AASLD2014:对于正在进行的低级病毒血症治疗乙肝炎的证据长

StephenW

Evidence for Ongoing Low-level Viremia in Patients with Chronic Hepatitis B Receiving Long-term Nucleos(t)ide Analog TherapyPatrick Marcellin1, Edward J. Gane2, Robert Flisiak3, Michael P. Manns4, Kelly D. Kaita5, Anuj Gaggar6, Lanjia Lin6, Kathryn M. Kitrinos6, John F. Flaherty6, Mani Subramanian6, John G. McHutchison6, Harry L. Janssen7, Maria Buti8;1H6pital Beaujon, Clichy, France; 2Auckland City Hospital, Auckland, New Zealand; 3Medical University of Bialystok, Bialystok, Poland; 4Medical School of Hannover, Hannover, Germany; 5University of Manitoba, Winnipeg, MB, Canada; 6Gilead Sciences, Inc., Foster City, CA; 7University of Toronto, Toronto, ON, Canada; 8Hospital General Universitari Vall dHebron and Ciberehd, Barcelona, SpainIntroduction: Nucleos(t)ide analog (NA) therapy is a mainstay of treatment for chronic Hepatitis B (CHB) infection. Treatment with a potent NA such as tenofovir disoproxil fumarate (TDF) is associated with a high level of durable viral suppression, improvement in liver fibrosis, and no documented viral resistance in a cohort of patients followed for up to 5 years. The presence of low level viral replication below the lower limit of quantification (LLOQ) in the presence of ongoing NA therapy, however, has not been evaluated in detail. Methods: HBV DNA levels were assessed from two registrational studies of TDF for CHB in HBeAg-negative and HBeAg-positive patients. HBV DNA was quantified using the COBAS TaqMan V 2.0 having a lower limit of quantification (LLOQ) of 29 IU/mL and a lower limit of detection of 10 IU/mL. HBV DNA values less than 10 IU/mL are reported as target not detected (TND), while values between 10 IU/mL and 28 IU/mL are reported as target detected (TD). Results: The percentage of patients with undetectable HBV DNA less than LLOQ (TND) between weeks 96 and 240 is shown in the figure. Among patients who achieved HBV DNA < 29 IU/mL, the percentage with TND increased over time to 22-36 %after 5 years (240 weeks) of NA treatment for HBeAg positive and HBeAg negative patients respectively. No patients achieved and remained <LLOQ TND for the entire study period; only 65 %maintained TND at >50 %of visits between Weeks 96 and 240. For individuals who achieved HBV DNA suppression (<LLOQ), there was no association of TND frequency with HBsAg loss, HBsAg decline, or change in liver fibrosis. However, among HBeAg-positive patients, percentage of TND was associated with achievement of HBeAg loss (p<0.001) and anti-HBe seroconversion (p<0.001) by Week 240 . Conclusions: Low-level ongoing viral replication may be occurring in the presence of nucleoside analog therapy even after 5 years of therapy. The absence of low-level viremia was associated with HBeAg loss and seroconversion. Further evaluation into the mechanism of viral replication in the absence of overt drug resistance is warranted. These data provide a rationale for possible intensification of viral suppression through an orthogonal mechanism of action.

Disclosures:
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer, Abbvie
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie, Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche, Bristol Myers Squibb, Janssen, Novartis, Abbvie; Grant/Research Support: Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speaking and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead, Abbvie
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/ Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis
Kelly D. Kaita - Advisory Committees or Review Panels: Gilead, Merck, Roche, Janssen, Boehringer, BMS, GSK, Vertex, Abbvie; Grant/Research Support: Gilead, Merck, Roche
Anuj Gaggar - Employment: Gilead Sciences
Lanjia Lin - Employment: Gilead; Stock Shareholder: Gilead
Kathryn M. Kitrinos - Employment: Gilead Sciences, Gilead Sciences; Stock Shareholder: Gilead Sciences, Gilead Sciences
John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex, MSD; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

StephenW

对于正在进行的低级病毒血症治疗慢性乙型肝炎的证据长期接受核苷（酸）IDE模拟疗法
帕特里克Marcellin1，爱德华·J·Gane2，罗伯特Flisiak3，迈克尔P. Manns4，凯利D. Kaita5，Anuj Gaggar6，兰家Lin6，凯瑟琳M. Kitrinos6，约翰·Flaherty6，玛尼Subramanian6，约翰G. McHutchison6，哈里L。Janssen7，玛丽亚Buti8;
1H6pital Beaujon，克利希，法国; 2Auckland市医院，奥克兰，新西兰;比亚韦斯托克，比亚韦斯托克，波兰3Medical大学; 4Medical学校汉诺威，汉诺威，德国; 5University马尼托巴省，温尼伯，马尼托巴省，加拿大; 6Gilead科学公司，福斯特城，CA; 7University多伦多，多伦多，加拿大; 8Hospital一般Universitari瓦尔dHebron和Ciberehd，巴塞罗那，西班牙

简介：核苷（酸）类似物的IDE（NA）治疗是治疗慢性乙型肝炎（CHB）感染的中流砥柱。治疗一个强有力的NA，如富马酸替诺福韦酯（TDF）与耐用抑制病毒，改善肝纤维化的高水平有关，并没有记载病毒耐药的患者队列随访了5年。低水平的病毒复制下面的量化（LLOQ）在正在进行的NA治疗存在的下限的情况下，然而，还没有详细评价。
方法：HBV DNA水平从TDF的慢性乙型肝炎2 registrational研究HBeAg阴性和HBeAg阳性患者进行评估。利用COBAS TaqMan探针2.0版具有29 IU / mL的定量（LLOQ）的下限值和检测的10国际单位/毫升的下限值的HBV DNA进行定量。 HBV DNA的值小于10国际单位/毫升被报告为未检测到目标（TND），而10 IU / mL和28国际单位/毫升之间的值被报告为目标检测（TD）。
结果：患者的不可检测的HBV DNA低于LLOQ（TND）周96和240之间的百分数示于图中。当中谁取得了HBV DNA的患者<29 IU / mL时，分别为5年NA处理的（240周）为HBeAg阳性和HBeAg阴性患者后用TND的百分比随着时间增加至22-36％。没有患者达到并保持<最低定量限为TND在整个研究期间;只有65 TND保持在96周和240之间的互访>50％，谁取得的HBV DNA抑制（<LLOQ）个体％，有TND频率HBsAg转阴，乙肝表面抗原下降，或改变肝纤维化的无关联。然而，在HBeAg阳性患者，TND百分比与成就HBeAg消失（P <0.001），抗HBe血清学转换（P <0.001），按周240有关。结论：低层次的持续病毒复制，即使经过5年的治疗可发生在核苷类似物治疗的存在。没有低级病毒血症与HBeAg消失和血清转换相关联。进一步评价为病毒复制中不存在明显的耐药性的机制是必要的。这些数据通过行动的正交机制为抑制病毒的可能激化的理由。
图片

披露：

帕特里克Marcellin - 咨询：罗氏公司，Gilead公司，拜耳，顶点，诺华，西安杨森，默沙东，Abbvie，Alios生物制药，Idenix公司，阿克伦城;格兰特/研究支持：罗氏公司，Gilead公司，拜耳，诺华，西安杨森，默沙东，Alios生物制药;口语和教学：罗氏，基列，拜耳，顶点，诺华，西安杨森，默沙东，勃林格，辉瑞，Abbvie

爱德华·J·甘恩 - 咨询委员会或审查小组：Novira，AbbVie，诺华公司，Gilead Sciences公司，西安杨森Cilag公司，顶点，艾琪尔顿，Tekmira，默克，IDE-nix的;口语和教学：AbbVie，诺华，Gilead Sciences公司，西安杨森Cilag公司

罗伯特Flisiak - 咨询委员会或审查小组：Gilead公司，默克，罗氏，施贵宝公司，西安杨森，诺华，Abbvie;格兰特/研究支持：罗氏，施贵宝公司，西安杨森，诺华，基列，顶点，默克公司;口语和教学：扬森，默克，罗氏，施贵宝公司，Gilead公司，Abbvie

迈克尔P.曼斯 - 咨询：罗氏，拜耳，Gilead公司，勃林格殷格翰，诺华，Idenix公司，艾琪尔顿，葛兰素史克，默克/默沙东，西安杨森，Medgenics;格兰特/研究支持：默克/默沙东，罗氏，Gilead公司，诺华，勃林格殷格翰，拜耳;口语和教学：默克/默沙东，罗氏，拜耳，基列，扬森，葛兰素史克，诺华

凯利D.海田 - 咨询委员会或审查小组：Gilead公司，默克，罗氏，杨森，勃林格，拜耳，葛兰素史克，顶点，Abbvie;格兰特/研究支持：Gilead公司，默克，罗氏

Anuj Gaggar - 就业：Gilead Sciences公司

兰家林 - 就业：基列;股股东：吉利德

凯瑟琳M. Kitrinos - 就业：Gilead Sciences公司，Gilead科学;股股东：Gilead Sciences公司，Gilead科学

约翰·弗莱厄蒂 - 就业：Gilead Sciences公司;股股东：Gilead Sciences公司

玛尼萨勃拉曼尼亚 - 就业：Gilead Sciences公司

约翰G. McHutchison - 就业：Gilead Sciences公司;股股东：Gilead Sciences公司

哈里L.詹森 - 咨询：雅培，施贵宝公司，德彪，Gilead Sciences公司，默克公司，美敦力公司，诺华，罗氏，Santaris;格兰特/研究支持：Anadys公司，施贵宝公司，Gilead科学，Innogenetics公司，麒麟，默克公司，美敦力公司，诺华，罗氏，Santaris

玛丽亚·布提 - 咨询委员会或审查小组：Gilead公司，西安杨森，顶点，MSD;格兰特/研究支持：Gilead公司，扬森;口语和教学：Gilead公司，西安杨森，顶点，诺华

咬牙硬挺

好复杂，不太明白

StephenW

回复 咬牙硬挺 的帖子

HBVDNA检测不到并不代表 0 HBVDNA.

肝肠欲断

HBVDNA检测不到并不代表没有乙肝病毒，就是表面抗原S检测不到也并不代表没有乙肝病毒！感觉只有清除了CCCDNA才行！

StephenW

回复 肝肠欲断 的帖子

非常同意.如果HBVDNA〜= 0与HBsAg〜= 0时，是功能性治愈.