EASL: Having Only Wild-type Hepatitis B Virus Predicts Response to Interferon

StephenW

[The abstract of this paper was posted before. Here it contains more detail. Please note that Virus genotypes B & C seem to have presence of more core and precore mutants. I wonder why?    StephenW]

EASL: Having Only Wild-type Hepatitis B Virus Predicts Response to Interferon                    Category: HBV Treatment
Published on Friday, 04 May 2012 00:00
Written by Liz Highleyman               
                                                                                                

Milan Sonneveld (Photo: Liz Highleyman)

                                       
               
               
                Chronic hepatitis B patients who do not have 2 common HBV mutations are more likely to achieve undetectable viral load and HBsAg loss when treated with pegylated interferon, according to study findings presented at the 47th International Liver Congress (EASL 2012) last month in Barcelona.
         Hepatitis B virus (HBV) may carry variations in the "precore" and "core promoter" regions of its genome, which affect production of hepatitis B "e" antigen (HBeAg). Prior research has shown that these mutations are associated with more severe disease progression and poorer response to treatment compared with wild-type, or non-mutated, virus.
        HBeAg loss in people who start out HBeAg positive is a measure of treatment success, along with undetectable HBV DNA viral load and hepatitis B surface antigen (HBsAg) loss; 1 study saw an HBeAg loss rate of 30% among patients treated with pegylated interferon. However, people who experience HBeAg loss still often have detectable HBV DNA and positive HBsAg, indicating that they are not cured.
        Milan Sonneveld from Erasmus Medical Center in Rotterdam and colleagues performed a study to look at the relationship between the presence of precore/core promoter mutations and HBV DNA, HBeAg, and HBsAg persistence during interferon treatment.
        The analysis included 214 HBeAg positive chronic hepatitis B patients treated with pegylated interferon alfa-2b (PegIntron); about half also received lamivudine (3TC; Epivir) for 52 weeks. Most (78%) were men, three-quarters were white, 19% were Asian, and the mean age was 34 years. Approximately one-third had HBV genotype A, 9% had genotype B, 14% had genotype C, and 40% had genotype D.
        Participants were classified at baseline as having either only wild-type HBV or non-wild-type virus with detectable precore and/or core promoter mutations. Treatment response was evaluated 6 months after completion of therapy (week 78), with long-term follow-up at 3 years.
        Results

• Precore and/or core promoter mutations were detected in 64% of patients, with frequencies varying substantially across different genotypes:
  
  • Genotype A: 69% wild-type, 7% precore, 24% core promoter, 0% both mutations;
  • Genotype B: 26%, 68%, 0%, and 5%, respectively;
  • Genotype C: 24%, 7%, 45%, and 24%, respectively;
  • Genotype D: 11%, 40%, 18%, and 32%, respectively.
    
•                 At baseline, participants with only wild-type virus had significantly higher levels of HBV DNA (9.20 vs 8.86 log copies/mL), HBeAg (2.81 vs 2.33 log IU/mL), and HBsAg (4.53 vs 4.28 log IU/mL) than those with precore/core promoter mutations.
•                 Participants with only wild-type HBV were significantly more likely than those with mutations to respond to treatment by all measures at 78 weeks:
  
  • Undetectable HBV DNA (<400 copies/mL): 20% vs 2%, respectively;
  • HBsAg loss: 18% vs 2%, respectively;
  • HBeAg loss: 42% vs 32%, respectively;
  • Combined response of HBeAg loss + HBV DNA < 10,000 copies/mL: 34% vs 11%, respectively.
    
• After 3 years of follow-up, response rates were higher overall, and wild-type virus still predicted better response:
  
  • Undetectable HBV DNA: 78% vs 25%, respectively;
  • HBsAg loss: 61% vs 13%, respectively;
  • Sustained HBeAg loss: 87% vs 80% (no longer significant).
    
• In a multivariate analysis, exclusively wild-type HBV at baseline was the strongest pre-treatment predictor of 78-week outcomes:
• HBV DNA undetectability: odds ratio (OR) 7.93, or about 8-fold higher likelihood;
• HBsAg clearance: OR 4.64, or nearly 5-fold higher;
• Combined response: OR 2.90, or about triple likelihood.
•   Alanine aminotransferase (ALT) level had a minimal effect on treatment response among patients with wild-type virus compared with a nearly linear association for those with precore/core promoter mutations.
  

        "Precore and core promoter mutants may be detected in a majority of HBeAg positive chronic hepatitis B patients," the investigators concluded. "Presence of mutants before [pegylated interferon treatment] is association with treatment failure."
        "Patients with only wild-type virus have a high probability of virological response and HBsAg clearance through long-term follow-up," they continued. "Assessment of presence of mutants can help select patients with the highest probability of response [to pegylated interferon]."
        During the question period, Sonneveld suggested that these findings may indicate that HBV with precore/core promoter mutations survive better in cells, and are perhaps less targeted by T-cells.
        In a related study, Sonneveld's group also analyzed the relationship between precore/core promoter mutations and HBeAg levels and seroconversion in 138 HBeAg positive chronic hepatitis patients treated the nucleoside/nucleotide analogs lamivudine, adefovir (Hepsera), entecavir (Baraclude), and/or tenofovir (Viread).
        They found that the presence of precore/core promoter mutations was associated with lower HBeAg levels and higher probability of HBeAg seroconversion. However, these mutations also predisposed patients to persistent HBV replication or HBeAg relapse after seroconversion, as was the case with pegylated interferon.
        5/4/12
        References
        M Sonneveld, V Rijckborts, S Zeuzem, et al. Title Presence of Only Wildtype Virus is the Strongest Determinant of HBV DNA Undetectability and HBsAg Clearance in HBeAg-positive Chronic Hepatitis B Patients Treated with Peginterferon. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 54.
        R Zoutendijk, M Sonneveld, J Reijnders, et al. Relationship between Precore/Core Promoter Mutants, HBeAg Levels and Serological Response in HBeAg-positive Chronic Hepatitis B Treated with Nucleos(t)ide Analogues. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 551.
        

StephenW

[本文摘要之前已经发贴。在这里，包含更多的细节。请注意，B，C病毒基因型似乎有更多的核心和前C 突变株存在。不知道为什么？ StephenW]
欧洲肝病学会：只有野生型乙肝病毒在预测干扰素

   
详情
    分类：乙肝治疗
    上发表，2012年05月04日（星期五）00:00
    书面利兹Highleyman



，米兰Sonneveld（照片：利兹Highleyman）

谁不有2个共同的乙肝病毒基因突变的慢性乙型肝炎患者更容易实现与聚乙二醇干扰素治疗时，无法检测的病毒载量和HBsAg消失，根据研究结果在第47届国际肝病会议（2012年欧洲肝病学会）上个月在巴塞罗那。

B型肝炎病毒（HBV）可携带“前C区”和“核心启动子”的地区，它的基因组，从而影响生产的B型肝炎的“e”抗原（HBeAg）的变化。此前的研究表明，这些突变更严重的疾病进展和治疗反应较差相比，与野生型或突变，病毒。

HBeAg阳性的人开始HBeAg阳性的损失，是治疗成功的措施，以及检测不到HBV DNA的病毒负荷和乙肝表面抗原（HBsAg）的损失;看到1研究与聚乙二醇干扰素治疗的患者中30％的HBeAg消失率。然而，谁遇到HBeAg消失的人还是经常有检测HBV DNA和HBsAg阳性，表明他们是无法治愈。

米兰Sonneveld和他的同事在鹿特丹Erasmus医学中心进行的一项研究，看存在前C区/核心启动子突变与HBV DNA，HBeAg阳性，HBsAg和干扰素治疗过程中的持久性之间的关系。

分析包括214 e抗原阳性慢性乙型肝炎患者治疗与聚乙二醇干扰素α-2b（佩乐能）的一半左右，还收到52周的拉米夫定（3TC;拉米）。大多数（78％）为男性，四分之三是白色的，19％为亚洲人，并平均年龄为34岁。大约三分之一HBV基因型A，9％的B型，14％，C基因型，40％D基因型

参与者被分为基线，要么只野生型HBV或非野生型病毒检测前C区和/或核心启动子突变。 6个月治疗结束后（78周）治疗的反应进行了评估，在3年的长期随访。

结果

    前C区和/或核心启动子突变进行检测，大大不同基因型在不同的频率在64％的患者：
        基因型：野生型69％，7％前C区，24％的核心启动子，0％两个突变;
        B型：26％，68％，0％和5％，分别;
        基因型C：24％，7％，45％和24％，分别;
        D型：11％，40％，18％和32％分别。
    在基线，只有野生型病毒的参与者比显着较高水平的乙型肝炎病毒DNA（9.20比8.86日志拷贝/毫升），e抗原（2.81比2.33日志IU /毫升），和HBsAg（4.53比4.28日志IU /毫升）那些与前C区/核心启动子突变。
    只有野生型HBV的参与者大大超过那些突变有可能作​​出反应，在78周的一切措施治疗：
        检测不到乙肝病毒DNA（<400拷贝/ ml）分别为20％和2％;
        HBsAg消失，分别为18％和2％;
        HBeAg消失，分别为42％和32％;
        HBeAg消失的联合响应+乙型肝炎病毒DNA <10,000拷贝/毫升：34％比11％，分别。
    经过3年的随访，应答率分别为更高的整体，与野生型病毒仍然预测更好的回应：
        检测不到HBV DNA的分别为78％和25％;
        HBsAg消失，分别为61％和13％;
        持续HBeAg消失：87％和80％（不再显著）。
    在多变量分析中，只野生型HBV基线是最强的治疗前78周的成果预测：
    HBV DNA的不可检测：胜算比7.93，或约8倍的可能性更高（或）;
    HBsAg清除：OR 4.64，或近5倍;
    结合反应：2.90，或三重的可能性。
    丙氨酸转氨酶（ALT）水平与野生型病毒的患者对治疗反应的影响最小，与前C区/核心启动子突变的近线性关系。

“前C区和核心启动子突变体，可在大多数HBeAg阳性慢性乙型肝炎患者检测，研究人员得出结论。” “[聚乙二醇干扰素治疗前突变体的存在，是治疗失败的关联。”

“只有野生型病毒的患者有高概率的病毒学应答和HBsAg通过长期随访间隙，他们继续。” “评估的突变体的存在可以帮助与响应[聚乙二醇干扰素]概率最高的选择病人。”

在这个问题期间，Sonneveld建议，这些研究结果可能表明，乙肝病毒前C区/核心启动子突变生存在细胞更好，也许不太有针对性的T细胞。

在一项相关研究，Sonneveld的研究小组还分析了前C区/核心启动子突变与HBeAg的水平和血清转换之间，在138的关系e抗原阳性慢性乙型肝炎患者治疗的核苷/核苷酸类似物拉米夫定，阿德福韦（阿德福韦酯）恩替卡韦（博路定），和/或泰诺福韦（VIREAD）。

他们发现，存在前C区/核心启动子突变与HBeAg的水平较低和较高的HBeAg血清转换的概率。然而，这些突变也倾向于持续HBV复制或HBeAg的血清转换后复发的患者，是聚乙二醇干扰素的情况。

12年5月4日

参考文献

中号Sonneveld，V Rijckborts，S Zeuzem，等。标题只野生种病毒的存在，是最强的行列式的HBV DNA不可检测HBsAg和HBeAg阳性与聚乙二醇干扰素治疗慢性乙型肝炎患者的间隙。欧洲肝脏（欧洲肝病学会2012年）的研究协会第47届年会。巴塞罗那，2012年4月18日至22日。摘要54。

ŕZoutendijk，M Sonneveld，J Reijnders，等。前C区/核心启动子突变，HBeAg的水平和血清学反应在核苷（酸）IDE类似物治疗HBeAg阳性慢性乙型肝炎乙之间的关系。第47届国际肝病会议（欧洲肝病学会2012年）。巴塞罗那，2012年4月18日至22日。摘要551。

咬牙硬挺

就是说小三阳肝炎用长效干扰素无效是吧？

咬牙硬挺

可恶的变异

StephenW

回复 咬牙硬挺 的帖子

不是. 研究关注HBeAg阳性患者. 在你的肝脏, 乙肝病毒种群(population)可以包括野生型和许多突变型.
1. 如果你没有核心或前C区突变体(mutants)的存在，干扰素对你是更有效.

下面是我的意见:
2. 似乎如果您的野生型病毒(genotype)是B型或C型 (在中国最常见的), 您有更多的核心和前C区突变体存在.
3. 如果有核心和前C区突变体存在, 您的HBeAg水平和HBVDNA水平将会较低, 似乎抗病毒治疗是比较容易转换eAntigen, 但转换是不持久.

1 + 2 + 3 =>  免疫系统更难控制核心和前C区突变体病毒.

咬牙硬挺

回复 StephenW 的帖子

你说的这种情况就是小三阳肝炎的症状，干扰时表现为e抗原先完成转换而病毒量还未转阴，骆抗先说这种情况干扰见效快但复发率高于70%，建议直接上核苷