因素预测HBeAg阴性乙型肝炎病毒感染的患者持续正常肝功能的

StephenW

PLoS One. 2016 Dec 9;11(12):e0166543. doi: 10.1371/journal.pone.0166543. eCollection 2016.
Factors Predicting HBsAg Seroclearance and Alanine Transaminase Elevation in HBeAg-Negative Hepatitis B Virus-Infected Patients with Persistently Normal Liver Function.Chien TL1, Wang JH2, Kee KM2, Chen CH2, Hung CH2, Lu SN2.
Author information

• 1Division of Hepato-Gastroenterology, Department of Internal Medicine, Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Donggang Township, Pingtung County, Taiwan.
• 2Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, Taiwan.
  

AbstractBACKGROUND: A certain proportion of hepatitis B virus (HBV)-infected patients with persistently normal alanine transaminase (ALT) levels have significant fibrosis. Using liver stiffness measurements (Fibroscan®) and laboratory data, including serum ALT, quantitative HBsAg (qHBsAg), and HBV DNA, we attempted to predict the natural histories of these patients.
METHODS: Non-cirrhotic HBeAg-negative chronic hepatitis B patients with persistently normal ALT were followed up prospectively with the end points of HBsAg seroclearance and ALT elevation above the upper limit of normal. The factors that were predictive of the end points were identified.
RESULTS: A total of 235 patients with an average age of 48.1 +/- 10.7 years were followed up for 7 years. Eight patients (3.4%) lost HBsAg, and 15 patients (6.4%) experienced ALT elevation. The overall cumulative HBsAg seroclearances were 0.4%, 1.3% and 2.3% at years 1, 3 and 5, respectively. Regarding HBsAg seroclearance, the qHBsAg (< 30 IU/ml) cutoff resulted in a hazard ratio (HR) of 19.6 with a 95% confidence interval (CI) of 2.2-166.7 (P = 0.008). The baseline ALT level (odd ratio (OR) 1.075, 95% CI 1.020-1.132, P = 0.006) and a qHBsAg above 1000 IU/ml (3.7, 1.1-12.4, P = 0.032) were associated with ALT elevation. Limited to men, the baseline liver stiffness (1.6, 1.0-2.5, P = 0.031) and a qHBsAg above 1000 IU/ml (10.4, 2.1-52.4, P = 0.004) were factors that were independently associated with ALT elevation.
CONCLUSION: A low qHBsAg level predicted HBsAg clearance. Baseline ALT and a qHBsAg above 1000 IU/ml were independent predictive factors for ALT elevation. Among the men, the independent predictive factors for ALT elevation were qHBsAg and liver stiffness.


PMID:27935953DOI:10.1371/journal.pone.0166543

StephenW

PLoS One。 2016 Dec 9; 11（12）：e0166543。 Doi：10.1371 / journal.pone.0166543。 ECollection 2016。
因素预测HBeAg阴性乙型肝炎病毒感染的患者持续正常肝功能的HBsAg Seroclearance和丙氨酸转氨酶升高。
Chien TL1，Wang JH2，Kee KM2，Chen CH2，Hung CH2，Lu SN2。
作者信息

1台安泰医疗保健合作中心肝内科，内分泌科，台湾屏东县东港镇安泰天盛纪念医院。
高雄长庚纪念医院和长庚大学医学院，台湾高雄市内科医学院肝胆肠病学研究室。

抽象
背景：

（ALT），重大HBsAg（qHBsAg）和HBV（乙型肝炎病毒（HBV））慢性乙型肝炎病毒（HBV）DNA，我们试图预测这些病人的自然病史。
方法：

非肝硬化HBeAg阴性的慢性乙型肝炎患者持续正常的ALT随访HBsAg血清清除的终点和提高高于正常上限的前瞻性。确定了预测终点的因素。
结果：

共有235例平均年龄为48.1±10.7岁的患者随访7年。 8名患者（3.4％）失去HBsAg，15名患者（6.4％）经历升高，总体累积HBsAg血清清除率为0.4的HBsAg血清清除，qHBsAg（<30 IU / ml）切除导致危险比具有95％置信区间（CI）（比值比（OR）1.075,95％CI 1.020-1.132，P = 0.006）和高于1000IU / ml的qHBsAg（3.7,1.1-12.4，P = 0.032）男性的升高，基线肝硬度（1.6,1.0-2.5，P = 0.031）和高于1000IU / ml的qHBsAg（10.4,2.1-52.4，P = 0.004）是与升高独立相关的因素，
结论：

低qHBsAg水平预测HBsAg清除率。基线ALT和高于1000IU / ml的qHBsAg是升高的独立预测因子，在男性中，升高的独立预测因子是qHBsAg和肝硬度。

PMID：
27935953
DOI：
10.1371 / journal.pone.0166543

StephenW

StephenW

Discussion

HBsAg seroclearance is a landmark in the treatment of chronic HBV infection because hepatitis B is mainly immune-mediated, and the elimination of HBsAg is considered to be an indicator of the effective treatment of HBV infection. A lower HBsAg level may indicate better host immune control of HBV duplication and a decreased level of intrahepatic covalently closed circular DNA [10]. The annual HBsAg seroclearance rate of hepatitis B patients is between 0.5% and 2.26% per year depending on enrollment in treatment [11–13]. In a study conducted in Taiwan regarding spontaneous HBsAg seroconversion, the average follow-up period of hepatitis B patients was 7.4 years, and 18 patients of 3,000 cleared HBsAg with an annual rate of 0.6%. At 1 year after HBeAg seroconversion, low serum levels of HBsAg predicted the elimination of HBsAg in patients with genotype B or C infections [14]. A Korean study demonstrated that the overall annual HBsAg seroclearance rate was 1.8%, but the annual HBsAg seroclearance rate of the older-aged group was higher, i.e., the annual seroclearance rate was 2.69% among patients aged over 60, whereas the annual seroclearance rate was 1.91% among the patients aged between 40 and 59. The cumulative probabilities of HBsAg seroclearance were 1.2%, 3.8% and 8.7% for patients who were followed for 1, 3 and 5 years, respectively [15]. The annual HBsAg seroclearance rate in our study was 0.48%, i.e., 8 patients exhibited HBsAg seroclearance in the 1645 person-years study, and the rate was 0.3%, i.e., 5 patients exhibited HBsAg seroclearance in the 1624 person-years study. The overall cumulative HBsAg seroclearance rates were 0.4%, 1.3% and 2.3% for the patients who were followed up for 1, 3 and 5 years, respectively. In the present study, the HBsAg seroclearance rate was lower than that in the aforementioned Korean study. In the Korean study, the patients were all genotype C, and approximately 20% of them were treated with an antiviral agent or interferon; however, in our study, the patients were all treatment-naïve, and genotype B was predominant.

Given that there is no evidence of liver cirrhosis or HCV/HDV super infection and the subject’s age is <50 years at the time of the HBsAg loss, there is a minimal risk of HCC development [16]. The REVEAL-HBV study demonstrated that HBsAg seroclearance is significantly associated with increased age, a low serum HBV DNA level (100000 vs ≧ 100000 copies/mL) and a high body mass index (30 vs 30 kg/m2) [17]. In the natural course of chronic HBV infection, a lower HBV DNA level has been reported to be important in determining the subsequent elimination of HBsAg, and the HBV DNA levels in the sera of 95.8% of patients have been found to be undetectable before the elimination of HBsAg [18]. The HBsAg level was a better indicator than the HBV DNA level regarding the prediction of HBsAg elimination in patients who were followed for 6 years. Comparison of the patients with HBsAg levels ≧ 1000 IU/ml with those with HBsAg levels that were 100~999 and < 100 IU/ml revealed that the hazard ratios were 4.4 (95% CI, 1.1–17) and 24.3 (8.7–67.5), respectively, which indicated that the HBsAg loss rate of the latter group was higher. [14]. In a longitudinal study of 117 patients performed in Hong Kong, during the natural course of chronic hepatitis B, a HBsAg reduction > 1 log10 IU/ml was associated with greater viral suppression [19]. Our study revealed that the baseline HBV DNA level had nothing to do with HBsAg seroclearance, and only the qHBsAg was associated with HBsAg seroclearance; at the cutoff of qHBsAg 30 IU/ml, the HR was 19.230, and 95% CI was 2.2–166.7. There was no significant relationship between genotype and HBsAg seroclearance in our study. This study suggested the existence of an uncoupled immune effect on HBsAg production and viral duplication. However, a low qHBsAg level might suggest a more complete immune clearance than a low HBV DNA level.

At present, there is little data available for predicting spontaneous ALT elevation above the ULN in asymptomatic chronic HBV-infected patients with persistently normal ALT. In a recent study performed in India with patients with HBeAg-negative chronic hepatitis B who were yet asymptomatic and had normal ALT levels, the factors that were found to be predictive of the occurrence of spontaneous ALT flares were the male gender, the presence of precore mutants and an age equal to or above 30 years old at baseline. ALT flares were defined as elevations in the serum ALT level to above 2 times the ULN in combination with an HBV DNA level ≧105 copies/ml or a 100-fold rise in the HBV DNA from the previous baseline level. The rate of ALT flares was approximately 4.3% per year. The examined patients were predominantly genotypes D and A [20]. In a prospective study performed in Canada, ALT elevation was defined as a change from a normal ALT (ALT ≦ 40 IU/ml) to an elevated ALT (ALT > 40 IU/ml). This study followed 37 HBeAg-negative patients with normal ALT levels at baseline for a median of 3 years (0.67–4 years), and their baseline HBV DNA levels were found to be highly predictive of future ALT elevations above the ULN [21]. In contrast, a study of chronic hepatitis B among Asian American patients found that the ALT levels were normal (genotype B or C), and there were no strong associations of ALT flares with any of the assessed clinical factors, which included an age ≧ 50, gender, ALT at biopsy ≧ 1/2 ULN, fibrosis stage > 1, inflammation grade > 1, HBV DNA ≧ 100000 IU/ml or ≧ 20000 IU/ml, HBeAg positivity, HBV PC mutation, HBV BCP mutation, all combinations of PC and BCP mutations, and genotypes B or C. However, this study of Asian Americans did not test qHBsAg [22]. In our study, the annual rate of spontaneous ALT elevation was 0.9%, and the qHBsAg played a more important role in predicting ALT elevations. According to the medical care guide of the Taiwan National Health Insurance Administration, in the patient group with ALT elevations above the ULN, 7 of 15 patients (46.7%) would receive nucleoside/nucleotide analogues.

Arena et al. demonstrated that there is a strong association between liver stiffness and serum aminotransferase level [23]. In CHB patients with ALT flares, liver stiffness increases and returns to normal levels after 6 months [24]. A recent meta-analysis demonstrated that the FibroTest has good accuracy in terms of the identification of HBV-associated significant fibrosis and cirrhosis [25]. Regarding the prediction of ALT elevations above the ULN, the patients were further divided into male and female groups because different etiologies may be present in the different genders. However, there were only 3 females, so it was not possible to statistically analyze the females, and we only analyzed the male patients in the subgroup analysis. Baseline liver stiffness was correlated with future ALT elevation in our cohort. Across all patients, liver stiffness was only significant in the univariate analysis. However, in the subgroup analysis of the male patients, liver stiffness was significant in both univariate and multivariate analyses. We also analyzed the fibrosis-4 score (FIB-4) and AST to platelet ratio index (APRI). However, there was no significant relationship between these scores and ALT elevation.

qHBsAg provides not only a very useful means to identify the HBV-related cause of liver damage in HBsAg carriers but also it is the most important predictor of clinically relevant outcomes associated with HBV-induced liver disease. In a prospective study performed in France, reactivation of hepatitis among HBeAg-negative asymptomatic patients could be predicted by a combination of HBsAg > 1000 IU/ml and HBV-DNA > 200 IU/ml (92% sensitivity and 96% negative predictive value) [26]. Tseng TC et al. showed that HBsAg, ALT and age could be used as predictors for hepatocellular carcinoma in HBeAg negative patients with HBV DNA < 2000 IU/ml. This study revealed higher risk of HCC in patients with HBsAg ≥1000 IU/ml compared with those <1000 IU/ml (adjusted hazard ratio 13.7, 95% confidence interval: 4.8–39.3) [27]. Another prospective study from Korea also demonstrated that combined HBsAg and HBV DNA (> 850 IU/ml and 850 IU/ml, respectively) could predict the reactivation of HBV with 84.6% diagnostic accuracy [28]. One recent study showed that combined HBV DNA with qHBsAg or liver stiffness measurement could correctly identify inactive carrier at a single time point [29]. Our study emphasizes the influence of single baseline ALT, qHBsAg and liver stiffness measurement on natural history of asymptomatic hepatitis B infected patients. However, our study has some limitations. This study conducted only on a small sample size of population with relatively short duration of follow-up. We used the same level of ALT normal cutoff value (40 IU/ml) for both genders (2016 American Association for the Study of Liver Disease Guideline: normal ALT levels are <30 IU/ml for males and <10 IU/ml for female) because we use the same normal ALT cutoff value in real-world clinical practice in Taiwan.

In conclusion, our study demonstrated that a single baseline qHBsAg is an important factor for future ALT elevations above the ULN and qHBsAg seroclearance. Very few studies have used baseline liver stiffness to predict future ALT elevations. Currently, no simple and readily available markers are able to accurately predict biochemical elevations in HBV-infected patients. Using the qHBsAg, liver stiffness and HBV DNA, we have demonstrated a new perspective for predicting the natural course of HBeAg-negative patients with persistently normal liver function.

StephenW

讨论

HBsAg血清清除是治疗慢性HBV感染的一个里程碑，因为乙型肝炎主要是免疫介导的，消除HBsAg被认为是有效治疗HBV感染的指标。较低的HBsAg水平可以指示更好的宿主对HBV重复的免疫控制和降低的肝内共价闭合环状DNA水平[10]。根据入选的治疗，乙型肝炎患者的年HBsAg血清清除率每年在0.5％和2.26％之间[11-13]。在台湾进行的关于自发性HBsAg血清学转换的研究中，乙型肝炎患者的平均随访期为7.4年，并且18位患者中的3000位清除HBsAg，年率为0.6％。在HBeAg血清学转换后1年，低血清水平的HBsAg预测在患有基因型B或C感染的患者中HBsAg的消除[14]。韩国研究表明，年总HBsAg血清清除率为1.8％，但老年组的年度HBsAg血清清除率较高，即年龄超过60岁的患者的年血清清除率为2.69％，而年龄血清清除率在40和59岁之间的患者中为1.91％。HBsAg血清清除的累积概率分别为1.2％，3.8％和8.7％，分别为1年，3年和5年随访的患者[15]。我们的研究中的年HBsAg血清清除率为0.48％，即在1645人 - 年研究中8名患者表现出HBsAg血清清除率，并且该比率为0.3％，即在1624人年研究中5名患者表现出HBsAg血清清除率。对于随访1年，3年和5年的患者，总的累积HBsAg血清清除率分别为0.4％，1.3％和2.3％。在本研究中，HBsAg血清清除率低于上述韩国研究。在韩国研究中，患者均为基因型C，其中约20％用抗病毒剂或干扰素治疗;然而，在我们的研究中，患者都是初治的，基因型B是主要的。

鉴于没有肝硬化或HCV / HDV超感染的证据，并且受试者的年龄在HBsAg缺失时<50年，所以HCC发展的风险最小[16]。 REVEAL-HBV研究表明HBsAg血清清除率与年龄增加，血清HBV DNA水平低（100000 vs≧100000拷贝/ mL）和高身体质量指数（30 vs 30 kg / m2）显着相关[17]。在慢性HBV感染的自然过程中，已经报道了较低的HBV DNA水平对于确定随后消除HBsAg是重要的，并且在消除之前发现95.8％的患者的血清中的HBV DNA水平是不可检测的的HBsAg [18]。 HBsAg水平是一个更好的指标比HBV DNA水平关于预测HBsAg消除患者谁跟踪6年。 HBsAg水平≥1000IU / ml的患者与HBsAg水平为100〜999和<100 IU / ml的患者比较显示，风险比为4.4（95％CI，1.1-17）和24.3（8.7-67.5 ），说明后一组的HBsAg消失率较高。 [14]。在香港进行的117例患者的纵向研究中，在慢性乙型肝炎的自然过程中，HBsAg减少> 1log10 IU / ml与更大的病毒抑制相关[19]。我们的研究显示，基线HBV DNA水平与HBsAg血清清除无关，只有qHBsAg与HBsAg血清清除相关;在qHBsAg 30IU / ml的截止值，HR为19.230，95％CI为2.2-166.7。在我们的研究中，基因型和HBsAg血清清除率之间没有显着的相关性。这项研究表明存在解偶联的免疫效应对HBsAg生产和病毒复制。然而，低的qHBsAg水平可能表明比低HBV DNA水平更完全的免疫清除。

目前，对于持续正常ALT的无症状慢性HBV感染患者，几乎没有可用于预测超过ULN的自发性ALT升高的数据。在印度最近进行的一项研究中，HBeAg阴性的慢性乙型肝炎患者无症状，ALT水平正常，发现ALT自发发生的预测因素是男性，突变体，在基线时年龄等于或大于30岁。 ALT火炬定义为血清ALT水平升高至ULN的2倍以上，同时HBV DNA水平≥105拷贝/ ml或HBV DNA从前一基线水平升高100倍。 ALT爆发的发生率约为每年4.3％。检查的患者主要是基因型D和A [20]。在加拿大进行的前瞻性研究中，ALT升高定义为从正常ALT（ALT≤40IU/ ml）到升高的ALT（ALT> 40IU / ml）的变化。这项研究遵循HBeAg阴性患者在基线时的中位数为3年（0.67-4岁）的正常ALT水平，并且他们的基线HBV DNA水平被发现是高于ULN的未来ALT升高的高度预测性[21]。相比之下，亚洲裔美国患者的慢性乙型肝炎的研究发现，ALT水平正常（基因型B或C），并且没有ALT flares与任何评估的临床因素的强烈关联，其包括年龄≥50 ，性别，活检时ALT≥1/ 2ULN，纤维化分期≥1，炎症分级> 1，HBVDNA≥100000IU/ ml或≥20000IU/ ml，HBeAg阳性，HBV PC突变，HBV BCP突变，所有组合PC和BCP突变，以及基因型B或C.然而，这项亚裔美国人的研究没有检测qHBsAg [22]。在我们的研究中，自发性ALT升高的年率为0.9％，并且qHBsAg在预测ALT升高中发挥更重要的作用。根据台湾国家健康保险局的医疗指南，在ALT升高高于ULN的患者组中，15名患者中有7名（46.7％）将接受核苷/核苷酸类似物。

Arena et al。表明肝硬度与血清氨基转移酶水平之间存在强相关性[23]。在CHB患者ALT发烧，肝硬度增加，并在6个月后恢复正常水平[24]。最近的荟萃分析表明，FibroTest在鉴定HBV相关的显着肝纤维化和肝硬化方面具有良好的准确性[25]。关于ULN上方的ALT升高的预测，将患者进一步分为男性和女性组，因为在不同性别中可能存在不同的病因。然而，只有3个女性，因此不可能对女性进行统计分析，我们只在亚组分析中分析了男性患者。基线肝硬度与我们队列中未来ALT升高相关。在所有患者中，肝硬度仅在单变量分析中显着。然而，在男性患者的亚组分析中，肝硬度在单变量和多变量分析中都是显着的。我们还分析了纤维化-4评分（FIB-4）和AST与血小板比率指数（APRI）。然而，这些分数与ALT升高之间没有显着的相关性。

qHBsAg不仅提供了一种非常有用的方法来鉴定HBsAg携带者中HBV相关的肝损伤原因，而且它是与HBV诱导的肝病相关的临床相关结果的最重要的预测因子。在法国进行的前瞻性研究中，通过HBsAg> 1000 IU / ml和HBV-DNA> 200 IU / ml（92％敏感性和96％阴性预测值）的组合可以预测HBeAg阴性无症状患者中肝炎的再激活， [26]。 Tseng TC et al。 HBsAg，ALT和年龄可用作HBeAg阴性患者HBV DNA <2000 IU / ml的肝细胞癌的预测因子。这项研究显示HBsAg≥1000IU / ml患者的HCC风险高于1000 IU / ml（校正的风险比为13.7,95％置信区间：4.8-39.3）[27]。来自韩国的另一项前瞻性研究也表明，HBsAg和HBV DNA的合并（> 850 IU / ml和850 IU / ml）可以预测HBV的再激活率为84.6％[28]。最近的一项研究表明，联合HBV DNA与qHBsAg或肝硬度测量可以在单个时间点正确识别不活动载体[29]。我们的研究强调单基线ALT，qHBsAg和肝硬度测量对无症状乙型肝炎感染患者的自然史的影响。然而，我们的研究有一些限制。本研究仅对样本量较小的人群进行，其随访时间相对较短。我们对两种性别使用相同水平的ALT正常截断值（40IU / ml）（2016美国肝病研究协会指南：对于男性，正常ALT水平<30 IU / ml，对于女性，正常ALT水平<10 IU / ），因为我们在台湾现实临床实践中使用相同的正常ALT临界值。

总之，我们的研究表明，单一基线qHBsAg是未来ALT升高超过ULN和qHBsAg血清清除率的重要因素。很少有研究使用基线肝硬度来预测未来的ALT升高。目前，没有简单和容易获得的标记能够准确地预测HBV感染患者的生化升高。使用qHBsAg，肝硬度和HBV DNA，我们已经展示了一个新的观点，用于预测持续正常肝功能的HBeAg阴性患者的自然过程。