体更长。这些结果表明，当与性别和LC一起考虑时，年龄和HBsAg丧失之间的相关性是有意义的。此外，40岁以上的携带者HBsAg缺失的频率高于年轻携带者，这一趋势与台湾[18]，日本[20]和新西兰[29]报道的趋势相似。这些结果可能与长期随访期间HBsAg血清清除率高有关，如Chu和Liaw的研究报道[18]。

无活性载体通常具有良好的预后。事实上，在Kawerau，新西兰[19]或高加索人的研究[5]中，没有一个患者发生HBsAg消失后的HCC（中位随访72 mo）。相比之下，在香港和美国进行的研究中，1.4％-2.4％的患者在HBsAg血清清除后发展HCC [7,14,28]。在我们的研究中，4.82％具有HBsAg血清清除的携带者在HBsAg消失后发生HCC，表明HBsAg血清清除不能保证患者的HCC患者安全。

在一项研究中，在<50岁的个体中HBsAg血清清除显示与HCC发展的较低风险相关[28]。在另一项研究中，HBsAg阳性和HCC的白蛋白和家族史的低基线水平已被证明与HCC发生的高风险相关，即使在HBsAg清除时<50岁的个体中也是如此[ 14]。在我们的研究中，HCC在一个50岁以上的患者和三个60岁以上的HBsAg血清清除后发展。所有患者在登记时均有无症状LC，并且在随访期间没有肝功能恶化的证据。此外，这些患者中没有一个具有HCC的家族史。三个人是过度饮酒者，一个女人患有垂直HBV感染。

总之，HBsAg血清清除不表明HCC的安全性，特别是在LC患者中。自发性HBsAg消失可能发生在大部分隐源性LC和HCC病例在韩国，并且监测应该继续HBsAg损失后与HBsAg阳性患者相同的方式。使用常规测试测量的序列HBsAg-SCR数据对于载体的长期管理非常有用，类似于HBsAg水平。

疯一点好

这么说表面抗原消失并不是一件好事，可能在短期内风险更高，

StephenW

回复 疯一点好 的帖子

我不明白你的结论!

在韩国，大量隐源性肝硬化和HCC病例可能发生自发HBsAg消失.那就是HBsAg消失之前, 许多患者已经具有肝硬化和/或HCC.

newchinabok

肝癌的发生有十多年的过程，有个癌前病变过程。hcc不是一天发生的

newchinabok

以前hbsag消失就认为治愈，现在认识hbsag深入了，以前的论断就需要更新。

newchinabok

核苷药就是hcc二级预防，尽可能阻止癌前病变发展，核衣壳抑制剂也同理

newchinabok

核苷药就是hcc二级预防，尽可能阻止癌前病变发展，核衣壳抑制剂也同理