不良事件

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)                                      
  

      
   
   
  Adverse Events                                    Summary                                       

• Some nucleos(t)ide analogues inhibit human mitochondrial DNA polymerases, which may result in lactic acidosis, neuropathy, and myopathy
• Most nucleos(t)ide analogues present limited risk of adverse events during the first years of therapy in patients with compensated liver disease
  
  • Adverse event rates with lamivudine were similar to those seen with placebo in a randomized study[Dienstag 1999]
  • Adverse events with use of entecavir were indistinguishable from those seen with lamivudine in a randomized trial[Chang 2006]
  • Adefovir is nephrotoxic in up to one third of patients[Izzedine 2004]
  • Tenofovir DF has been shown to be well tolerated in patients with chronic HBV infection treated for up to 5 years[Marcellin 2008b; Marcellin 2013]
    
    • Renal toxicity and bone density loss have been reported in HIV-infected patients treated with tenofovir DF[Fontana 2009; Grigsby 2010]
      
  • Tenofovir AF, a new formulation of tenofovir with reduced bone and kidney toxicity as compared with tenofovir DF,[Chan 2016; Buti 2016] was recently approved for the treatment of chronic HBV in the setting of compensated liver disease[FDA TAF]
  • Telbivudine is associated with increases in creatine kinase, and myopathy, although it also appears to improve creatinine clearance[FDA Telbivudine; Gane 2014]
    
    • The combination of telbivudine with peginterferon is contraindicated
      

                    
               
    Nucleos(t)ide analogues generally have favorable adverse event profiles. However, all nucleos(t)ide analogues theoretically pose a risk of adverse events because most agents inhibit not only viral but also human DNA polymerases.[Fontana 2009] In addition, some agents inhibit human mitochondrial DNA polymerases that may result in a clinical syndrome including lactic acidosis, neuropathy, and myopathy.[Fontana 2009] Fortunately, most nucleos(t)ide analogues used for chronic hepatitis B virus (HBV) infection have shown few adverse events during the first years of therapy, although it should be noted that most studies were performed in relatively healthy patients with compensated liver disease. A recent population-based study confirmed the relative safety of nucleo(s)tide analogues regarding renal and bone events, although there was an increase of hip fractures with nucleotides when compared with nucleosides (HR: 5.69; P = .001).[Wong 2015] The absolute risk, however, remains very low.
Lamivudine treatment had similar rates of adverse events compared with placebo in a randomized study,[Dienstag 1999] and the adverse event profile of entecavir was indistinguishable from that of lamivudine.[Chang 2006] By contrast, adefovir is known to be nephrotoxic in up to one third of patients.[Izzedine 2004] Renal toxicity has also been described in HIV-infected patients treated with tenofovir DF, necessitating creatinine monitoring, especially during prolonged treatment.[Fontana 2009] Bone density loss has been reported as well in patients receiving tenofovir DF.[Grigsby 2010] Nevertheless, tenofovir DF was well tolerated and safe during the first 5 years of therapy in patients with chronic HBV infection.[Marcellin 2008b;Marcellin 2013] Tenofovir AF, a new formulation of tenofovir recently approved for the treatment of chronic HBV infection in the setting of compensated liver disease,[FDA TAF] was shown to have reduced bone and kidney toxicity as compared with tenofovir DF in 2 phase III studies.[Chan 2016; Buti 2016] A study of patients with advanced liver disease showed that entecavir therapy in patients with a Model for End-Stage Liver Disease score of > 20 may be associated with the occurrence of severe lactic acidosis,[Lange 2009] although lactic acidosis is a risk with all nucleoside analogues. Lactic acidosis was self-limiting or resolved after entecavir discontinuation in the majority of cases, although 1 fatality was reported.[Lange 2009] Increases in creatine kinase, as well as myopathy, may be observed in a limited number of patients receiving telbivudine,[FDA Telbivudine] although notably, telbivudine appears to improve creatinine clearance.[Gane 2014] The combination of telbivudine with peginterferon is contraindicated because of an increased risk of peripheral neuropathy.[FDA Telbivudine]

                                    Keywords:                Hepatitis B,                Hepatitis B-Adverse Events,                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）

不良事件
概要

    一些核苷类似物抑制人类线粒体DNA聚合酶，这可能导致乳酸性酸中毒，神经病变和肌病
    大多数核心（t）ide类似物在补偿性肝病患者的治疗的头几年内存在有限的不良事件风险
        随机研究中拉米夫定的不良事件发生率与安慰剂组相似[Dienstag 1999]
        随机试验中使用恩替卡韦的不良事件与拉米夫定无关[Chang 2006]
        阿德福韦酯在多达三分之一的患者中是肾毒性的[Izzedine 2004]
        已证实，替诺福韦DF在治疗长达5年的慢性HBV感染患者中耐受性良好[Marcellin 2008b; Marcellin 2013]
            已报道在用替诺福韦DF治疗的HIV感染患者中，肾毒性和骨密度降低[Fontana 2009; Grigsby 2010]
        替诺福韦AF，与替诺福韦DF相比，替诺福韦的骨髓和肾毒性降低的新配方[Chan 2016; Buti 2016]最近被批准用于治疗补偿性肝病的环境中的慢性HBV [FDA TAF]
        替比夫定与肌酸激酶和肌病的增加有关，尽管它似乎也改善了肌酐清除率[FDA Telbivudine; Gane 2014]
            替比夫定与聚乙二醇化干扰素的组合是禁忌的

Nucleos（t）ide类似物通常具有有利的不良事件分布。然而，所有核（t）ide类似物理论上都构成不良事件的风险，因为大多数药物不仅可以抑制病毒，而且还抑制人类DNA聚合酶。[Fontana 2009]另外，一些药物抑制可能导致临床综合征的人类线粒体DNA聚合酶包括乳酸性酸中毒，神经病变和肌病[Fontana 2009]幸运的是，用于慢性乙型肝炎病毒（HBV）感染的大多数核苷类似物在治疗的第一年显示出很少的不良事件，尽管应该指出大多数研究在相对健康的补偿性肝病患者中进行。最近的一项基于人群的研究证实了核苷类似物对肾和骨事件的相对安全性，尽管与核苷相比，核苷酸的髋部骨折增加（HR：5.69; P = 0.001）[Wong 2015]绝对风险仍然很低。

拉米夫定治疗在随机研究中与安慰剂相比具有相似的不良事件发生率[Dienstag 1999]，恩替卡韦的不良事件曲线与拉米夫定无显着差异[Chang 2006]相比之下，阿德福韦已知是肾毒性三分之一的患者[Izzedine 2004]，在接受替诺福韦DF治疗的艾滋病毒感染患者中也描述了肾毒性，特别是在长时间治疗期间需要肌酐监测[Fontana 2009]在接受替诺福韦治疗的患者中也报道了骨密度损失DF。[Grigsby 2010]然而，替诺福韦DF在慢性HBV感染患者的头5年治疗中耐受性好，安全性[Marcellin 2008b; Marcellin 2013]替诺福韦AF，一种新的替诺福韦组合物，最近批准用于治疗慢性乙型肝炎病毒感染在补偿肝脏疾病的设置中，[FDA TAF]显示与2倍的替诺福韦DF相比具有降低的骨和肾毒性第三项研究[Chan 2016; Buti 2016]对晚期肝病患者的研究表明，恩替卡韦治疗终末期肝病模型评分≥20的患者可能与严重乳酸性酸中毒的发生有关[Lange 2009]虽然乳酸性酸中毒所有核苷类似物的风险。在大多数情况下，恩替卡韦中止后，乳酸性酸中毒是自限性或解决的，尽管有1例死亡。[Lange 2009]在有限数量的接受替比夫定的患者中可观察到肌酸激酶以及肌病的增加， FDA替比夫定]虽然显着，telbivudine似乎可以改善肌酐清除率[Gane 2014]替比夫定与聚乙二醇化干扰素的组合是禁忌的，因为周围神经病变的风险增加[FDA Telbivudine]

关键词：乙型肝炎，乙型肝炎不良事件，乙型肝炎治疗