EASL2015:临床反应预测因子 TDF加PEG组合治疗

StephenW

RS-4263
Viral hepatitis
Hepatitis B & D - clinical (Therapy, new compounds, resistance)

PREDICTORS OF CLINICAL RESPONSE: RESULTS FROM A LARGE, RANDOMIZED CONTROLLED STUDY WITH TENOFOVIR DISOPROXIL FUMARATE (TDF) PLUS PEGINTERFERON ALFA-2A (PEG) COMBINATION FOR CHRONIC HEPATITIS B (CHB)
Henry L. Chan* 1, SH. Ahn2, WL. Chuang3, Aric J. Hui4, F. Tabak5, R. Mehta6, J. Petersen7, Chuan-Mo Lee8, Xiaoli Ma9, Florin A. Caruntu10, Won Y. Tak11, Magdy Elkhashab12, L. Lin13, P. Dinh13, EB Martins13, P. Charuworn13, JG Mc Hutchinson13, GM Subramanian13, SG Lim14, GR Foster15, Scott Fung16, Luis Morano17, Didier Samuel18, Kosh Agarwal19, Ramazan Idilman20, Simone  Strasser21, M. Buti22, GB. Gaeta23, AJ. Hui24, George Papatheodoridis25, R. Flisiak26, P. Marcellin27
1The Chinese University of Hong Kong, Hong Kong, China, 2Yonsei University College of Medicine, Seoul, Korea, South, 3Kaohsiung Medical University, Kaohsiung, , 4Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China, 5Istanbul University Cerrahpaşa Faculty of Medicine, Istanbul, , 6Liver Clinic, Surat, India, 7University of Hamburg, Hamburg, Germany, 8Kaohsiung Chang Gung Memorial Hospital ,  University College of Medicine, Kaohsiung, Taiwan, 9Drexel University College of Medicine, Philadelphia, United States, 10National Institute for Infectious Diseases “ Matei Bals”, Bucharest, Romania, 11Kyungpook National University Hospital, Daegu, Korea, South, 12Toronto Liver Center, Toronto, Canada, 13Gilead Sciences, Inc., Foster City, United States, 14Yong Loo Lin School of Medicine, Singapore, Singapore, 15Queen Marys University of London, London, United Kingdom, 16University of Toronto, Toronto General Hospital, Toronto, Canada, 17Hospital de Meixoeiro, Pontevedra, Spain, 18Hôpital Paul Brousse, Villejuif, , 19King's College Hospital, London, United Kingdom, 20Ankara University School of Medicine, Ankara, , 21Royal Prince Alfred Hospital, Sydney, Australia, 22Hospital Universitari Vall d'Hebron, Barcelona, Spain, 23Second University of Naples, Naples, Italy, 24The Chinese University of Hong Kong, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, Hong Kong, , 25Athens University Medical School, “Laiko” General Hospital of Athens, Athens, Greece, 26Medical University of Bialystok, Bialystok, Poland, 27Hôpital Beaujon, Paris, France



Corresponding author’s email: [email protected]


Background and Aims:
There are scarce on-treatment data on HBsAg and HBV DNA kinetics with concomitant nucleos(t)ide analog and immunomodulator HBV therapy. Predictors of clinical response may help manage patients on combination therapy.
Methods:
From study GS-US-174-0149, 740 CHB patients without advanced disease were randomized 1:1:1:1 to receive (TDF+PEG) x48 weeks (arm A); (TDF+PEG) x16 weeks followed by TDFx32 weeks (arm B); continuous TDF (arm C); PEGx48 weeks (arm D). Associations between baseline and on-treatment variables with change in HBV DNA (log10 IU/ml) or HBsAg (log10 IU/ml) levels from baseline to week 48 or HBsAg loss at Week 72 were examined via linear regression or Cox regression analyses, respectively, in univariate models as well as multivariate models.
Results:
In a multivariate analysis, treatment arms A, B, and C compared to arm D, baseline HBeAg-negative status, higher baseline HBV DNA, and lower baseline HBsAg levels were associated with greater HBV DNA decline at Week 48. For every 1 log10 IU/ml increase in baseline HBV DNA or 1 log10 IU/ml decrease in baseline HBsAg, there is an expected greater HBV DNA decline by 0.85 or 0.31 log10 IU/mL, respectively, at Week 48. On multivariate analysis, achieving HBsAg loss was associated with treatment Arm A, GT A, early ALT flare on treatment, and, at Week 12, with HBsAg decline from baseline >1 log10 IU/ml (table). The positive predictive values for achieving HBsAg loss at week 72 with (TDF+PEG)x 48 weeks with either 1 log10 IU/ml decline or HBsAg < 100 IU/ml at week 12 were 43% and 50%, respectively, and the negative predictive values (NPV) were 97% and 95%, respectively. TDF+ PEG combination for 48 weeks exhibited the largest HBsAg decline (log10 IU/ml) as compared to other treatment arms (Arm A: -1.1, B: -0.5, C: -0.3, D: -0.8; p < 0.01 for all comparisons of arm A versus others). Similar levels of HBsAg decline were observed in genotypes (GT) A and B (mean log10 IU/ml ± SD: -1.2±2.0 and -1.1±1.2, respectively), both of which exhibited a greater decline than GT C and D (-0.5±0.9 and-0.4±1.0, respectively) (p < 0.05).
Conclusions:
Higher baseline HBsAg levels appear to impact negatively on-treatment HBV DNA response. HBsAg decline on TDF plus PEG combination therapy x48weeks was synergistically greater than on either TDF or PEG monotherapy. HBsAg decline appears to favor HBV GT A and B. Moreover, HBsAg decline at week 12 shows high NPV for week 72 HBsAg loss and may provide a valuable tool for response-guided therapy in PEG+TDF combination treatment.


Disclosure of Interest: None Declared

StephenW

RS-4263

病毒性肝炎

乙肝＆D - 临床（治疗，新的化合物，电阻）





临床反应预测因子：结果从一个大的，随机对照富马酸替诺福韦酯（TDF）加聚乙二醇干扰素α-2a干扰素（PEG）组合治疗慢性乙型肝炎的研究（CHB）

亨利L.陈* 1，SH。 Ahn2，WL。 Chuang3，ARIC J. Hui4，F. Tabak5，R. Mehta6，J. Petersen7，传武Lee8，小莉MA9，林A. Caruntu10，赢得Y. Tak11，Magdy Elkhashab12，L. Lin13，P. Dinh13，EB Martins13 ，P. Charuworn13，JG麦当劳Hutchinson13，GM Subramanian13，SG Lim14，GR Foster15，斯科特Fung16，路易斯Morano17，迪迪埃Samuel18，信贷基金Agarwal19，拉马赞Idilman20，西蒙娜Strasser21，M. Buti22，GB。 Gaeta23，AJ。 Hui24，乔治Papatheodoridis25，R. Flisiak26，P. Marcellin27

1The中国香港大学，香港，中国，药品，首尔，韩国，3Kaohsiung医科大学，高雄2Yonsei大学学院，4Alice何妙龄那打素医院，香港，中国，医学5Istanbul大学Cerrahpaşa学院，伊斯坦布尔，6Liver诊所，苏拉特，印度，汉堡，汉堡，德国，8Kaohsiung长庚医院，医学大学，台湾高雄医学院9Drexel大学，费城，美国，10National研究所传染病7University“马太巴尔斯“，布加勒斯特，罗马尼亚，11Kyungpook国立大学医院，大邱，韩国，12Toronto肝病中心，多伦多，加拿大，13Gilead科学公司，福斯特城，美国，医药，新加坡，新加坡14Yong潞龄医学院，伦敦，英国伦敦，多伦多，多伦多综合医院，多伦多，加拿大，17Hospital德Meixoeiro，蓬特韦德拉，西班牙，18Hôpital保罗Brousse，维勒瑞夫，对16University的15Queen圣玛丽大学，19King学院医院，英国伦敦，20Ankara大学医学，安卡拉，21Royal阿尔弗雷德王子医院，悉尼，澳大利亚，22Hospital Universitari瓦勒d'Hebron城，西班牙巴塞罗那，那不勒斯，那不勒斯，意大利，香港的四条中国大学23Second大学，雅丽氏何妙龄那打素医院，香港香港，香港，25Athens大学医学院，雅典，雅典，希腊，比亚韦斯托克的26Medical大学，比亚韦斯托克，波兰，27HôpitalBeaujon，巴黎，法国“Laiko”综合医院



通讯作者的邮箱：[email protected]



背景和目的：有对HBsAg和HBV DNA动力学伴核苷（酸）IDE模拟和免疫调节剂治疗HBV稀缺的处理数据。临床反应的预测可以帮助管理患者联合治疗。

方法：从研究GS-US-174-0149，740例慢性乙型肝炎患者无疾病晚期患者随机1：1：1：1的接收（TDF + PEG）X48周（A组）; （TDF + PEG）X16周后TDFx32周（B组）;连续TDF（ARM C）; PEGx48周（ARM D）。基线之间和治疗与变化的HBV DNA（log10的国际单位/毫升）或乙肝表面抗原（log10的国际单位/毫升）从基线水平到48周或HBsAg消失在第72周的变量关联经由线性回归进行检查或Cox回归分析，分别在单因素模型以及多变量模型。

结果：在多变量分析，治疗组A，B，和C相比武装D，基线HBeAg阴性状态，较高的基线HBV DNA，和较低的基线HBsAg水平都与更高的HBV DNA下降为48周每1日志10 IU / ml的基线HBV DNA增加或1日志10 IU / ml的减少基线乙肝表面抗原，有0.85或0.31日志10 IU / mL时，分别为预期的更大的HBV DNA下降，为48周多变量分析显示，实现HBsAg消失用治疗臂A，GT的一个，在治疗早期的ALT耀斑相关联，并且，在第12周，从基线> 1 log10的国际单位/毫升（表）的HBsAg下降。阳性预测值实现HBsAg消失，在72周与（TDF + PEG）×48周任一1 log10的国际单位/毫升下降或HBsAg的<100IU / ml的在第12周分别为43％和50％，分别与负预测值（NPV）分别为97％和95％。 TDF + PEG结合48周展出的最大跌幅乙肝表面抗原（日志10 IU / ml）的相比其他治疗组（A组：-1.1，B：-0.5，C：-0.3，D：-0.8; P <0.01为所有A组与其他人）的比较。 HBsAg的下降水平相似，观察在基因型（GT）A和B（平均日志10 IU / ml的±SD：-1.2±2.0和-1.1±1.2，分别），两者表现出比GT C和D较大下降（ -0.5±0.9和-0.4±1.0，分别）（P <0.05）。

结论：较高的基线HBsAg水平似乎产生消极影响，治疗HBV DNA的反应。在TDF加PEG联合治疗x48weeks HBsAg的下降幅度比协同在任TDF或PEG单一更大。出现HBsAg的下降有利于HBV GT A和B.此外，HBsAg的下降在第12周显示出高NPV为72周HBsAg消失，并可能为应答指导治疗PEG + TDF联合治疗的宝贵工具。



股权变动：无申报

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结论:表面抗原定量高对抗病毒治疗效果不利，替诺与干扰素联合治疗再48周时的表面抗原下降比单独替诺或佩乐能更大，A型和B基因型病毒的效果疗效好。12周时表面抗原下降预测72周时表面抗原消失的几率高，这提供了一个有效的治疗预测措施，在替诺和佩乐能联合治疗中，将很有用。

相信会幸福

感觉不错哎

齐欢畅2

这个治疗方法貌似很多实验。