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安全和核酸聚合物在单药治疗的疗效和在治疗过的孟加拉例HB [复制链接]

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    PLoS One. 2016 Jun 3;11(6):e0156667. doi: 10.1371/journal.pone.0156667.
    Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection.Al-Mahtab M1, Bazinet M2, Vaillant A2.
    Author information
    • 1Bangabandhu Sheikh Mujib Medical University, Shahbagh Road, Dhaka-1000, Bangladesh.
    • 2Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P 2R2.


    AbstractPrevious in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2-7 log reductions of serum HBsAg, 3-9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10-1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT02646163 and NCT02646189.


    PMID:27257978 [PubMed - as supplied by publisher]  




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公共科学图书馆之一。 2016年6月3日; 11(6):e0156667。 DOI:10.1371 / journal.pone.0156667。
安全和核酸聚合物在单药治疗的疗效和在治疗过的孟加拉例HBeAg +慢性乙型肝炎病毒感染免疫治疗。
铝Mahtab M1,M2 Bazinet的威能A2。
作者信息

    1Bangabandhu谢赫穆吉布医科大学Shahbagh路,达卡 - 1000,孟加拉国。
    2Replicor公司,6100 Royalmount大道,蒙特利尔,魁北克,加拿大H4P 2R2。

抽象

以前的体内研究表明,核酸聚合物(行动方案)可以通过从感染的肝细胞,并且这种影响阻断其释放可具有临床效益降低血液中的HBsAg的循环水平。 NAP治疗,两个临床研​​究评价患者HBeAg阳性慢性HBV感染。该REP 101研究审查REP 2055单药治疗8例和REP 102研究审查REP 2139-CA,在单药治疗12例,其中9过渡到短期的联合治疗与聚乙二醇化干扰素α2a或胸腺素α1.在两项研究中NAP单一疗法伴随血清HBsAg的2-7数减少,3-9数减少血清HBV DNA和血清抗HBsAg抗体出现(10-1712 MIU / ml)中。 9例在REP 102学习过渡到以免疫治疗(聚乙二醇干扰素或胸腺素α1)联合治疗的经历八HBsAg消失,所有9名患者经历的治疗撤离前血清中抗乙肝表面抗原抗体滴度大幅增加。对于去除REP 2055的治疗后52周,血清病毒血症的反弹(HBV DNA> 1000拷贝/ ml,乙肝表面抗原> 1 IU / ml)的3/8例,没有观察到。血清virema抑制在这些患者中的2,继续保持290和231周。在过渡到联合治疗在REP 102研究的9例患者全部治疗停药后,8例患者达到HBV DNA <116拷贝/ ml治疗后停药。病毒反弹发生在7例患者,为期12至123个星期,但仍然没有在两名患者在135和137周的随访。与REP 2055年观察到的管理耐受性问题是罕见的与REP 2139钙,但REP 2139钙治疗伴有脱发,吞咽困难和被认为与在试验现场的重金属曝光地方性味觉障碍。这些初步研究表明,N​​AP可以治疗可提高免疫治疗的效果期间引发重要的抗病毒反应。行动方案可能是未来的联合疗法的慢性乙型肝炎的治疗潜在有用成分
试验注册:

ClinicalTrials.gov NCT02646163和NCT02646189。

结论:
    27257978
    [考研 - 由出版商提供]

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发表于 2016-6-5 12:26 |只看该作者
顶一下,关注

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发表于 2016-6-5 12:28 |只看该作者
Discussion
NAP tolerability

NAPs are phosphorothioated oligonucleotides (PS-ONs) whose antiviral effect against HBV infection is independent of nucleotide sequence [11, 12]. Unlike standard antisense compounds, NAPs can be more easily engineered to remove the secondary pro-inflammatory / immunostimulatory effects of single stranded nucleic acids while maintaining their antiviral activity in vivo [13, 15]. The primary tolerability issue with REP 2055 in the REP 101 study was IV administration related side effects similar to those reported for other PS-ONs administered to humans by IV infusion [16, 17] which was well controlled with REP 2139-Ca in the REP 102 study. Additionally, short term combination therapy with REP 2139-Ca and thymosin or peg-IFN up to 26 weeks was well tolerated. The liver flares during monotherapy with either REP 2055 or REP 2139-Ca occurred following initial reductions of serum HBsAg and HBV DNA, were self-resolving with continued NAP therapy and were not accompanied by any symptoms or serological evidence of liver dysfunction. These liver flares are also routinely observed with treatment with interferons, and are thought to be evidence of re-activation of immune function in the liver [18]. These liver flares may be evidence of reactivation of the immune response in the liver with reduction of circulating HBsAg (discussed below) but additional analysis of T-cell response during transaminase flares concomitant with serum HBsAg reduction in future trials will be required to address this hypothesis.

PS-ONs increase mineral elimination in the urine [19] and the resulting compensatory response includes liberation of mineral stores (along with heavy metals if present) from the bones into the circulation. All study patients and untreated control subjects at the trial site were shown to have substantial pre-existing heavy metal loads (data not shown) as a result of chronic heavy metal exposure known to be endemic at the trial site [20–22]. The 2’ ribose modifications present in REP 2139 are absent in REP 2055 (Fig 2) and serve to reduce immunoreactivity [23, 24] but also block degradation by endonucleases [25], rendering REP 2139 substantially more stable than REP 2055 and leading to greater accumulation of REP 2139-Ca in pre-clinical models with chronic exposure (A. Vaillant, unpublished data). Thus chronic exposure to REP 2139-Ca likely establishes a greater mineral elimination (and heavy metal liberation) than REP 2055, consistent with development of hair loss, dysphagia and dysgeusia observed in patients with REP 2139-Ca therapy but not with REP 2055.

These symptoms have not been previously reported with the clinical use of PS-ONs, however, these studies are the first to be conducted in a locale where substantial heavy metal exposure is highly endemic in the population. Importantly, in a currently ongoing clinical trial with REP 2139-Ca in Caucasian patients (REP 301 study, NCT02233075) in a European locale where patients with heavy metal exposure were excluded from participation, none of these symptoms have been observed with comparable REP 2139-Ca exposure in combination with peg-IFN (A. Vaillant, unpublished data).

These clinical observations underscore the importance of being aware of the potential complications of the enhanced mineral elimination known to occur with PS-ON therapy in general and further suggest that mineral supplementation should accompany any oligonucleotide based therapy, regardless of the disease state in patients receiving therapy.
Therapeutic implications of NAPs

Although further controlled trials will be required to confirm the initial safety observations and findings of antiviral activity observed in the proof-of-concept studies presented here, NAP monotherapy (either REP 2055 or REP 2139-Ca) was clearly accompanied by substantial reductions or clearance of serum HBsAg and appearance of anti-HBs < 10 mIU / ml with concomitant reductions in serum HBV DNA in 16 of 20 patients with HBeAg+ chronic HBV infection. These effects are very similar to the antiviral effects of REP 2055 reported in Pekin ducks with previously established persistent DHBV infection [13]. No evidence of virologic breakthrough was observed during NAP monotherapy lasting as long as 54 weeks or during combined treatment with immunotherapy in these initial studies. Moreover, two patients receiving an initial course of NAP therapy (REP 2055 in patients 2 and 7 in the REP 101 protocol), who experienced viral rebound during follow-up off-treatment responded identically with a second course of NAP therapy (REP 101 patient 2 responded to a second course of REP 2055 following viral rebound and in REP 101 patient 7, who became REP 102 patient 9, viral rebound after withdrawal of REP 2055 responded to REP 2139-Ca) suggesting the development of resistance to NAP therapy may be unlikely, however larger clinical trials will be required to ascertain if viral resistance to NAP therapy can occur.

The absence of rebound of HBV infection after cessation of REP 2055 treatment in 3/7 patients for 52 weeks parallels the sustained control of DHBV infection observed in vivo after REP 2055 monotherapy in ducks, which was correlated with transcriptional inactivation and clearance of cccDNA [13]. The more durable and complete suppression of serum viremia achieved in 2 patients who received REP 2055 monotherapy (where serum HBV DNA is not detectable and HBsAg is not currently detectable or detectable at residual levels, see Table 4) may reflect the establishment of control of cccDNA and / or integrated HBV genomes in these patients but this remains to be proven. More frequent dosing with REP 2055 appeared to improve the clearance of HBsAg and allow the achievement of serum HBsAg < LLOQ however similar reductions in serum HBsAg were achieved with REP 2139-Ca in the absence of periods of more frequent dosing which may be related to the increased stability of REP 2139.

When REP 2055 was used therapeutically in vivo against persistent DHBV infection, many animals maintained substantial titers of serum DHBV DNA with no detectable levels of serum DHBsAg, moreover at the end of REP 2055 treatment in many ducks, DHBsAg was readily detectable in the liver but not detectable in the serum, suggesting that NAPs selectively block the release of DHBV subviral particles from infected hepatocytes by REP 2055 [13]. The persistence of significant serum HBV DNA titers while serum HBsAg was maintained near or < LLOQ with REP 2055 or REP 2139-Ca monotherapy in human patients has striking similarity to these effects observed with REP 2055 in ducks. Given that subviral particles constitute the bulk of serum (D)HBsAg in both DHBV infected ducks and human HBV infection [2, 26], these correlative observations of the effects of NAP monotherapy in DHBV and HBV infection suggest that selective blockage of subviral particle secretion by NAPs may also be occurring in human patients.

The continued suppression of viremia after withdrawal of NAP therapy may be related to reduction or clearance of serum HBsAg during therapy. Serum HBsAg sequesters anti-HBs but importantly has also been shown to have direct immunoinhibitory properties in vitro and in vivo [27–32]. HBsAg is the most abundantly circulating viral antigen and it may exert direct inhibition of the immune response (both adaptive and innate) to HBV infection. Therefore, when HBsAg is removed or substantially lowered, some form of restoration of the host immune response may occur, allowing for a functional control of infection to be established which persists after NAP therapy is withdrawn.

REP 2139-Ca was safely combined with short term duration (12–26 weeks) of either thymosin or peg-IFN, which resulted in a rapid and robust increase in anti-HBs production in all patients. More importantly, even with short term exposure to these immunotherapies, serum viremia did not rebound after withdrawal of treatment in 8/9 patients and although variable in duration, remained suppressed for extended periods (> 2 years) in 3 / 9 patients, suggesting that restoration of immune control of infection with immunotherapy might be easier to achieve with this novel combination therapy approach. These effects suggest a potentially synergistic improvement in the antiviral effect of peg-IFN and thymosin when combined with REP 2139-Ca. This synergism may be related to the reduction or absence of serum HBsAg in these patients as sustained control of infection after peg-IFN monotherapy is highly correlated with HBsAg clearance [3, 4]. The HBsAg protein itself has been shown to have direct immunoinhibitory properties on both innate and adaptive immune function [27–32] which may also interfere with the downstream effects of immunotherapeutic agents.

The persistence of serum HBV DNA in the absence of detectable serum HBsAg and in the presence of anti-HBs > 10 mIU / ml is a highly unusual clinical observation that was nevertheless common with NAP treatment in both REP 101 and 102 protocols and raises some important theoretical considerations: the amount of HBsAg present in the titers of HBV DNA persisting when serum HBsAg is < LLOQ may be below the LLOQ of the HBsAg test or may indicate the presence of immune escape HBV variants, which have been previously documented in human HBV infection [33–36]. Evaluation of the population genotypes of the HBV present in these patients during NAP therapy by deep sequencing is currently underway and may help to answer some of these questions. Fluctuations in anti-HBs levels were observed in the REP 101 study during treatment while HBsAg and HBV DNA declines were stable. However, fluctuations in serum anti-HBs were not observed in the REP 102 study during monotherapy. REP 2139 is significantly more stable than REP 2055 in human plasma (as discussed above) and may provide a more uniform antiviral effect between weekly doses than REP 2055. This reduced stability of REP 2055 could be an underlying factor in the fluctuating antibody response observed in the REP 101 study.
Future prospects

Both the REP 101 and 102 trials presented in this article and a third trial (REP 201 –NCT02726789) have been previously disclosed [37]. The REP 201 trial was a very small exploratory trial where REP 2139-Ca treatment with a full course of peg-IFN was attempted in three treatment naïve patients and two patients concurrently receiving ETV. Although similar responses in serum HBsAg, anti-HBs and HBV DNA were observed during treatment as in the REP 102 protocol, the very small patient numbers employed prevent conclusions on improvements in antiviral performance relative to those seen in the REP 102 trial. However the REP 201 trial suggests that NAPs might be used safely in combination with peg-IFN and ETV or other nucleos(t)ide based HBV polymerase inhibitors. This triple combination approach is currently being evaluated in patients with HBeAg negative chronic HBV infection in the REP 401 protocol (NCT02565719, see below).

The results of the REP 101 and REP 102 studies describe the preliminary steps of the development of NAPs for treatment of chronic HBV infection. They indicate that continued clinical evaluation of the antiviral efficacy of NAP-based combination therapy in chronic HBV infection is warranted. Although control groups were not possible in these studies, effective clearance of HBsAg and HBV DNA and the appearance of anti-HBs is unusual. Of greater potential interest is the potential synergistic improvement in the antiviral effects of immunotherapeutic agents when combined with NAP therapy as these might potentially be related to HBsAg reduction. Even with a limited course of immunotherapy, 8/9 patients were able to maintain suppression of serum viremia off-treatment, with many of these maintaining suppression longer than 1 year.

The proportion of patients able to maintain suppression of viremia off-treatment and the duration of this suppression may be significantly improved if NAP therapy was combined with a full course of immunotherapy (i.e. 48 weeks) or if used in combination therapy in patients already seroconverted for HBeAg or currently receiving therapy with ETV or TDF, agents which have been shown to lower intrahepatic cccDNA levels [38, 39]. These concepts are currently being evaluated in the protocol REP 401 protocol (NCT02565719), a randomized, controlled trial assessing the safety and efficacy of triple combination antiviral therapy with NAPs, peg-IFN and TDF in Caucasian patients with HBeAg negative chronic HBV.

Finally, additional trials with REP 2139-Ca should be conducted in patients from diverse ethnic groups and harbouring different HBV genotypes to investigate if the antiviral responses with NAP therapy observed in the patients in these studies could also be achieved in patients from other geographic regions.

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发表于 2016-6-5 12:29 |只看该作者
讨论
NAP耐受性

国家行动方案硫代磷酸酯,其抗病毒作用预防HBV感染是独立的核苷酸序列[11,12]寡核苷酸(PS-ONS)。不同于标准的反义化合物,行动方案可以更容易地设计,以除去单链核酸的二级促炎性/免疫刺激作用,同时保持它们在体内的抗病毒活性[13,15]。与在所述REP 101研究REP 2055主耐受性问题是IV施用相关的副作用类似于报道了通过IV输注[16,17]这是在REP与REP 2139钙很好地控制给药于人类以外的PS-寡核苷酸102研究。此外,随着REP 2139-Ca和胸腺肽或PEG-IFN最多26周的短期联合治疗的耐受性良好。单药治疗期间肝脏耀斑无论是与2055 REP REP或2139钙发生以下血清HBsAg和HBV DNA的初始减少,是自我解决与持续NAP治疗和不伴有任何症状或肝功能不全的血清学证据。这些肝耀斑也经常与治疗观察干扰素,和被认为是免疫功能的肝脏中[18]重新活化的证据。这些肝耀斑可以是将被要求来解决这一假说与还原循环的HBsAg(下面讨论),但在用在未来的试验血清HBsAg减少伴随转氨酶耀斑T细胞应答的附加分析的肝的免疫应答的活化的证据。

PS附件增加矿物质消除尿[19]中,所得代偿性反应,包括矿物门店解放从骨子里进入循环(重金属如果存在一起)。所有研究患者和未治疗的对照组受试者在试验现场被证明有大量的预先存在的重金属负载(数据未显示)已知是在试验现场[20-22]地方性慢性重金属暴露的结果。 2'中存在的REP 2139核糖修改是在REP 2055(图2)不存在,并且用于降低免疫反应性[23,24],但也通过内切核酸酶方框降解[25],比REP 2055渲染REP 2139基本上更稳定,并导致在临床前模型慢性曝光(A.威能,未发表的数据)REP 2139钙更大积累。因此,长期暴露于REP 2139-CA有可能建立一个更大的矿物消除(及重金属解放),比2055 REP,脱发,吞咽困难和味觉障碍观察患者REP 2139钙治疗的发展相一致,但不与REP 2055。

这些症状与临床使用PS的插件报道过,然而,这些研究是在一个区域,其中大量的重金属暴露在人群中高度流行将进行了第一次。重要的是,在患者​​的重金属曝光被排除在参与欧洲区域当前进行的临床试验REP 2139钙的白人患者(REP 301研究,NCT02233075),没有这些症状已观察到具有可比性REP 2139-曝光钙结合PEG-IFN(A.威能,未公布的数据)。

这些临床观察强调的意识到增强矿物消除已知与PS-ON疗法一般地发生,并进一步表明,矿物质补充剂应伴随任何基于寡核苷酸的治疗的潜在并发症的重要性,无论疾病状态在接受治疗的患者。
国家行动方案的治疗意义

虽然进一步的对照试验将被要求确认这里提出的初步安全性观察和验证的概念研究中观察到的抗病毒活性的研究结果,NAP单药治疗(无论是REP 2055或REP 2139-CA)显然是伴随着大幅减少或清除的血清HBsAg和抗-HBs <10 MIU /毫升血清的HBV DNA相应减少20 16例HBeAg +的慢性HBV感染的外观。这些效果都非常相似,在北京鸭与先前建立的持续DHBV感染[13]报道REP 2055的抗病毒效果。 NAP单一疗法持续只要多达54个星期内,或者在这些初步的研究免疫联合治疗过程中观察到的病毒学突破没有证据。另外,两次后续断处理期间接收的NAP疗法,谁经历病毒反弹(患者2和7中所述REP 101协议REP 2055)的初始过程的患者与NAP疗法的第二个疗程相同回应(REP 101患者2回答REP 2055第二个疗程以下病毒反弹和REP 101例7,谁成为REP 102例9,REP 2055停药后病毒反弹回应REP 2139-CA)暗示性的发展,NAP治疗可能是不可能的,但是较大的临床试验将被要求,以确定是否向NAP治疗病毒抵抗可能发生。

在3/7患者REP 2055停止治疗后没有HBV感染的反弹52周平行DHBV感染鸭体内观察到的REP 2055单药治疗后,这与cccDNA的转录失活和清除[13相关的持续控制]。在谁收到REP 2例达到的血清病毒血症更耐用和完全抑制2055单一疗法(其中血清HBV DNA是不可检测与HBsAg不是当前在残余量检测的或可检测的,见表4)可以反映建立的cccDNA的控制的和/在这些患者中或整合的HBV基因组,但是这有待证实。更频繁给药与REP 2055出现改善乙肝表面抗原的清除,并允许在血清HBsAg血清HBsAg <LLOQ但是类似削减的成果用REP 2139钙的缺乏更频繁给药的周期可能会涉及到实现增加REP 2139的稳定性。

当REP 2055在针对持续DHBV感染体内治疗上使用,许多动物保持血清DHBV DNA的大量滴度血清DHBsAg的没有可检测的水平,而且在许多鸭子REP 2055治疗结束,DHBsAg是在肝脏中容易检测的,但在血清中未检测到,这表明行动方案通过REP 2055 [13]选择性地阻断从感染的肝细胞DHBV亚病毒颗粒的释放。显著血清HBV DNA滴度,而血清HBsAg是在人类患者维持在接近或<LLOQ与REP 2055或2139 REP钙单药治疗的持久性有惊人的相似这些影响与鸭REP 2055遵守。鉴于亚病毒颗粒构成散装血清(D)的HBsAg的两个DHBV感染鸭和人类HBV感染[2,26],在DHBV和HBV感染的NAP单一疗法的效果,这些相关的观察表明,亚病毒粒子分泌的选择性堵塞由国家行动方案也可以在人患者中发生。

NAP治疗的停药后病毒血症的持续抑制可能与治疗期间降低或血清HBsAg的间隙。血清HBsAg螯合抗-HBs,但重要的是也已显示出在体外和体内[27-32]直接免疫抑制性质。乙肝表面抗原是最丰富的循环病毒抗原,它可能产生的免疫反应(包括自适应和天生的)HBV感染的直接抑制。因此,当HBsAg的除去或基本上降低,可能会发生某种形式的宿主免疫应答的恢复,允许感染要建立的功能性控制的NAP疗法被撤回之后仍然存在。

REP 2139钙被安全地或者胸腺素或PEG-IFN,这导致了在所有患者快速和强大的增加抗HBs生产短期持续时间(12-26周)相结合。更重要的是,甚至与短期暴露于这些免疫治疗,血清病毒血症没有在8/9的患者治疗的停药后反弹,尽管可变的持续时间,仍然在九分之三患者抑制长时间(> 2年),这表明感染免疫的免疫控制的恢复可能会更容易实现与这种新颖的联合治疗方法。当与REP 2139钙结合这些效果表明在PEG-IFN和胸腺素的抗病毒效果的潜在协同改进。后PEG-IFN单一疗法高度与HBsAg清除相关本增效可能与在这些患者感染的持续控制的减少或不存在血清的HBsAg [3,4]。所述的HBsAg蛋白质本身已被证明对先天性和适应性免疫功能[27-32],它也可以与免疫治疗剂的下游效应干扰直接免疫抑制性质。

血清HBV DNA在不存在可检测的血清的HBsAg和抗-HBs> 10 MIU / ml的存在下的持久性是极不寻常的临床观察,这是仍然共同与两个REP 101和102的协议的NAP治疗和提出了一些重要的理论考虑:HBsAg的存在于HBV DNA的滴度的量持续时血清HBsAg是<LLOQ可以是乙肝表面抗原的测试的LLOQ低于或可指示免疫逃逸的HBV变体,其在人类HBV感染先前记录的存在[33-36]。目前这些患者HBV通过深度测序NAP治疗期间的人口基因型的评估正在进行,并可能有助于回答一些问题。在REP 101研究中观察治疗过程中抗-HBs水平的波动,而HBsAg和HBV DNA下降是稳定的。然而,血清中的抗-HBs的波动没有在REP 102研究单一疗法过程中观察到。 REP 2139是显著比REP 2055人血浆中更稳定的(如以上所讨论的),并且可以提供每周剂量之间的更均匀的抗病毒效果比REP 2055这种减小REP 2055的稳定性可能是在观察到的波动抗体应答的潜在因素REP的101研究。
前景

无论是REP 101和102的试验本文中介绍和第三审判(REP 201 -NCT02726789)此前已公开[37]。该REP 201试验是一个非常小的探索性试验,其中试图在三个治疗初治患者,2例同时接收ETV与PEG-IFN的全部课程REP 2139-Ca处理。虽然处理,在所述REP 102协议期间未观察到血清HBsAg,抗-HBs和HBV DNA类似的反应,使用的非常小的患者数量防止在相对于那些在REP 102试验看出抗病毒药性能改进的结论。然而,REP 201试验表明,国家行动方案可能会在PEG-IFN和ETV或其他核苷(酸)基于IDE HBV聚合酶抑制剂联合使用安全。这三重组合的方式,目前正在治疗HBeAg阴性慢性HBV感染的REP 401协议评估(NCT02565719,见下文)。

在REP 101和REP 102研究的结果说明治疗慢性HBV感染的国家行动方案的初步发展步骤。他们表明,慢性HBV感染者的NAP联合用药的抗病毒疗效的持续临床评估是必要的。尽管对照组在这些研究中是不可能的,HBsAg和HBV-DNA的有效清除和抗-HBs的外观是不寻常的。更大的潜在兴趣是免疫治疗药物的抗病毒效果的潜在协同改进时与NAP结合治疗,因为这些可能潜在地与HBsAg的减少。甚至与免疫治疗的有限当然8/9患者能够维持血清病毒血症断处理抑制,许多这些维持抑制长于1年。

的能够维持病毒血症断处理和这种抑制的持续时间抑制患者的比例可能会如果NAP治疗与免疫疗法(即48周)的全部课程组合而显著改善或如果在联合治疗中的患者使用已经血清转变为e抗原或与ETV或TDF目前接受治疗,这已被证明剂降低肝内cccDNA的水平[38,39]。这些概念目前在协议REP 401协议(NCT02565719),评估了随机对照试验评估三联抗病毒治疗与国家行动方案,PEG-IFN和TDF在白人患者HBeAg阴性慢性乙肝的安全性和有效性。

最后,REP 2139钙更多的审判,应在患者来自不同族群进行,窝藏不同HBV基因型调查,如果用在患者中观察到这些研究NAP治疗的抗病毒反应也可以从其他地理区域的患者来实现。

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发表于 2016-6-5 12:30 |只看该作者

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发表于 2016-6-5 19:08 |只看该作者
回复 StephenW 的帖子

老兄能否概括几句话啊??

好消息还是坏消息???

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发表于 2016-6-5 21:12 |只看该作者
回复 hao2014 的帖子

不容易回答你的问题. 论文提供了大量有关REP9AC细节: 功效(治疗期间和治疗后,副作用). 我不明白一切, 有好消息, 有坏消息, 有更多疑问.
目前我个人的意见:
好消息 - NAP(REP2055, REP2139-CA)可以显著降低血清HBsAg 和 增加乙肝HBsAb.
坏消息 - REP2139-CA有副作用 - mineral elimination矿物消除(及heavy metal release重金属解放)导致(??) 脱发, dysgeusia味觉障碍, dysphagia吞咽困难.

疑问 - 在一些HBeAg阳性患者, 治疗可导致(HBV DNA < 1000 copies / ml and HBsAg < 1 IU / ml)很长一段的时间 - 该机制是什么?

这些都只是我个人的,非专家的意见.
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