NATAP/EASL HBV的PegLambda

StephenW

> Subject: NATAP/EASL: PegLambda for HBV
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> ALT Flares During Treatment with Peginterferon Lambda-1a or Peginterferon Alfa in Patients With HBeAg-positive Chronic Hepatitis B Infection (CHB) - see attached full poster report
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> Reported by Jules Levin
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> EASL 2013 April 24-28 Amsterdam
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> Chan HL,1 Ahn SH,2 Chang TT,3 Peng CY,4 Wong DK,5 Coffin CS,6 Lim SG,7 Chen PJ,8 Janssen HLA,9 Marcellin P,10 Serfaty L,11 Zeuzem S,12 Hu W,13 Critelli L,13 Wind-Rotolo M,14 Srinivasan, S,13 Lopez-Talavera JC,13 Cooney E13
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> CONCLUSIONS
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>  The frequency of ALT flares was numerically greater with Lambda vs alfa
>  ALT flares were generally well tolerated, without any signs of hepatic decompensation
>         – The majority of ALT flares could be treated through without intervention, although rates of dose reduction were higher with Lambda
> – Rates of ALT flare-associated hyperbilirubinemia were higher with Lambda (19% ) vs alfa (8%), however the majority (two-thirds) were low grade (1–2)
>  Over 90% of the ALT flares observed in the Lambda treatment group were associated with a preceding decline from baseline in HBV DNA compared with 78% in the alfa treatment group
>       – Three of the five events of HBeAg seroconversion in the Lambda group were preceded
> by an ALT flare which in each case was associated with a prior decline from baseline in
> HBV DNA
>  For those baseline factors explored, no clear predictors of ALT flare associated with HBV DNA decline were identified. Similarly, no correlation was observed between the Week 4 change from baseline in the selected biomarkers tested and the occurrence of an ALT flare associated with HBV DNA decline
>  A recent study by Sonneveld et al. characterized “host-induced” flares by a steep ALT flare preceding pronounced declines of HBV DNA, HBeAg, and HBsAg.3 This finding is of interest in light of the pattern of DNA decline observed in patients who evidenced the equivalent of a host-induced flare, irrespective of treatment group, in the present analysis where the onset of the viral load decline occurred prior to or concurrent with the onset of the flare rather than following the flare.
> The explanation for these observed differences in pattern of HBV DNA decline noted in the two studies remains to be characterized
>  Correlation of on-treatment ALT flares with other markers of efficacy and characterization of the pathogenesis of these events (temporal analysis of changes in additional cell surface and serum markers) are ongoing
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> BACKGROUND
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>  In chronic hepatitis B virus (HBV) infection (CHB), alanine aminotransferase (ALT) flares (acute exacerbations of hepatitis) can occur spontaneously, or during or after treatment with conventional or pegylated interferon alfa (alfa) or a nucleos(t)ide analog1
>  Alfa-associated ALT flares have been primarily studied in CHB patients with hepatitis B e antigen-positive (HBeAg+) disease, where the reported frequency has ranged from 25% to 40%2
>  Irrespective of setting, ALT flares in CHB are believed to reflect an immunologic interaction between the infected host and virus, whereby host effector cells are responding to wild-type or mutant viral antigens present on infected hepatocytes1,2
>  Alfa-associated ALT flares have been categorized in the literature according to the associated HBV DNA changes, as either host-mediated (followed by an HBV DNA decline) or virus-mediated (preceded by a DNA rise)2
>  On-treatment ALT flares associated with HBV DNA decline typically occur early following initiation of therapy, and are believed to reflect activation or boosting of effective anti-HBV responses, resulting from the diminished antigenemia. Such flares have been associated with an increased probability of HBeAg and hepatitis B surface antigen (HBsAg) loss2,3
>  On-treatment ALT flares associated with HBV DNA increase typically occur later during treatment and in at least some cases may reflect activation of host immune responses to viral escape mutants. Such events have been correlated with an unfavorable disease course1–3
>  Peginterferon lambda-1a (Lambda) is a type III interferon that has demonstrated activity against HBV in vitro and in transgenic mice4,5 and has shown a more rapid and pronounced early viral decline and improved tolerability compared with alfa when studied in chronic hepatitis C virus infection6,7
>  Study AI452005 (LIRA-B) is an ongoing phase 2b study of Lambda vs alfa-2a monotherapy in patients with HBeAg+ CHB
>             – The previously presented Week 24 interim analysis demonstrated greater early reductions of HBV DNA and quantitative HBsAg, and improved safety and tolerability with Lambda as compared with alfa8
>  The current analysis presents ALT flare data from this interim Week 24 analysis, including predictive factors and correlations with immune biomarker changes
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StephenW

结论
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ALT升高的频率数值大于拉姆达与阿尔法
ALT升高一般耐受性良好，没有任何迹象肝功能失代偿
>  -  ALT升高的大部分可以通过无需干预治疗，减少剂量率虽然均高于拉姆达
>  - 所有价格均高于ALT耀斑相关的高胆红素血症与拉姆达（19％）与α（8％），但多数（三分之二）为低年级（1-2）
超过90％，观察到在拉姆达治疗组的ALT升高相关alfa治疗组的78％相比，与前面从基线HBV DNA下降
>  - 三五个事件的Lambda组的HBeAg血清学转换之前
>按ALT耀斑在每一种情况下是与之前从基线下降
> HBV-DNA
>对于那些基线因素探讨，没有明确的预测HBV DNA下降伴有ALT耀斑进行了鉴定。同样，也没有4周的变化，从基准测试在选定的生物标志物和HBV DNA下降伴有ALT耀斑发生之间的相关性观察
Sonneveld等人最近的一项研究。由一个陡峭的ALT耀斑前明显的下降大三阳，乙肝病毒DNA，HBsAg.3这一发现证明相当于一台主机诱导患者中观察到的DNA下降的格局，是利益“主机诱导”火炬的特点光晕，不论治疗组，在目前的分析，病毒载量下降发生在发病之前或同时发病耀斑，而不是跟随火炬。
>解释这些观察到的差异在两项研究中指出HBV DNA下降的格局仍然被定性
相关治疗ALT升高与其他标志物的疗效和表征这些事件的发病机制（颞额外的细胞表面及血清标志物的变化分析）正在进行
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>背景
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在慢性乙型肝炎病毒（HBV）感染（CHB），丙氨酸转氨酶（ALT）耀斑（急性肝炎）可以自发地发生，或常规或聚乙二醇干扰素α（阿尔法）或核苷治疗期间或之后（T ）ide ANALOG1的
阿尔法相关的ALT升高主要研究慢性乙型肝炎患者，乙肝e抗原阳性（大三阳）病，报告的频率已经从25％到40％不等
无论设置在CHB，ALT升高被视为可反映感染的宿主和病毒的免疫之间的相互作用，从而宿主效应细胞响应的野生型或突变型病毒抗原上存在感染的hepatocytes1，2
阿尔法相关的ALT升高已在文献分类根据相关的HBV DNA的变化，无论是宿主介导的HBV DNA下降或​​病毒介导的（前面的DNA上涨）2
>治疗ALT升高伴有HBV DNA下降，通常会出现以下早期开始治疗，被认为反映激活或提高有效抗HBV回应，产生抗原减弱。这种耀斑已与HBeAg和乙肝表面抗原（HBsAg）loss2，3的概率增加
在治疗ALT升高伴有HBV DNA增加以后，通常会发生在治疗过程中，至少在某些情况下，可能反映了激活宿主的免疫反应，病毒逃避突变。这样的事件已与一个不利疾病course1中的3
>聚乙二醇化干扰素的λ-1α（拉姆达），是III型干扰素的已经证明在体外和转基因mice4 5的抗HBV活性，并已显示出更快速的和明显的早期病毒下降和改进的耐受性比阿尔法研究慢性肝炎时肝炎病毒，7 infection6
研究AI452005（LIRA-B）是一个持续的阶段2b研究拉姆达与干扰素α-2a单药治疗的患者的HBeAg + CHB
>  - 先前提出的24周中期分析结果显示更大的早期HBV DNA和HBsAg定量减少，并提高了安全性和耐受性与拉姆达与alfa8相比
目前的分析介绍ALT耀斑从这个中期24周分析数据，包括预测的因素和免疫生物标志物的变化的相关性
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