GS9620乙肝病毒和HIV

StephenW

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B….Treatment with a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys…..
http://www.natap.org/2015/CROI/croi_37.htm

Preclinical Characterization of GS-9620, A Potent and Selective Oral TLR7 Agonist…..
http://www.natap.org/2011/EASL/EASL_57.htm

The Antiviral Response to the Toll-Like Receptor 7 Agonist GS-9620 in Preclinical Models of Chronic Hepatitis B Is Associated With an Intrahepatic Cytotoxic T Cell Transcriptional Signature…...
http://www.natap.org/2014/AASLD/AASLD_140.htmTLR7 Agonist GS-9620 Activates HIV-1 in PBMCs from HIV-Infected Patients on cART…..http://www.natap.org/2015/CROI/croi_25.htmCytokines Induced by a Toll-Like Receptor 7 Agonist Potently Inhibit HBV RNA, DNA, and Antigen Levels in Primary Human Hepatocytes…..http://www.natap.org/2014/AASLD/AASLD_139.htm

The Antiviral Response to the Toll-Like Receptor 7 Agonist GS-9620 in Preclinical Models of Chronic Hepatitis B is Associated With an Intrahepatic Cytotoxic T Cell Transcriptional Signature…..http://www.natap.org/2014/AASLD/AASLD_148.htm
Targeting Innate Immunity [GS-9620]: A New Step in the Development of Combination Therapy for Chronic Hepatitis B …...http://www.natap.org/2014/HBV/010515_06.htm    


Journal of Hepatology 2015




"In summary, short duration treatment with GS-9620 induced a sustained antiviral response and anti-WHs antibody seroconversion in the woodchuck model of CHB. These data suggest that GS-9620 may have the potential to therapeutically induce sustained immunological control of chronic HBV infection in patients…….GS-9620 treatment induced marked, sustained reductions in serum WHV DNA noted as early as the first week of treatment. GS-9620 induced reductions in viremia occurred in nearly all GS-9620-treated woodchucks by week 4 (Fig. 3 and Table 2)…...In this group (group 5), GS-9620 treatment caused statistically significant reductions in viral load compared to pretreatment and the placebo control group at weeks 2–35 (all p <0.05) with a mean maximal viral load reduction of 6.1 log10 and a sustained mean 5.0 log10 viral load reduction at the end of the study (week 35). Strikingly, after completion of only 4 or 8 weeks of GS-9620 treatment, suppression of viral load was sustained through the end of the study (week 35) in all woodchucks in group 3 (QOD × 4 weeks), and in 4 of 5 woodchucks in group 5 (QW × 8 weeks) that completed treatment (Fig. 3C and E)…...The incidence of HCC was markedly reduced in GS-9620-treated woodchucks (Table 2). In placebo-treated WHV-infected woodchucks, HCC occurred in 5 of the 7 (71%) woodchucks, consistent with the previous observation that nearly all chronic WHV carriers develop HCC over time [[url=]22[/url]]. In contrast, for all GS-9620-treated woodchucks that completed treatment and had a viral load reduction in response to treatment, the incidence was 2 of 15 (13%). Importantly, in GS-9620-treated woodchucks that had a sustained reduction in viral load, the incidence of HCC was only 1 of 12 (8%) (Table 2).

The results demonstrate that short duration treatment with GS-9620 can induce a durable therapeutic antiviral immune response during chronic hepadnavirus infection. In a previous study in chimpanzees chronically infected with HBV, GS-9620 treatment caused a sustained, albeit less marked reduction in viral load and HBsAg [[url=]10[/url]]. While studies are ongoing to define the cellular and molecular characteristics of the antiviral response to GS-9620, it likely involves local induction of IFN-α, as well as induction of antiviral NK and CD8+ T cell responses [[url=][8][/url], [url=][31][/url], [url=][32][/url]]. In addition, direct activation of B cells by GS-9620 may also be an important mechanism that contributes to viral clearance [[url=]33[/url]].
The antiviral responses induced by GS-9620 are clearly differentiated from those observed with nucleos(t)ides evaluated in the woodchuck model of CHB. While the duration of viral load reduction was markedly longer with GS-9620 compared to similar treatment with nucleos(t)ides, the most important finding was that, in contrast to GS-9620, nucleos(t)ide treatment induced a sustained loss of WHsAg in only a small minority of WHV-infected woodchucks and induction of anti-WHsAb was rare [[url=][3][/url], [url=][14][/url]]. Other therapeutic strategies in this model have included therapeutic vaccination, IL-12 gene therapy and inhibition of PD-L1 [[url=][24][/url], [url=][25][/url], [url=][26][/url]]. Although, in some instances, these therapies have yielded transient reductions in viral load, WHsAg and induction of anti-WHsAb, no single agent has been reported to induce a comparable antiviral response to GS-9620. Most notably, while treatment of chronically infected woodchucks with recombinant woodchuck IFN-α strongly reduced serum WHV DNA and WHsAg in some treated animals, this was a transient response that was not accompanied by anti-WHsAb seroconversion in most woodchucks (Menne S, unpublished data).
Treatment of WHV-infected woodchucks with GS-9620 resulted in rapid, marked and sustained antiviral response. GS-9620 pharmacodynamic responses were consistent with activation of TLR7 and correlated statistically with antiviral efficacy. Importantly, the magnitude of ISG induction in chronically infected woodchucks was similar to that induced in humans at well tolerated doses (Supplementary Table 1) [[url=]11[/url]]. Strikingly, in most chronically infected animals GS-9620 induced a multi-log reduction in viral load, WHsAg loss and anti-WHs antibody seroconversion, and reduced cccDNA levels and HCC incidence. Specifically, reductions in viral load occurred in 15 of 19 woodchucks that completed treatment (regardless of regimen) and viral load reductions were sustained through the end of the study in 12 of these 15 woodchucks. Sustained WHsAg loss occurred in 13 of 15 woodchucks that completed treatment. Importantly, in 8 of 13 treated woodchucks with WHsAg loss, induction of WHsAb occurred and persisted. In GS-9620-treated woodchucks that had a sustained reduction in viral load, the incidence of HCC was less than 10% compared to a rate of over 70% in the placebo group."







Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis BJournal of Hepatology 2015








Stephan Menne1,⇑,
, Daniel B. Tumas2,
, Katherine H. Liu3, Linta Thampi1, Dalal AlDeghaither1, Betty H. Baldwin3, Christine A. Bellezza3, Paul J. Cote1, Jim Zheng4, Randall Halcomb5, Abigail Fosdick6, Simon P. Fletcher2, Stephane Daffis2, Li Li7, Peng Yue7, Grushenka H.I. Wolfgang6, Bud C. Tennant3
1Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States; 2Department of
Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States; 3Department of Clinical Sciences, Gastrointestinal Unit,
College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States; 4Department of Drug Metabolism, Gilead Sciences, Inc., 333
Lakeside Drive, Foster City, CA 94404, United States; 5Department of Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404,
United States; 6Department of Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States;
7Department of Biomarkers, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
Background & AimsNew therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV).
MethodsAfter evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n = 7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules.
ResultsGS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon response transcriptional signatures.
ConclusionsThe data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.

StephenW

GS9620乙肝病毒HIV和
持续的疗效和血清转换与Toll样受体激动剂7 GS-9620在慢性乙型肝炎的土拨鼠模型......。
治疗用TLR7激动剂诱导短暂的病毒血症SIV感染ART抑制猴子... ..
http://www.natap.org/2015/CROI/croi_37.htm

GS-9620的临床表征，强效选择性口头TLR7激动剂... ..
http://www.natap.org/2011/EASL/EASL_57.htm

在抗病毒应答的Toll样受体激动剂7 GS-9620治疗慢性乙型肝炎的临床前模型是一个肝内细胞毒性T细胞的转录签名关联......
http://www.natap.org/2014/AASLD/AASLD_140.htm
TLR7激动剂GS-9620激活HIV-1的车从HIV感染患者外周血单个核细胞... ..http：//www.natap.org/2015/CROI/croi_25.htm
细胞因子Toll样受体激动剂7强效抑制乙肝病毒的RNA，DNA诱导和抗原水平的人原代肝... ..http：//www.natap.org/2014/AASLD/AASLD_139.htm

在抗病毒应答的Toll样受体激动剂7 GS-9620治疗慢性乙型肝炎的临床前模型相关联随着肝内细胞毒性T细胞的转录签名...... ..http：//www.natap.org/2014/AASLD/AASLD_148。 HTM
针对先天免疫[GS-9620]：中西医结合治疗的慢性乙型肝炎发展的新步...... HTTP：//www.natap.org/2014/HBV/010515_06.htm
  

中华肝脏病杂志2015


“总之，用GS-9620短持续时间治疗诱导慢性乙型肝炎的土拨鼠模型的持续的抗病毒反应，抗WHS抗体血清转化。这些数据表明，GS-9620可能必须治疗诱导的慢性HBV感染持续免疫控制的电位患者...... .GS-9620治疗诱导的标记，持续降低血清WHV DNA为早治疗的第一周注意到GS-9620诱导的降低病毒血症发生在几乎所有的GS-9620处理的土拨鼠用4周（图3和表2）......在这组（组5），GS-9620治疗导致相比预处理和在周2-35安慰剂对照组（所有P <0.05统计学显著减少病毒载量）与意味着最大病毒载量下降6.1日志10和一个持续平均5.0日志10病毒载量在研究结束时减少（周35）。引人注目的是，仅4周或8周的GS-9620治疗结束后，抑制病毒载量被持续通过研究结束（每周35）在第3组的所有土拨鼠（QOD×4周），并在4土拨鼠在组5（QW×8周）已完成处理（图3C和E）......肝癌的发病率显着在GS-9620处理的土拨鼠（表2）减少。在安慰剂治疗WHV感染土拨鼠，肝癌发生在5 7（71％）旱獭，与以前的观察相一致，几乎所有的慢性携带者WHV肝癌发展随着时间的推移[22]。相反，对于所有的GS-9620处理的土拨鼠已完成治疗并有病毒载量的减少对治疗的反应，发生率为2的15（13％）。重要的是，在GS-9620处理的土拨鼠即有持续减少病毒载量，肝癌的发病率仅为1 12（8％）（表2）。

结果表明，与GS-9620短持续时间的治疗可诱导在慢性肝DNA病毒感染的持久治疗的抗病毒免疫应答。在先前的研究中慢性乙型肝炎病毒感染，GS-9620治疗的黑猩猩引起了持续的，尽管不那么明显减少病毒载量与HBsAg [10]。而研究正在进行以限定到GS-9620的抗病毒应答的细胞和分子的特性，它可能涉及局部诱导的IFN-α，以及诱导的抗病毒NK细胞和CD8 + T细胞应答[8]，[31] [32]。此外，由GS-9620直接激活B细胞也可以是有利于病毒清除[33]的重要机制。
诱导GS-9620的抗病毒反应的显然不同于那些在慢性乙型肝炎的土拨鼠模型评估核苷（酸）的IDE观察。而病毒载量减少的持续时间显着较长用GS-9620相比，与核苷（酸）的IDE类似治疗，最重要的发现是，与此相反的GS-9620，核苷（酸）的ide治疗诱导的持续损失WHsAg在只有少数WHV感染土拨鼠和诱导抗WHsAb的是罕见的[3]，[14]]。在该模型中的其它治疗策略包括治疗性疫苗接种的PD-L1的IL-12基因治疗和抑制[24]，[25]，[26]]。虽然，在某些情况下，这些疗法已产生暂态减少病毒载量，WHsAg和诱导抗WHsAb的，没有单一试剂已报道诱导到GS-9620可比的抗病毒反应。最值得注意的是，尽管治疗的慢性感染土拨鼠用重组土拨鼠IFN-α强烈降低血清WHV DNA和WHsAg在一些治疗的动物中，这是没有伴随着抗WHsAb血清转化中最旱獭一个瞬态响应（Menne S，未发表的数据）。
WHV的感染旱獭与GS-9620治疗导致迅速，标记和持续的抗病毒反应。 GS-9620药效的反应是用TLR7激活一致，并与抗病毒疗效显着相关。重要的是，ISG诱导在慢性感染的土拨鼠的大小相似，诱导人类在良好耐受的剂量（附加表1）[11]。引人注目的是，在大多数慢性感染动物的GS-9620诱导的病毒载量，WHsAg损耗和抗WHS抗体血清转化的多对数减少，并降低的cccDNA水平和肝癌的发病率。具体地，减少病毒载量发生在15 19的已完成处理（无论方案的）土拨鼠和病毒载量的减少通过研究在这些15旱獭12的端被维持。持续WHsAg损失发生在13 15的完成治疗旱獭。重要的是，在13处理旱獭与WHsAg损失8，感应WHsAb的发生和持续。在GS-9620处理的土拨鼠即有持续减少病毒载量，肝细胞癌的发生率小于10％，相比之下，超过70％，而安慰剂组的速率“。




持续的疗效和血清转换与Toll样受体激动剂7 GS-9620在慢性乙型肝炎的土拨鼠模型
中华肝脏病杂志2015


斯蒂芬Menne1，⇑,,丹尼尔B. Tumas2 ,,凯瑟琳·H·柳，林塔Thampi1，达拉尔AlDeghaither1，贝蒂H. Baldwin3，恭A. Bellezza3，保罗J. Cote1，吉姆Zheng4，兰德尔Halcomb5，阿比盖尔Fosdick6，西蒙P.的fletcher2，斯特凡Daffis2，李LI7，彭Yue7，Grushenka HI Wolfgang6，芽C. Tennant3
微生物学与免疫学，乔治敦大学医学中心，华盛顿特区，20057的教研室，美国;教研室的
生物学，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国; 3Department的临床科学，胃肠部，
兽医学院，康奈尔大学，纽约州14853，美国;药物代谢，吉利德科学公司，333 4Department
湖滨驱动器，福斯特市，CA 94404，美国; 5Department化学，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404的，
美国;药物安全性评价，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404的6Department，美国;
7Department生物标志物，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国
背景与目的

迫切需要新的治疗慢性乙型肝炎（CHB），因为目前的治疗很少导致治愈。我们评估了口服小分子toll样受体（TLR7）激动剂GS-9620是否可以诱导在慢性感染土拨鼠肝炎病毒（WHV）旱獭耐久抗病毒效力，肝DNA病毒密切相关的人乙型肝炎病毒（HBV）。
方法

评估药代动力学，药效学和口服GS-9620在未感染的土拨鼠耐受性后，成人土拨鼠慢性感染WHV（每组n = 7）给药GS-9620或安慰剂治疗4周或8周的不同的治疗方案。
结果

GS-9620治疗诱导的快速，标记和持续减少血清病毒DNA（平均最大6.2日志10减少），和肝WHV DNA复制中间体，WHV cccDNA的和WHV的RNA，以及可检测的血清WHV表面抗原（WHsAg）的损失。 GS-9620治疗也诱导在动物中的一个子集对WHsAg持续的抗体应答。引人注目的是，治疗的71％，而安慰剂组减少肝细胞癌（HCC）的发生率，以8％的GS-9620处理的土拨鼠用持续的病毒载量下降。 GS-9620治疗与可逆增加血清肝酶和血小板减少，并诱导肝内CD8 + T细胞，NK细胞，B细胞和干扰素反应转录签名。
结论

该数据表明，短的持续时间，与口腔TLR7激动剂GS-9620有限治疗可诱导在慢性乙型肝炎的土拨鼠模型的持续的抗病毒反应，以及该化合物作为治疗方法以达到慢性乙型肝炎患者的官能固化的支持调查。

StephenW

Discussion

Treatment of WHV-infected woodchucks with GS-9620 resulted in rapid, marked and sustained antiviral response. GS-9620 pharmacodynamic responses were consistent with activation of TLR7 and correlated statistically with antiviral efficacy. Importantly, the magnitude of ISG induction in chronically infected woodchucks was similar to that induced in humans at well tolerated doses (Supplementary Table 1) [11]. Strikingly, in most chronically infected animals GS-9620 induced a multi-log reduction in viral load, WHsAg loss and anti-WHs antibody seroconversion, and reduced cccDNA levels and HCC incidence. Specifically, reductions in viral load occurred in 15 of 19 woodchucks that completed treatment (regardless of regimen) and viral load reductions were sustained through the end of the study in 12 of these 15 woodchucks. Sustained WHsAg loss occurred in 13 of 15 woodchucks that completed treatment. Importantly, in 8 of 13 treated woodchucks with WHsAg loss, induction of WHsAb occurred and persisted. In GS-9620-treated woodchucks that had a sustained reduction in viral load, the incidence of HCC was less than 10% compared to a rate of over 70% in the placebo group.

The antiviral responses induced by GS-9620 are clearly differentiated from those observed with nucleos(t)ides evaluated in the woodchuck model of CHB. While the duration of viral load reduction was markedly longer with GS-9620 compared to similar treatment with nucleos(t)ides, the most important finding was that, in contrast to GS-9620, nucleos(t)ide treatment induced a sustained loss of WHsAg in only a small minority of WHV-infected woodchucks and induction of anti-WHsAb was rare [[3], [14]]. Other therapeutic strategies in this model have included therapeutic vaccination, IL-12 gene therapy and inhibition of PD-L1 [[24], [25], [26]]. Although, in some instances, these therapies have yielded transient reductions in viral load, WHsAg and induction of anti-WHsAb, no single agent has been reported to induce a comparable antiviral response to GS-9620. Most notably, while treatment of chronically infected woodchucks with recombinant woodchuck IFN-α strongly reduced serum WHV DNA and WHsAg in some treated animals, this was a transient response that was not accompanied by anti-WHsAb seroconversion in most woodchucks (Menne S, unpublished data).

Similar to a previous report in HBV-infected chimpanzees [10], GS-9620 treatment in woodchucks was associated with thrombocytopenia and liver enzyme increases. These adverse effects were transient, reversed with dose holiday, had reduced incidence and severity with lower doses, and were monitored by routine clinical laboratory parameters. Increases in liver enzymes were noted in some animals throughout all groups, including placebo-treated animals, and were reversible in most cases without dose reduction or treatment cessation. The mechanism by which GS-9620 treatment caused platelet reductions in woodchucks is not clear. However, recent reports show that TLR7 is expressed in platelets, that TLR7 activation can induce a reduction in platelet count with no influence on thrombotic properties, and these effects enhanced host immune response and survival to viral infection [27]. As elevations in liver enzymes noted in GS-9620-treated animals were temporally associated with reductions in hepatic cccDNA, liver enzyme increases may represent immune-mediated killing of infected hepatocytes. This is consistent with the induction of an intrahepatic cytotoxic CD8+ T cell and/or NK cell transcriptional signature during GS-9620 treatment. Notably, transient increases in liver enzymes often precede clearance of acute hepadnavirus infection in woodchucks, chimpanzees and humans, and are thought to represent development of effective intrahepatic antiviral immunity [[28], [29], [30]].

The results demonstrate that short duration treatment with GS-9620 can induce a durable therapeutic antiviral immune response during chronic hepadnavirus infection. In a previous study in chimpanzees chronically infected with HBV, GS-9620 treatment caused a sustained, albeit less marked reduction in viral load and HBsAg [10]. While studies are ongoing to define the cellular and molecular characteristics of the antiviral response to GS-9620, it likely involves local induction of IFN-α, as well as induction of antiviral NK and CD8+ T cell responses [[8], [31], [32]]. In addition, direct activation of B cells by GS-9620 may also be an important mechanism that contributes to viral clearance [33].

In summary, short duration treatment with GS-9620 induced a sustained antiviral response and anti-WHs antibody seroconversion in the woodchuck model of CHB. These data suggest that GS-9620 may have the potential to therapeutically induce sustained immunological control of chronic HBV infection in patients.

StephenW

讨论

WHV的感染旱獭与GS-9620治疗导致迅速，标记和持续的抗病毒反应。 GS-9620药效的反应是用TLR7激活一致，并与抗病毒疗效显着相关。重要的是，ISG诱导在慢性感染的土拨鼠的大小相似，诱导人类在良好耐受的剂量（附加表1）[11]。引人注目的是，在大多数慢性感染动物的GS-9620诱导的病毒载量，WHsAg损耗和抗WHS抗体血清转化的多对数减少，并降低的cccDNA水平和肝癌的发病率。具体地，减少病毒载量发生在15 19的已完成处理（无论方案的）土拨鼠和病毒载量的减少通过研究在这些15旱獭12的端被维持。持续WHsAg损失发生在13 15的完成治疗旱獭。重要的是，在13处理旱獭与WHsAg损失8，感应WHsAb的发生和持续。在GS-9620处理的土拨鼠即有持续减少病毒载量，肝细胞癌的发生率小于10％，相比之下，超过70％，而安慰剂组的速率。

诱导GS-9620的抗病毒反应的显然不同于那些在慢性乙型肝炎的土拨鼠模型评估核苷（酸）的IDE观察。而病毒载量减少的持续时间显着较长用GS-9620相比，与核苷（酸）的IDE类似治疗，最重要的发现是，与此相反的GS-9620，核苷（酸）的ide治疗诱导的持续损失WHsAg在只有少数WHV感染土拨鼠和诱导抗WHsAb的是罕见的[3]，[14]]。在该模型中的其它治疗策略包括治疗性疫苗接种的PD-L1的IL-12基因治疗和抑制[24]，[25]，[26]]。虽然，在某些情况下，这些疗法已产生暂态减少病毒载量，WHsAg和诱导抗WHsAb的，没有单一试剂已报道诱导到GS-9620可比的抗病毒反应。最值得注意的是，尽管治疗的慢性感染土拨鼠用重组土拨鼠IFN-α强烈降低血清WHV DNA和WHsAg在一些治疗的动物中，这是没有伴随着抗WHsAb血清转化中最旱獭一个瞬态响应（Menne S，未发表的数据）。

类似于HBV感染黑猩猩[10]先前的一份报告，GS-9620治疗土拨鼠与血小板减少和肝酶升高有关。这些不利的影响是短暂的，与逆转度假剂量，降低了发病率和严重程度与低剂量，并通过常规临床实验室参数进行了监测。增加肝酶，指出在一些动物在所有群体，包括安慰剂治疗的动物，并且是可逆的，在大多数情况下，没有剂量减少或停止治疗。通过该GS-9620治疗导致血小板减少土拨鼠的机制尚不清楚。然而，最近的报告表明，TLR7表达在血小板，即TLR7活化可诱导血小板计数的减少与血栓形成性能没有影响，而这些影响增强宿主的免疫应答和存活病毒感染[27]。如在GS-9620治疗的动物注意肝酶升高是时间上与降低肝相关的cccDNA，肝酶升高可能代表免疫介导的杀伤感染的肝细胞。这是一个带有肝内细胞毒性CD8 + T细胞和/或NK细胞的转录签名的诱导过程中的GS-9620治疗是一致的。值得注意的是，短暂增加，肝酶常常先于急性肝DNA病毒感染的土拨鼠，黑猩猩和人间隙，并且被认为是代表了有效肝内抗病毒免疫的发展[[28]，[29]，[30]]。

结果表明，与GS-9620短持续时间的治疗可诱导在慢性肝DNA病毒感染的持久治疗的抗病毒免疫应答。在先前的研究中慢性乙型肝炎病毒感染，GS-9620治疗的黑猩猩引起了持续的，尽管不那么明显减少病毒载量与HBsAg [10]。而研究正在进行以限定到GS-9620的抗病毒应答的细胞和分子的特性，它可能涉及局部诱导的IFN-α，以及诱导的抗病毒NK细胞和CD8 + T细胞应答[8]，[31] [32]。此外，由GS-9620直接激活B细胞也可以是有利于病毒清除[33]的重要机制。

综上所述，随着GS-9620短治疗时间致慢性乙型肝炎的土拨鼠模型持续的抗病毒反应和抗WHS抗体阳转。这些数据表明，GS-9620可能必须治疗诱导的慢性HBV感染的患者持续免疫控制的潜力。

M15399835388

有希望么

StephenW

回复 M15399835388 的帖子

应该有, 人类首次临床试验, 结果一般. 现在，在第2阶段 (Phase 2)

M15399835388

回复 StephenW 的帖子

有希望就好

newchinabok

小期待，gs9620几月出结果？八月份吗？

战天斗hbv

newchinabok 发表于 2015-5-21 15:47
小期待，gs9620几月出结果？八月份吗？

Estimated Enrollment:        150
Study Start Date:        June 2014
Estimated Study Completion Date:        June 2016
Estimated Primary Completion Date:        September 2015 (Final data collection date for primary outcome measure)

战天斗hbv

newchinabok 发表于 2015-5-21 15:47
小期待，gs9620几月出结果？八月份吗？

现在ARC520和9620还有4774都改变策略了、以治愈病毒抑制患者为目标