监测患者对核（t）ide类似物的反应

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)                                      
  

      
   
   
  Monitoring Patient Response to Nucleos(t)ide Analogues                                    Summary                                       

• Persistent viral replication during nucleos(t)ide analogue therapy is a major risk factor for development of antiviral resistance[Zeuzem 2009; Hadziyannis 2006; Liaw 2009b; Yuen 2001]
• EASL guidelines recommend monitoring HBV DNA levels at least every 3-6 months with a sensitive assay (lower limit of detection of newest assays is < 20 IU/mL) in patients treated with nucleos(t)ide analogues;[EASL HBV] AASLD guidelines recommend monitoring every 3 months until HBV DNA is undetectable, and every 3-6 months after that[Terrault 2016]; APASL guidelines recommend monitoring at Month 3 and 6 and then at regular intervals, depending on genetic barrier to resistance of the nucleos(t)de analogue used
  
  • Complete virologic responders are patients who accomplish undetectable levels of HBV DNA within 48 weeks of therapy
  • Primary nonresponders are patients who fail to achieve ≥ 1 log10 IU/mL drop in HBV DNA levels by 3 months after commencing therapy
  • Partial response is defined as an on-treatment decline in HBV DNA of ≥ 1 log10 IU/mL but failure to achieve undetectable HBV DNA levels at Week 24 (for lamivudine and telbivudine) or Week 48 (for adefovir, entecavir, and tenofovir DF)
  • Virologic breakthrough is defined as an increase in serum HBV DNA > 1 log10 above nadir after achieving a virologic response during continued treatment[EASL HBV; Terrault 2016]
    
• According to international guidelines, patients with a suboptimal response to nucleos(t)ide analogues at predefined time points are eligible for treatment modification
  
  • Evidence supports treatment modification in patients with persistent viremia during therapy with lamivudine, telbivudine, and adefovir
  • It is unclear whether treatment modification will improve results for nonresponders or partial responders to entecavir or tenofovir DF (detectable HBV DNA at Week 96).
  • Prolongation of therapy may be considered in patients treated with these agents where HBV DNA is declining
    
  Adherence to Nucleos(t)ide Analogues
  • Medication adherence is an important factor for success of nucleos(t)ide analogue therapy
  • Adherence should be reviewed in patients with virologic breakthrough on therapy and the presence of antiviral resistance confirmed with genotypic testing[Terrault 2016]
    

                    
               
    Currently approved nucleos(t)ide analogues can adequately suppress HBV DNA levels, normalize alanine aminotransferase levels, and improve liver histology,[Dienstag 2009;Marcellin 2013] but their antiviral efficacy is markedly reduced in patients who develop drug-resistant hepatitis B virus variants, resulting in virologic breakthrough, hepatitis flares, and a reduction in clinical benefits.[Liaw 2004] Averting emergence of viral resistance is therefore essential to successful antiviral therapy with nucleos(t)ide analogues.
Persistent viral replication during antiviral therapy (measured by HBV DNA levels) is a major risk factor for the subsequent development of antiviral resistance.[Zeuzem 2009;Hadziyannis 2006;Liaw 2009b;Yuen 2001] Therefore, HBV DNA levels should be monitored at least every 3-6 months with a sensitive assay (lower limit of detection of newest assays is < 20 IU/mL) in patients treated with nucleos(t)ide analogues according to the European Association for the Study of the Liver (Management Guidelines).[EASL HBV] The American Association for the Study of Liver Diseases (AASLD) guidelines recommend monitoring every 3 months until HBV DNA is undetectable, and every 3-6 months after that (Management Guidelines).[Terrault 2016] The Asian-Pacific Association for the Study of the Liver recommend monitoring HBV DNA at Month 3 and 6 and then at regular intervals, depending on the genetic barrier to resistance of the nucleos(t)ide analogues used: every 3-6 months for agents with low-genetic barrier (ie, lamivudine, adefovir, telbivudine) or every 6 months for agents with high-genetic barrier (ie, entecavir, tenofovir DF) (Management Guidelines).[APASL HBV]
Current European guidelines recommend treatment modification in patients with detectable HBV DNA levels after a predefined duration of treatment.[EASL HBV;Zeuzem 2009;Janssen 2009] The European Association for the Study of the Liver guidelines have attempted to classify response patterns to nucleos(t)ide analogues and to advise treatment modification in suboptimal responders to prevent the development of resistance (Figure 4)[EASL HBV]:

• Complete virologic responders are those patients who accomplish undetectable levels of HBV DNA within 48 weeks of therapy. These patients have a low probability of emergence of viral resistance.
• Among those patients with a suboptimal response, primary nonresponse is considered distinct from a partial response. The former group is defined as patients who fail to achieve ≥ 1 log10 IU/mL drop in HBV DNA levels by 3 months after commencing therapy. A partial response is defined as an on-treatment decline in HBV DNA of ≥ 1 log10 IU/mL but failure to achieve undetectable HBV DNA levels at Week 24 (for lamivudine and telbivudine) or Week 48 (for adefovir, entecavir, tenofovir) DF. Different requirements have been set for lamivudine and telbivudine vs adefovir, entecavir, and tenofovir DF because of the lower barrier to resistance of lamivudine and telbivudine.[EASL HBV]
• Virologic breakthrough is defined as an increase in serum HBV DNA > 1 log10 above nadir after achieving a virologic response during continued treatment.[EASL HBV]
  

Figure 4. Patterns of response to nucleos(t)ide analogues.[Zoulim 2009]
According to guidelines, patients with a suboptimal response to nucleos(t)ide analogues at the predefined time points are eligible for treatment modification. Although there is an abundance of evidence for the advantages of treatment modification in patients with persistent viremia during therapy with lamivudine, telbivudine, and adefovir, such evidence is currently lacking for entecavir and tenofovir DF. It is unclear whether treatment modification will improve results for nonresponders or partial responders to entecavir or tenofovir DF. In fact, therapy can probably be prolonged safely in partial responders to entecavir because treatment-naive patients treated with entecavir showed very low risk of resistance after 3 years of treatment, even in those with detectable HBV DNA.[Zoutendijk 2011;Lampertico 2009;Yuen 2011] In one study, partial responders to entecavir with HBV DNA < 1000 IU/mL at Week 48 of treatment were very likely to achieve undetectable HBV DNA during prolonged therapy; indeed 81% of patients achieved this endpoint.[Zoutendijk 2011] Similarly, a considerable number of patients continued to achieve undetectable HBV DNA through Years 2 and 3 of therapy in the entecavir and tenofovir DF registration trials and investigator-initiated cohort studies.[Heathcote 2011;Chang 2009;Zoutendijk 2011;van Bommel 2010] Prolongation of therapy, as opposed to treatment modification, therefore may be justified, for example in patients with a high HBV DNA at baseline or slow responders who may require additional months of therapy to achieve undetectable levels of HBV DNA.[Zeuzem 2009;van Bommel 2010; Kwon 2013; Yang 2014; Gordon 2013] Accordingly, the European Association for the Study of the Liver practice guidelines suggest that patients with declining serum HBV DNA at 48 weeks of therapy may continue therapy with the same agent, either entecavir or tenofovir DF.[EASL HBV]
The AASLD guidelines recommend continuing monotherapy with entecavir or tenofovir DF, regardless of ALT, in patients with persistent low-level viremia, defined as a plateau in the decline of HBV DNA and/or failure to achieve undetectable HBV DNA level after 96 weeks of therapy.[Terrault 2016]
Adherence to Nucleos(t)ide AnaloguesNucleos(t)ide analogue therapy for chronic hepatitis B is often lifelong, and therefore, adherence to therapy is an important factor for success. One study showed that nearly 40% of virologic breakthroughs on therapy were not related to drug resistance,[Hongthanakorn 2011] and thus, suboptimal adherence can be suspected. Another study showed that within a 16-week follow-up period, adequate adherence was observed in only 70% of patients and adherence was even lower among younger patients.[van Vlerken 2015] Therefore, in patients with virologic breakthrough on therapy, it is important to check for medication compliance and confirm antiviral resistance with genotypic testing (Management Guidelines).[Terrault 2016] An accurate assessment of the cause of virologic breakthrough is important to avoid unnecessary changes in the treatment regimen.

                                    Keywords:                Hepatitis B,                Hepatitis B-Monitoring,                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）

监测患者对核（t）ide类似物的反应
概要

    核苷类似物治疗期间持续的病毒复制是抗病毒药物发展的主要危险因素[Zeuzem 2009; Hadziyannis 2006; Liaw 2009b;元2001“
    EASL指南建议使用核苷（t）ide类似物治疗的患者，至少每3-6个月监测HBV DNA水平（敏感检测下限（最新检测下限为<20 IU / mL）; [EASL HBV] AASLD指南建议每3个月监测一次，直到HBV DNA检测不到，并且每3-6个月后[Terrault 2016]; APASL指南建议在第3和6月进行监测，然后定期监测，这取决于所使用的核苷类似物（t）的抗性的遗传障碍
        完整的病毒学应答者是在治疗48周内完成不可检测的HBV DNA水平的患者
        主要无应答者是开始治疗3个月后HBV DNA水平下降≥1 log10 IU / mL的患者
        部分反应定义为HBV DNA的治疗下降≥1log10 IU / mL，但在第24周（拉米夫定和替比夫定）或第48周（阿德福韦，恩替卡韦和替诺福韦DF）未达到不可检测的HBV DNA水平
        病毒学突破被定义为在连续治疗期间获得病毒学应答后，血清HBV DNA> 10log10在天底以上的增加[EASL HBV; Terrault 2016]
    根据国际指南，在预定时间点对核苷（t）ide类似物反应次优的患者有资格进行治疗修饰
        证据支持拉米夫定，替比夫定和阿德福韦治疗期间持续性病毒血症患者的治疗改变
        治疗改变是否会改善无应答者或部分应答恩替卡韦或替诺福韦DF（第96周时可检测的HBV DNA）的结果。
        在HBV DNA正在下降的这些药物治疗的患者中可以考虑延长治疗
    遵守Nucleos（t）ide类似物
        药物依从性是核心（t）ide类似物治疗成功的重要因素
        应该对患有病毒学突破的治疗患者和基因型检测证实的抗病毒药物耐药性进行评估[Terrault 2016]

目前批准的核苷类似物可以充分抑制HBV DNA水平，使丙氨酸氨基转移酶水平正常化，并改善肝脏组织学[Dienstag 2009; Marcellin 2013]，但在开发耐药性乙型肝炎病毒变体的患者中，其抗病毒药效显着降低，导致病毒学突破，肝炎爆发和临床益处的降低。[Liaw 2004]因此，病毒抗性的逆转出现对于成功使用核苷（t）ide类似物进行抗病毒治疗至关重要。

抗病毒治疗期间持续的病毒复制（以HBV DNA水平测定）是抗病毒药物耐药性后续发展的主要危险因素[Zeuzem 2009; Hadziyannis 2006; Liaw 2009b; Yuen 2001]因此，应至少监测HBV DNA水平根据欧洲肝脏研究协会（“管理指南”），用核苷（t）ide类似物治疗的患者，使用敏感检测（3-6次）检测的最低检测次数为3-6个月（最新检测的下限为<20 IU / mL） EASL HBV]美国肝病研究协会（AASLD）指南建议每3个月监测一次，直到HBV DNA检测不到，每3-6个月后（管理指南）。[Terrault 2016]亚太地区协会肝脏研究建议在第3和第6期监测HBV DNA，然后按照间隔时间进行监测，具体取决于使用的核苷类似物的抗性的遗传屏障：每3-6个月使用低遗传屏障（即拉米夫定，阿德福韦，替比夫定）或每6个月进行高遗传障碍的药物（即恩替卡韦，替诺福韦DF）（“管理指南”）[APASL HBV]

目前的欧洲指南建议在预定治疗持续时间后可检测HBV DNA水平的患者进行治疗修改[EASL HBV; Zeuzem 2009; Janssen 2009]欧洲肝脏研究协会已经尝试将反应模式分类为核（t ）ide类似物，并建议在次最佳反应者中进行治疗修饰，以防止抗性的发展（图4）[EASL HBV]：

    完整的病毒学应答者是在治疗48周内完成HBV DNA检测不到水平的患者。这些病人的病毒抵抗概率很低。
   在具有次最佳反应的患者中，主要的无反应被认为与部分反应不同。前组定义为在开始治疗3个月后HBV DNA水平下降≥1log10 IU / mL的患者。被定义为HBV DNA的治疗下降≥1log10 IU / mL，但在第24周（拉米夫定和替比夫定）或第48周（阿德福韦，恩替卡韦，替诺福韦）DF未达到不可检测的HBV DNA水平。拉米夫定和替比夫定对阿德福韦，恩替卡韦和替诺福韦DF的不同要求，因为拉米夫定和替比夫定耐药性较低。 [EASL HBV]
病毒学突破被定义为在连续治疗期间达到病毒学应答后，血清HBV DNA> 1 log10在天底以上的增加。 [EASL HBV]

图4.对核（t）ide类似物的反应模式。 [Zoulim 2009]

根据指导原则，在预定义的时间点对核苷（t）ide类似物的次最佳反应的患者有资格进行治疗修饰。尽管在使用拉米夫定，替比夫定和阿德福韦的运动期间，持续性病毒血症患者治疗改变的兴趣有很多证据，但这些证据并不适用于恩替卡韦和替诺福韦DF。不清楚只有治疗改变将改善无应答者或部分应答恩替卡韦或替诺福韦DF的结果。事实上，治疗可以安全地延长部分应答恩替卡韦由于治疗初始患者恩替卡韦治疗3年后显示出非常低的抗药性，即使是那些具有可检测HBV DNA的患者。 [Zoutendijk 2011; Lampertico 2009; Yuen 2011]在一项研究中，治疗第48周HBV DNA <1000 IU / mL的恩替卡韦的部分应答在长期治疗期间很可能达不到HBV DNA;事实上，81％的患者达到了这个终点。 [Zoutendijk 2011]同样，在恩替卡韦和替诺福韦DF登记试验和研究者启动的队列研究中，大量患者在治疗的第二和第三年继续实现不可检测的HBV DNA。 [Heathcote 2011; Chang 2009; Zoutendijk 2011; van Bommel 2010]因此，与治疗改变相反，治疗的延长可能是正当的，例如在基线时HBV DNA较高的患者或慢性反应者，可能需要额外的数月治疗，不能检测不到HBV DNA水平。 [Zeuzem 2009;范博梅尔2010; Kwon 2013;杨2014年Gordon 2013]手中，欧洲肝脏实践指南研究协会指出，48周治疗血清HBV DNA下降的患者可能会继续使用相同的药物，包括恩替卡韦或替诺福韦DF治疗。 [EASL HBV]

AASLD指南建议在持续性低水平病毒血症的患者中使用恩替卡韦或替诺福韦DF持续单药治疗，定义为HBV DNA下降的高原和/或在96周治疗后未达到不可检测的HBV DNA水平。 [Terrault 2016]
遵守Nucleos（t）ide类似物

慢性乙型肝炎的核心（t）ide类似物治疗通常是终身的，因此，坚持治疗是成功的重要因素。一项研究表明，近40％的治疗病毒学突破与耐药无关，[Hongthanakorn 2011]因此，可以考虑次优依从性。另一项研究显示，在16周的随访期间，仅70％的患者观察到足够的依从性，年轻患者的依从性更低。 [Van Vlerken 2015]因此，在治疗病毒学突破的患者中，重要的是检查药物依从性，并通过基因分型检测确认抗病毒药物的耐药性（“管理指南”）。 [Terrault 2016]准确评估病毒学突破的原因对于避免治疗方案不必要的变化很重要。

关键词：乙型肝炎乙型肝炎监测乙型肝炎治疗

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