中止的核苷（酸）类似物IDE治疗慢性乙型肝炎后持续病毒学

StephenW

Year : 2015  |  Volume           : 21             |  Issue : 4  |  Page : 245-253

Predictors of sustained virologic response after discontinuation of nucleos(t)ide analog treatment for chronic hepatitis B

Jie Peng,  Jiawei Cao,  Tao Yu,  Shaohang Cai,  Zhandong Li,  Xiaoyong Zhang,  Jian Sun        State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infescious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China                 Click here for correspondence address and email       Date of Submission 15-Oct-2014 Date of Acceptance 01-Jan-2015 Date of Web Publication 29-Jul-2015

Abstract Background/Aims: The aim of this study was to identify the predictors for relapse after discontinuation of oral nucleos(t)ide analog treatment for chronic hepatitis B (CHB). Patients and Methods: We evaluated patients who were receiving long-term, regular antiviral therapy with nucleos(t)ide analogs, and subsequently achieved the discontinuation criteria from the Asia-Pacific guideline. After they voluntarily discontinued the drug therapy, data were prospectively collected to observe the potential virologic relapse, and the parameters that predicted recurrence were analyzed. Results: Sixty-five patients met the inclusion criteria, and were included in this study. Twenty-eight patients relapsed, and the accumulative recurrence rates at the 3-month, 6-month, and 1-year follow-ups were 13.85%, 32.31%, and 49.23%, respectively. There was no difference in the accumulative recurrence rate 12 months after discontinuation among patients who were positive or negative for the hepatitis B e antigen (HBeAg) before they received the medication. Logistic regression analysis revealed that the time to complete response, age at discontinuation, and HBsAg levels at discontinuation affected the rate of relapse. Conclusions: Among patients who received orally administrated nucleos(t)ide analogs, serum levels of HBsAg, age at discontinuation, and the time to complete response might be used as a guide to discontinue treatment. Among younger patients, those with low serum HBsAg levels, and those with an earlier complete response, the risk of relapse is lower and discontinuation is much safer. Keywords: Chronic hepatitis B, complete response time, nucleos(t)ide analogs, surface antigen titer, virologic relapse

StephenW

年份：2015年|体积：21 |第4 |页：245-253
中止的核苷（酸）类似物IDE治疗慢性乙型肝炎后持续病毒学应答预测

彭杰，曹嘉伟，于涛，Shaohang蔡，李Zhandong，小勇张，孙立坚
器官功能衰竭研究国家重点实验室，病毒性肝炎研究广东省重点实验室，Infescious病，南方医院，南方医科大学，广州510515，中国系

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提交日期10月15日 - 2014年
验收日期01 01月2015年
Web出版物29月 - 2015年的日期


   抽象

背景/目的：这项研究的目的是口服核苷（酸）类似物IDE治疗慢性乙型肝炎（CHB）停药后，以确定预测复发。患者和方法：我们评估谁是接受长期，定期的抗病毒治疗核苷（酸）类似物的患者，并随后从亚太方针实现停药标准。之后，他们自愿中止药物治疗，数据收集前瞻性观察潜在的病毒学复发，而且复发预测的参数进行了分析。结果：60名患者符合纳入标准，并纳入本研究。 28例复发，累计复发率在3个月，6个月和1年的随访分别为13.85％，32.31％，49.23和％，分别为。有停药后中他们收到了服药前谁是阳性或阴性乙肝e抗原（HBeAg）患者在累积复发率12月无差异。 Logistic回归分析显示，该时间内完成响应，年龄停药，与HBsAg水平影响停药复发率。结论：在谁收到口服给药核苷（酸）类似物，乙肝表面抗原的血清水平，年龄在停药的患者，和时间来完成反应可能被用来作为一个导引中断治疗。在年轻患者中，那些具有低血清HBsAg水平，和那些与先前完全缓解，复发的风险较低，停药是更安全。

关键词：慢性乙型肝炎，完整的响应时间，核苷（酸）类似物，表面抗原滴度，病毒学复发

StephenW

Discussion                 Top


In recent decades, NUCs have been widely used to treat CHB, thereby preventing or delaying the development of liver disease. However, many clinical studies have reported a high relapse rate after discontinuation of NUCs treatment.[13] The Asia-Pacific Association for the Study of the Liver (APASL) Guidelines recommend that treatment for patients who are HBeAg positive should be continued for at least 12 months, and after reaching CR, their treatment should be consolidated for at least 12 months before discontinuation is considered. Treatment for patients who are HBeAg negative should be continued for at least 12 months, and after reaching CR, their treatment should be consolidated for at least 18 months before discontinuation is considered.[14] However, the APASL recommendations lack sufficient evidence-based support, as there are currently only a small number of factors that are known to be related to recurrence after discontinuation. One study of 467 South Korean patients with CHB, who were HBeAg positive and received LAM antiviral therapy, reported that patients younger than 40 years and with a CT time >12 months after HBeAg seroconversion exhibited a 20% relapse rate. In contrast, patients younger than 40 years, or with a CT time > 12 months after HBeAg seroconversion, exhibited a 50% relapse rate, whereas patients older than 40 years and with a CT time < 12 months after HBeAg seroconversion, exhibited a relapse rate of up to 90%. Thus, the relapse rate is directly related to the patient’s age and the duration of CT.[15] Another study of 17 patients from Shanghai who had CHB and were HBeAg positive revealed that HBsAg < 2 log10IU/mL at the 104th week of treatment accurately predicted postdiscontinuation SVR after 2 years of LdT antiretroviral therapy and 2 years of follow-up. In addition, the decreasing levels of HBsAg at the 24th and 52nd weeks of treatment could more accurately predict postdiscontinuation SVR compared with HBV DNA levels (in the same period).[16]

The purpose of this study was to identify the predictors of a sustained response after NUCs discontinuation. All patients enrolled into this study were strictly screened according to the APASL guidelines for discontinuation, and we then analyzed the postdiscontinuation VR rates. Using logistic regression analysis, we observed that HBsAg levels and age at discontinuation, as well as CR time, were predictors of postdiscontinuation VR. Low HBsAg levels at discontinuation indicated a low risk, with younger patients less prone to VR compared with elderly patients. In addition, shorter CR time during the treatment predicted a lower risk of postdiscontinuation VR. However, we did not observe any other significant predictors of relapse among the various parameters examined. Likewise, in a study of NUCs use in 48 South Korean patients with CHB (HBeAg positive) reported that patient age (>40 years) and the duration of CT (≥15 months) were significant predictive factors for off-treatment durability [P = 0.049; relative risk (RR): 0.31; 95% CI: 0.096–0.998 and P = 0.005; RR: 11.29; 95% CI: 2.054–65.12, respectively]. However, younger patients (≤40 years) with extended CT (≥15 months) had significantly improved durability (P = 0.014). These results suggest that treatment for >15 months (after HBeAg seroconversion) in patients who are ≤40 years old may provide a sustained virologic response.[17] Another study from Guangzhou, China, reported that the age at discontinuation, baseline ALT levels, and prolonged CT were associated with VR after discontinuation.[18] The results of these clinical studies indicate that during NUCs treatment, CT time, age at discontinuation, and ALT levels before treatment could be used to guide discontinuation of NUCs treatment. However, we did not observe a significant difference in the CT time and baseline ALT levels among VR and SVR patients. Feng et al., has reported from data collected after the discontinuation of LAM treatment in 61 patients who were HBeAg negative. Their total treatment time was ≥24 months, the CT time was ≥18 months, and relapse was defined as HBV DNA > 104 copies/mL. Cox regression analysis revealed that age was the only predictor in that study, with younger patients exhibiting a lower relapse rate.[19] Another study investigated ADV antiretroviral therapy in 145 patients with CHB (HBeAg negative) from Shanghai, and reported that the total treatment time for all patients was ≥ 24 months and the CT time was ≥ 18 months. During the postdiscontinuation follow-up period, 95 cases relapsed (relapse was defined as HBV DNA > 104 copies/mL), with 93% of these patients experiencing relapse within 12 months of discontinuation.[20] In their Cox correlation analysis, age was the only factor that was significantly associated with relapse. The results of these studies indicated that age is an important predictor for postdiscontinuation relapse, which is similar to our results; therefore, younger patients do not appear to be prone to relapse after discontinuation.

In this study, follow-up revealed that only 5 of the 44 cases of HBeAg-positive CHB experienced HBeAg reversion, indicating that NUC-induced HBeAg seroconversion was durable. This result is consistent with the results of a 2-year drug discontinuation study, which reported that 80% patients maintained HBeAg seroconversion 2 years after discontinuation.[21]

The loss of HBsAg and the development of anti-HBs antibodies (HBsAg seroconversion) are the ultimate goals of anti-HBV therapy, and therefore the HBsAg levels might be a useful prognostic indicator. In recent years, serum HBsAg quantitation has become a popular field for research. In addition, it has been reported that HBsAg levels can reflect the levels of HBV DNA or covalently closed circular DNA inside liver cells, as this DNA acts as a transcription template for viral RNA. Therefore, HBsAg levels are recommended as an alternative indicator for HBV infection of liver cells.[22] In the natural history of hepatitis B, it was discovered that low serum HBsAg levels were related with disease improvement and virus removal.[22] In studies regarding interferon therapy, it has been reported that low HBsAg levels during treatment could predict a sustained response to the therapy.[23],[24] Another study reported that LdT treatment induced a significant decline in HBsAg levels during treatment, and that HBsAg clearance was related to the sustained remission of disease.[25] In the present study, we observed that the serum HBsAg levels in the VR group were higher than those in the SVR group. Interestingly, 60% of patients with HBsAg > 2.715 IU/mL experienced VR after discontinuation, whereas only 23.33% of patients with HBsAg < 2.715 IU/mL experienced VR. These findings agree with recent findings from Guangxi, China, where HBsAg < 2 logIU/mL could predict sustained remission among 84 patients with hepatitis B, who had patients who had discontinued NUCs treatment.[26]

In the present study, we also observed that the risk of postdiscontinuation VR was lower among patients who achieved CR earlier compared with those who achieved CR later. Among the 51 patients who achieved CR within 32.5 months, only 17 cases (33.33%) experienced VR by the end of the follow-up, whereas 11 of 14 patients (78.57%) who achieved CR in >32.5 months experienced VR by the end of the follow-up. In addition, we concluded that serum HBsAg, age at discontinuation, and CR time were predictors of postdiscontinuation relapse. These factors could be used to guide clinical discontinuation of treatment, as younger patients, those with lower serum HBsAg levels, and those with earlier CR would have a lower risk of postdiscontinuation relapse.

This study also had several limitations. The first one is the small sample size, which may lead to bias from the real world treatment. As our data from the beginning of NUCs therapy to discontinuation was retrospectively obtained, and we had no serum samples from the time the patients started treatment and during the treatment period. Therefore, we were unable to evaluate any possible quantitative changes in HBsAg levels during treatment, and could not analyze the impacts of these changes on the incidence of relapse. With the limitation of retrospective information such as this, we may be able to plan prospective studies in future. In addition, the quantitation of HBV DNA before discontinuation was performed using a Chinese PCR-assay (detection limit: 1000 copies/mL), which is not as accurate as the Cobas TaqMan method used in the follow up (detection limit: 20 IU/mL).[27]


   Acknowledgments                 Top


This study was supported by Guangdong Natural Science Foundation (S2013010014658), Chinese Foundation for Hepatitis Prevention, and Control-TianQing Liver Disease Research Fund Subject (TQGB2011001).

StephenW

探讨


近几十年来，NUCs已被广泛用于治疗慢性乙型肝炎，从而防止或延缓肝病的发展。然而，许多临床研究报道NUCs停药后复发率较高。[13]亚太协会肝（APASL）准则的研究建议治疗病人谁是HBeAg阳性应持续至少12个月，达到缓解后，其治疗应合并为至少12个月前终止被认为是。治疗病人谁是HBeAg阴性应持续至少12个月，并达到缓解后，其治疗应合并为至少18个月前​​终止考虑。[14]然而，APASL建议缺乏足够的证据为基础的支持作为目前只有少量的已知可能与复发停药后的因素。 467韩国慢性乙型肝炎患者，谁是HBeAg阳性和林接受抗病毒治疗，一项研究报告说，患者年龄小于40岁，与CT时间> 12个月后HBeAg血清转换表现出20％的复发率。相比之下，患者的年龄小于40岁，或HBeAg血清转换时间> 12个月后进行CT，显示出50％的复发率，而年龄大于40岁，有一次CT患者<HBeAg血清转换后12个月，展出了复发率高达90％。因此，复发率，直接关系到患者的年龄和CT的持续时间。[15]的17名患者，从上海谁了CHB和为HBeAg阳性的另一项研究显示，乙肝表面抗原<2 log10IU / mL的在治疗的第104周准确预测postdiscontinuation SVR 2年后LDT抗逆转录病毒疗法和2年的随访。此外，HBV DNA水平（在相同时段）相比HBsAg的水平降低，在第24和第52周的治疗可以更准确地预测postdiscontinuation SVR。[16]

这项研究的目的是确定的NUCs停药后持续应答的预测。所有患者均纳入本研究根据停药的APASL指南进行了严格的筛选，然后我们分析了postdiscontinuation VR率。采用Logistic回归分析，我们发现HBsAg水平和年龄停药，以及CR时间，是postdiscontinuation VR的预测。低HBsAg水平在停药表示的低风险，有年轻患者不易出现VR与老年患者相比。此外，在处理期间较短CR时间预测postdiscontinuation VR的风险较低。然而，我们没有观察到审查的各个参数之间复发任何其他显著的预测。同样，在NUCs的研究在48个韩国使用患者慢性乙型肝炎（HBeAg阳性）报道，患者年龄（> 40岁）和CT的持续时间（≥15个月）分别为显著预测因子休治疗耐久性[P = 0.049;相对危险度（RR）：0.31; 95％CI：0.096-0.998和P = 0.005; RR：11.29; 95％CI：2.054-65.12，分别]。然而，年轻的患者（≤40岁）与扩展CT（≥15个月）有显著提高耐用性（P = 0.014）。这些结果表明，治疗的“15个月的患者谁是≤40岁，可提供持续病毒学应答（HBeAg血清转换后）。[17]来自中国广州，另一项研究报告说，年龄停药，基线ALT水平，和长期的CT均与停药后的VR。这些临床研究[18]结果表明，在NUCs治疗，CT时间，年龄在停药，和ALT水平治疗之前可用于指导NUCs停药。然而，我们没有观察到在CT和时间之间VR和SVR患者基线ALT水平显著差异。凤等人，已经从LAM治疗的61例患者停药谁是HBeAg阴性后收集的​​数据报告。其总的治疗时间为≥24个月，CT时间≥18个月，复发被定义为HBV DNA> 104拷贝/毫升。 Cox回归分析显示，年龄在这项研究中唯一预测，与年轻患者表现出较低的复发率。从上海[19]另一项研究调查了ADV抗逆转录病毒治疗的145例慢性乙型肝炎（HBeAg阴性），并报告了总治疗时间对所有患者是≥24个月，在CT时间≥18个月。在postdiscontinuation随访95例，复发（复发被定义为HBV DNA> 104拷贝/毫升），与这些患者停药经历12个月内复发93％。[20]在他们的考克斯相关性分析，年龄这是显著与复发相关的唯一因素。这些研究的结果表明，年龄为postdiscontinuation复发，这是类似于我们的结果的重要预测指标;因此，年轻的患者似乎不容易出现复发停药后。

在这项研究中，随访发现，只有44例HBeAg阳性慢性乙型肝炎的5大三阳经历逆转，表明NUC引起的HBeAg血清学转换是持久的。这一结果与2年停药研究，报道称，80％的患者维持HBeAg血清转换停药2年后的结果是一致的。[21]

HBsAg的损失和抗-HBs抗体的开发（HBsAg血清）是抗HBV治疗的最终目标，因此，HBsAg水平可能是一个有用的预后指标。近年来，血清HBsAg定量已经成为一个热门的领域进行研究。此外，已经报道，HBsAg水平可以反映HBV DNA的水平或共价闭合环状DNA的肝细胞内，因为该DNA充当病毒RNA的转录的模板。因此，HBsAg水平被推荐作为HBV感染的肝细胞的另一指标。[22]在乙型肝炎的自然历史，人们发现低血清HBsAg水平与疾病的改善和病毒除去共发生。[22]在研究关于干扰素治疗，已经报道，在治疗过程中的低HBsAg水平可以预测对治疗的持续响应。[23]，[24]另一项研究报告说，LDT治疗诱导治疗期间中的HBsAg水平显著下降，而HBsAg清除是有关疾病的持续缓解。[25]在本研究中，我们观察到血清HBsAg水平的VR组均较SVR组高。有趣的是，患者的乙肝表面抗原> 2.715 IU / mL的60％经历了VR停药后，而只有23.33％的患者的HBsAg <2.715 IU / mL的经历VR。这些调查结果同意从广西，中国，乙肝表面抗原<2 logIU / mL的可以预测84间乙肝患者，谁曾谁已经停止NUCs治疗的患者持续缓解最近的调查结果。[26]

在本研究中，我们也观察到，postdiscontinuation VR的风险是其中CR谁取得与前面那些谁后取得CR病人相比较低。在谁32.5个月内达到CR的51例患者中，只有17例（33.33％）经历VR通过的后续结束，而11 14在谁>32.5个月经历VR年底达到CR患者（78.57％）的后续。此外，我们认为血清HBsAg，年龄停药，和CR时间分别为postdiscontinuation复发的危险因素。这些因素可以用于指导治疗的临床停止，因为年轻患者，那些具有降低血清HBsAg水平，和那些与前面的CR会对postdiscontinuation复发的风险较低。

这项研究也有一些局限性。第一个是小样本大小，这可能会导致偏压从现实世界治疗。如从NUCs治疗停药的开始我们的数据进行回顾性获得，并且我们没有血清样品从患者开始治疗的时间和在治疗期间。因此，我们无法在治疗过程中评估HBsAg水平的任何可能的量的变化，并不能分析有关复发的发生这些变化的影响。随着追溯信息的局限性，例如，我们也许能规划的前瞻性研究中的未来。此外，使用一个中国的PCR测定法进行HBV DNA的停止前的定量（检测极限：1000拷贝/ ml），这是不准确的，在后续（检测限用的Cobas的TaqMan方法：20 IU /毫升）。[27]


   确认顶部


这项研究是由广东省自然科学基金（S2013010014658），中国基金会肝炎防治和控制，天晴肝病研究基金主题（TQGB2011001）的支持。

StephenW

全文
http://www.saudijgastro.com/article.asp?issn=1319-3767;year=2015;volume=21;issue=4;spage=245;epage=253;aulast=Peng