EASL: Telbivudine Effective for Hepatitis B Patients Selected with Roadmap

StephenW

EASL: Telbivudine Effective for Hepatitis B Patients Selected with Roadmap                        Category: HBV Treatment
Published on Tuesday, 08 May 2012 00:00
Written by Liz Highleyman               
                                                                                                

HBV © Russell Kightley

                                       
               
               
Telbivudine (Tyzeka) is an effective treatment for chronic hepatitis B with minimal emergence of drug resistance when using the "Roadmap" algorithm for selecting appropriate patients and deciding when to add other agents, according to a trio of studies presented at the 47th International Liver Congress (EASL 2012) last month in Barcelona.
         Telbivudine (also known as LDT) is a nucleoside analog with potent activity against hepatitis B virus (HBV), but it has a relatively low genetic barrier to resistance.
        The Roadmap concept provides an optimized approach to reduce the incidence of virological breakthrough and genotypic resistance during nucleoside/nucleotide analog treatment of chronic hepatitis B. In April 2011, the U.S. Food and Drug Administration (FDA) announced a label change that incorporates this approach, stating that telbivudine should be limited to people with low baseline HBV DNA and should be stopped if viral load is still detectable at 24 weeks.
        Fabien Zoulim from INSERM in Lyon looked at resistance rates after 1 and 2 years on telbivudine among participants treated according to the Roadmap in the pivotal GLOBE trial. At baseline hepatitis B "e" antigen (HBeAg) positive patients (n=57) had HBV DNA < 9 log copies/mL and HBeAg negative patients (n=86) had < 7 log copies/mL; ALT was > 2 times the upper limit of normal (ULN). At week 24 of telbivudine monotherapy they had undetectable viral load.
        After 1 year on treatment, 97% of HBeAg positive and 98% of HBeAg negative patients still had undetectable HBV DNA; 40% of the HBeAg positive participants experience HBeAg seroconversion. After 2 years on telbivudine, the corresponding rates were 89% and 91% undetectable, with 52% HBeAg seroconversion. No patients had resistance mutations at year 1 and only about 2% did so at 2 years.
        "In patients with defined baseline characteristics and undetectable week 24 HBV DNA, no resistance after 1 year was reported," the researchers concluded. "2-year resistance is very low."
        In a related study, Jinlin Hou from Nanfang Medical University and colleagues looked at viral breakthrough and resistance in more than 600 HBeAg positive Chinese patients receiving telbivudine in the EFFORT study. At baseline they had HBV DNA > 5 log copies/mL and ALT 2-10 x ULN.
        All patients started on telbivudine monotherapy. In the Roadmap arm people with HBV DNA > 300 copies/mL at week 24 added adefovir (Hepsera) while those with lower levels stayed on monotherapy. The control group received telbivudine monotherapy for the entire 104 weeks.
        
        About two-thirds (68%) of participants in the Roadmap group added adefovir. In a 76-week analysis, Roadmap patients were significantly more likely to achieve HBV DNA < 300 copies/mL compared with the stable telbivudine monotherapy group (74% vs 61%, respectively). They were also less likely to have HBV DNA remaining above 4 log (6 vs 22), experience viral breakthrough (1.8% vs 13%), or develop genotypic resistance (1.4% vs 11%). In a multivariate analysis, HBV DNA > 300 copies/mL at week 24 was associated with much higher risk of viral breakthrough on telbivudine monotherapy (OR 11.7, or nearly 12-fold higher risk).
        
        "The week 24 optimized strategy improves HBV DNA suppression and reduces the incidences of virological breakthrough and genotypic resistance dramatically," the researchers summarized. "The failure to achieve early virological response predicts the development of virological breakthrough."
        Finally, Teerha Piratvisuth from Songklanagarind Hospital in Hat Yai, Thailand, and colleagues analyzed 2-year outcomes among more than 100 HBeAg positive patients who started treatment with telbivudine monotherapy in the Roadmap study A2410. In this study participants with HBV DNA > 300 copies/mL at week 24 could add tenofovir (Viread).
        At week 24, 55% of participants achieved undetectable viral load, and all patients with detectable HBV DNA added tenofovir. At week 104, 94% had undetectable HBV DNA, 50% experienced HBeAg loss, 44% achieved HBeAg seroconversion, 7% experienced hepatitis B surface antigen (HBsAg) loss, and 4% achieved HBsAg seroconversion.
        A single patient in the telbivudine monotherapy arm experienced viral breakthrough at week 72 and was found to have the M204I mutation; this person again achieved undetectable HBV DNA after adding tenofovir. In addition, 1 monotherapy patient experienced a HBV DNA "blip" that returned to undetectable without changing therapy. Treatment was well-tolerated with no cases of muscle damage (a potential side effect of telbivudine) and overall improvement in kidney function (a potential concern with tenofovir).
        "Telbivudine Roadmap with tenofovir add-on at 24 weeks in patients with detectable HBV DNA improved GFR [a measure of kidney function] in both [telbivudine-] and [telbivudine + tenofovir-] treated patients," with "favorable efficacy and safety profiles," the investigators concluded.
        In an overview of research on the final day of the conference, Jean-Michel Pawlotsky from the University of Paris highlighted the "revival" of telbivudine thanks to the Roadmap. "You can be confident that if you apply the Roadmap you will achieve good results," he said.
        5/8/12
        References
        F Zoulim, S Zeuzem, T Piratvisuth, et al. Genotypic Resistance Reduced to Very Low Levels in Chronic Hepatitis B (CHB) Patients Treated Over 2-Years with Telbivudine (LDT) When Considering Baseline Characteristics and Roadmap. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 496.
        J Hou, J Sun, Q Xie, et al. Virological Breakthrough and Genotypic Resistance in a Randomized, Controlled Study on Telbivudine Treatment Applying Roadmap Concept in CHB: W76 Interim Analysis of EFFORT Study. Abstract 515. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012.
        T Piratvisuth, P Komolmit, T Tanwandee. 2-Year Results of Telbivudine (LDT) Roadmap Study Verify the Optimal Efficacy and Safety Results in HBeAg Positive Chronic Hepatitis B (CHB) Patients. Abstract 539. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012.
        

StephenW

欧洲肝病学会：替比夫定为B型肝炎与路线图选定的病人有效

   

分类：乙肝治疗
    08日（星期二）发表2012年5月00:00
    书面利兹Highleyman

替比夫定（TYZEKA）是最小出现耐药的慢性乙型肝炎的有效治疗时，选择合适的患者，并决定何时添加其他药物使用的“路线图”的算法，根据在第47届国际肝病大会提交的三人的研究上个月在巴塞罗那（欧洲肝病学会2012年）。

替比夫定（也称的LDT）是一个强大的活动对B型肝炎病毒（HBV）的核苷类似物，但它有一个相对较低的基因屏障的抵抗。

路线图的概念提供了一个优化的方法，以减少病毒学突破，在2011年4月在模拟治疗慢性乙型肝炎的核苷/核苷酸基因型耐药率，美国食品和药物管理局（FDA）宣布标签的变化，采用这种方法，说明应限于低基线HBV DNA的人，替比夫定，如果病毒载量仍然是在24周的检测，并应停止。

法比安斯基在里昂（INSERM）Zoulim看着耐药率后1和参与者之间的替比夫定2年治疗，根据路线图在全球举足轻重的审判。在基线肝炎B“的E”抗原（HBeAg）阳性组（n = 57）患者血清HBV DNA <9日志拷贝/毫升和HBeAg阴性的患者（N = 86）<7log拷贝/ ml，ALT为2倍正常值上限（ULN）的。
替比夫定24周，他们无法检测的病毒载量。

治疗1年后，仍有97％的HBeAg阳性和HBeAg阴性患者98％有乙型肝炎病毒DNA检测不到40％的HBeAg阳性参与者HBeAg血清转换的经验。替比夫定2年后，相应比率分别为89％和91％不到，52％HBeAg血清转换。没有患者出现耐药突变，在今年1和2年只有2％左右。

“在患者定义的基线特征和不到24周时HBV DNA的，没有阻力，1年后报告”，研究人员得出结论。 “2年的阻力是非常低的。”

吉林省从南方医科大学侯和他的同事在一项相关研究中，看着病毒的突破和阻力，在600多个e抗原阳性的中国患者接受替比夫定在努力研究。他们在基线HBV DNA> 5log拷贝/ ml和ALT 2-10 x ULN的。

所有患者开始替比夫定单独治疗。在路线图臂人与HBV DNA> 300拷贝/毫升24周附加水平较低，而停留在单一阿德福韦（阿德福韦酯）。整个104周，对照组接受替比夫定单独治疗。

约三分之二的路线图组的参与者（68％）增加阿德福韦。在76周的分析，路线图的患者明显更容易达到HBV DNA <300拷贝/ ml，较稳定的替比夫定单独治疗组（74％比61％，分别）。他们也不太可能有HBV DNA的其余4log（6 22），经验病毒突破（1.8％比13％）以上，或发展基因型耐药（1.4％比11％）。在多变量分析，HBV DNA> 300拷贝/毫升24周与替比夫定单独治疗病毒突破的风险要高得多（或11.7点，或近12倍的风险较高）。

“24周的优化策略，提高HBV DNA抑制和减少病毒学突破和显着的基因型耐药率”，研究者总结。 “未能达到早期病毒学应答预测的病毒学突破的发展。”

最后，在合艾，泰国，和他的同事Songklanagarind医院Piratvisuth Teerha从分析2年的结果，在100多个e抗原阳性的患者开始使用telbivudine单一疗法治疗的路线图研究A2410。在这项研究的参与者与HBV DNA> 300拷贝/毫升24周，可以添加泰诺福韦（VIREAD）。

24周时，55％的参与者达到检测不到病毒载量，所有患者检测HBV DNA的补充泰诺福韦。在104周，94％有乙型肝炎病毒DNA检测不到，50％的HBeAg消失，44％实现HBeAg血清转换，7％的乙肝表面抗原（HBsAg）的损失，实现4％的乙肝表面抗原转阴。

经历72周时替比夫定的单药组中单个病人病毒的突破和发现有M204I突变，此人再次取得了加替诺福韦后检测不到乙肝病毒DNA。此外，1单药治疗的患者经历1 HBV DNA的“昙花一现”，治疗不改变返回到检测不到。治疗肌肉损伤（替比夫定一个潜在的副作用）和肾功能的整体改善（潜在的问题与泰诺福韦）案件的耐受性良好。

“替比夫定的路线图与替诺福韦检测HBV DNA的患者24周改善GFR衡量肾功能都[替比夫定，]和[替比夫定+替诺福韦]治疗的患者”，“良好的疗效和安全性“研究人员得出结论。

在最后一天的会议上研究的概述，从巴黎大学的让 - 米歇尔·Pawlotsky医师强调的“复兴”的“路线图”替比夫定的感谢。 “你可以相信，如果你申请”路线图“，你会取得好成绩，”他说。

12年5月8日

参考文献

F Zoulim，S Zeuzem，T Pi​​ratvisuth，等。基因型耐药减少到非常低的水平在慢性乙型肝炎（CHB）替比夫定治疗的患者超过2年（LDT中）时，考虑基线特征和发展蓝图。第47届国际肝病会议（2012年欧洲肝病学会）。巴塞罗那，2012年4月18日至22日。摘要496。

Q谢，J孙，J侯，等。病毒学突破，替比夫定的路线图的概念应用在CHB治疗的随机对照研究：宽76努力研究的中期分析和基因型耐药。摘要515。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。

ţPiratvisuth，磷Komolmit，：牛逼Tanwandee。 2年替比夫定（LDT的）路线图研究结果确认，在HBeAg阳性慢性乙型肝炎（CHB）患者最佳的疗效和安全性结果。摘要539。第47届国际肝病会议（2012年欧洲肝病学会）。巴塞罗那，2012年4月18日至22日。

9病成医