核苷酸终点模拟治疗核苷酸终点模拟治疗

StephenW

                Management of Hepatitis B Infection     

•                                       Authors:                                                          Harry L. A. Janssen, MD, PhD; Milan J. Sonneveld, MSc                                                                  (More Info)
•                                       Editor In Chief:                                                          Stefan Zeuzem, MD
•                                   Last Reviewed:                                  2/24/17                                                                                (What's New)                                      
  

      
   
   
  Endpoints of Nucleos(t)ide Analogue Therapy                                    Summary                                       

• Maintenance of undetectable HBV DNA levels is the key on-treatment goal in nucleos(t)ide analogue–treated patients
  
  • In HBeAg-positive patients, the definitive endpoint for therapy is HBeAg seroconversion. Treatment may be discontinued in patients without cirrhosis who have achieved this endpoint and completed ≥ 12 months of consolidation therapy after the appearance of anti-HBe (Table 8)[Terrault 2016]
    
    
    • AASLD recommends indefinite treatment for patients with cirrhosis[Terrault 2016]
      
  • In patients with HBeAg-negative disease, AASLD recommends indefinite nucleos(t)ide analogue therapy (Table 8)[Terrault 2016]
    
    
    • Discontinuing treatment in patients who experience HBsAg loss may be considered, but evidence to support this approach is currently insufficient
      

                    
               
    Maintenance of undetectable HBV DNA levels is the most important on-treatment goal in nucleos(t)ide analogue–treated patients because a persistently detectable HBV DNA level during treatment is a major risk factor for the development of virologic breakthrough (a rise of HBV DNA ≥ 1 log above the nadir) and antiviral resistance.[Zeuzem 2009; Kurashige 2008; Yuen 2007] However, the definitive endpoint for hepatitis B e antigen (HBeAg)–positive patients receiving nucleos(t)ide analogue therapy is HBeAg seroconversion, and treatment may be discontinued in patients who have achieved this endpoint and completed ≥ 12 months of consolidation therapy (the period of treatment after HBeAg seroconversion) after the appearance of anti-HBe (Management Guidelines) (Table 8).[Terrault 2016] Despite this, discontinuation of treatment after nucleos(t)ide analogue–induced HBeAg seroconversion is associated with a high probability of posttreatment relapse (23% to 67%).[Reijnders 2010b; Fung 2009; van Nunen 2003; Chien 2003; Lee 2002; Song 2000] Because it is unknown whether a longer consolidation period would reduce relapse rates, the AASLD suggests that an alternative approach is to continue treatment until patients experience loss of hepatitis B surface antigen (HBsAg). Similarly, based on concerns about decompensation and death, the AASLD suggests continuing treatment indefinitely in patients with cirrhosis unless there is a strong reason to discontinue.[Terrault 2016]
Similarly, discontinuing nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection will cause virologic relapse, defined as detectable HBV DNA after achieving a virologic response, in nearly all patients.[Shouval 2009; Seto 2015] For some patients, this posttreatment HBV DNA flare could result in an activation of the immune response resulting in viral clearance and HBsAg loss, but at the risk of severe hepatitis flares.[Hadziyannis 2012] The safety of such a strategy is currently under investigation and is not recommended outside of clinical studies at this time. Therefore, the AASLD recommends continuing treatment indefinitely in patients with HBeAg-negative immuneactive chronic HBV (Management Guidelines) (Table 8).[Terrault 2016] The guidance panel notes that discontinuing treatment in patients who experience HBsAg loss may be considered, but that currently there is insufficient evidence on this strategy.
For a Video Insight by Harry L. A. Janssen, MD, PhD, discussing treatment endpoints including the role of HBsAg loss, click here.
Table 8. Duration and Endpoints of Therapy for Chronic HBV Infection[Lok 2009;  Terrault 2016; EASL HBV]

Agents	Monitoring Recommendations During Treatment	Duration of Therapy		Treatment Endpoints
		HBeAg-Positive Patients*	HBeAg-Negative Patients	HBeAg-Positive Patients	HBeAg-Negative Patients
Nucleotide analogues	Liver chemistry every 12 wks HBV DNA every 12-24 wks (less frequent monitoring may be warranted with entecavir and tenofovir DF) HBeAg/anti-HBe every 24 wks Serum creatinine every 12 wks for patients receiving adefovir or tenofovir DF HBsAg every 6-12 mos	12 mos              (AASLD) or 6 mos (EASL) after HBeAg seroconversion, undetectable serum HBV DNA, normal ALT levels, and appearance of anti-HBe	Indefinitely (AASLD)† Until HBsAg loss (EASL)	HBeAg seroconversion, HBsAg loss, HBV DNA undetectability, ALT normalization	HBsAg loss, HBV DNA undetectability, ALT normalization
Peginterferon alfa	Liver chemistry and CBC every 4 wks HBV DNA and TSH every 12 wks HBeAg/anti-HBe every 24 wks HBsAg every 6 mos	48 wks		HBeAg loss or seroconversion with concomitant HBV DNA < 2000 IU/mL, HBsAg loss	Undetectable HBV DNA, HBsAg loss

ALT, alanine aminotransferase; CBC, complete blood count; TSH, thyroid stimulating hormone.
*Patients without cirrhosis. AASLD recommends indefinite treatment for those with cirrhosis.
†AASLD guidelines allow considering discontinuation after HBsAg loss.


                                    Keywords:                Hepatitis B,                Hepatitis B-Treatment        

StephenW

乙型肝炎感染管理

    作者：Harry L. A. Janssen，MD，PhD;米兰J. Sonneveld，硕士（更多信息）
    总编辑：Stefan Zeuzem，MD
    最新评论：2/24/17（最新消息）

核苷酸终点模拟治疗
概要

    不可检测的HBV DNA水平的维持是核苷类似物治疗患者的关键治疗目标

        在HBeAg阳性患者中，治疗的最终终点是HBeAg血清学转换。治疗可能在没有肝硬化的患者中停止，这些患者在出现抗HBe后已经达到该终点并且完成≥12个月的巩固治疗（表8）[Terrault 2016]
            AASLD建议对肝硬化患者进行无限期治疗[Terrault 2016]

        在HBeAg阴性疾病患者中，AASLD推荐使用无限期核苷类似物治疗（表8）[Terrault 2016]
            可能会考虑在经历HBsAg损失的患者中停止治疗，但目前支持这种方法的证据不足

不可检测的HBV DNA水平的维持是核苷类似物治疗患者中最重要的治疗目标，因为治疗期间持续可检测的HBV DNA水平是发展病毒学突破的主要危险因素（HBV DNA升高≥1 log在最低点之上）和抗病毒药物抗性[Zeuzem 2009;仓敷2008;然而，乙型肝炎e抗原（HBeAg）阳性患者接受核苷类似物治疗的最终终点是HBeAg血清学转换，治疗可能在已达到该终点并完成≥12个月巩固的患者中停止治疗（HBeAg血清学转换后的治疗时间）抗HBe出现后（表8）[Terrault 2016]尽管如此，核苷酸（t）ide类似物诱导的HBeAg血清学转换后停止治疗与治疗后复发的可能性很高（23％〜67％）[Reijnders 2010b;冯2009; van Nunen 2003; Chien 2003;李2002; Song 2000]由于不清楚长期巩固期是否会降低复发率，AASLD建议替代方法是继续治疗，直到患者经历乙型肝炎表面抗原（HBsAg）的丧失。同样，基于对失代偿和死亡的担忧，AASLD建议持续治疗肝硬化患者，除非有很强的理由停药。[Terrault 2016]

类似地，在几乎所有患者中，HBeAg阴性慢性乙型肝炎病毒（HBV）感染患者停止核心（t）ide类似物治疗将导致病毒学复发，定义为达到病毒学应答后的可检测HBV DNA [Shouval 2009;对于一些患者，这种治疗后的HBV DNA闪烁可能导致免疫反应的激活，导致病毒清除和HBsAg的丧失，但存在严重的肝炎发作的风险[Hadziyannis 2012]这种策略的安全性是目前目前正在调查中，不建议在临床研究之外。因此，AASLD建议持续治疗HBeAg阴性免疫性慢性HBV患者（管理指南）（表8）。[Terrault 2016]指导小组注意到，可能会考虑在HBsAg损失患者中停止治疗，但目前没有足够的证据证明这一策略。

对于Harry L. A. Janssen博士的视频分析，博士，讨论包括HBsAg丢失的作用在内的治疗终点，点击此处。

表8.慢性HBV感染治疗的持续时间和终点[Lok 2009; Terrault 2016; EASL HBV]