核酸聚合物：D型肝炎急需的希望？

StephenW

www.natap.org

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Nucleic acid polymers: much-needed hope for hepatitis D?

Lancet Gastroenterology& Hepatology - *Dulce Alfaiate, Francesco Negro
Department of Pathology and Immunology, University of Geneva,
Geneva 1211, Switzerland (DA); and Divisions of Gastroenterology
and Hepatology and Clinical Pathology, University Hospitals of
Geneva, Geneva, Switzerland (FN)


In the Lancet Gastroenterology & Hepatology, Michel Bazinet and colleagues1 describe the results of a phase 2 clinical trial on the safety and efficacy of combined treatment with the nucleic acid polymer REP 2139 and pegylated interferon alfa-2a for treatment of patients with chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection.

Chronic hepatitis D is considered the most severe and most difficult form of chronic viral hepatitis to treat. Despite affecting an estimated 15–20 million people worldwide, often in impoverished settings, the allocation of resources for the treatment of chronic hepatitis D is low compared with other chronic infections of similar prevalence.2 At present, pegylated interferon alfa-2a is the only approved therapy for chronic hepatitis D, for which only a minority of patients are eligible because of the known safety issues of the drug.3 Moreover, response rates are poor and late relapses are common, highlighting the urgent need for new therapeutic strategies.4

Nucleic acid polymers have shown antiviral activity against HBV, both in experimental models and in a proof-of-concept clinical trial.5 The proposed mechanism of action involves both the inhibition of viral entry and, most importantly, the blockade of hepatitis B virus surface antigen (HBsAg) release and secretion of subviral particles, enabling restoration of the host immune response against the virus.5 Because HDV is a defective virus that also depends on HBsAg for its assembly and is hypothesised to use the subviral particle secretion pathway for its egress,6 these molecules are very attractive candidates to target HDV.

In this proof-of-principle trial by Bazinet and colleagues,1 12 patients, all without cirrhosis, received REP 2139, first as monotherapy for 15 weeks and then combined with pegylated interferon alfa-2a for another 15 weeks, followed by a 33 week course of pegylated interferon alfa-2a monotherapy. Substantial declines in both HBsAg concentrations and HDV RNA were observed by the end of REP 2139 monotherapy, which remained stable in most patients for 1 year after treatment withdrawal. The regimen also appeared to be relatively safe, despite the induction of pronounced alanine aminotransferase flares in some patients, which might limit the applicability of the treatment for patients with cirrhosis. Although these results appear promising, a more thorough evaluation of these molecules is warranted to validate their use.

First, the results of this uncontrolled study must be confirmed by a randomised controlled trial that includes at least a pegylated interferon alfa-2a monotherapy arm. Indeed, although all patients were reported to have had HDV infection for more than 1 year before treatment and the decline of HDV RNA and HBsAg concentrations was faster than that expected during the natural course of disease, data on IgM antibodies against hepatitis B core antigen were not provided. Thus, the possibility that some enrolled patients had a protracted acute HDV infection that spontaneously cleared cannot be excluded.

Second, the possibility of late relapses must be carefully ruled out, not only because they are common in patients with chronic hepatitis D infection who receive pegylated interferon alfa-2a,4 but also because in the authors' previous study7 on the efficacy of REP 2139 in patients with chronic HBV infection, relapses occurred as late as 123 weeks after treatment withdrawal, supporting the possibility of a transient, incomplete viral clearance. Long-term follow-up will also allow the risk of complications associated with the intrahepatic accumulation of viral products to be investigated.

Beyond the clinical implications, this study raises interesting questions about the effects of nucleic acid polymers on the life cycle of HDV. In most patients a steep decline in serum HDV RNA was observed before the introduction of pegylated interferon alfa-2a, which is consistent with the proposed inhibition of HBsAg assembly and egress by nucleic acid polymers, although this mechanism of action remains to be investigated in the context of HDV infection. More importantly, in some patients, the HDV RNA decrease occurred irrespective of HBsAg decline, and preceded the increase in alanine aminotransferase concentration that occurred after the introduction of pegylated interferon alfa-2a, which indicates that substantial lysis of infected cells is an unlikely explanation. Furthermore, direct inhibition of HDV replication by nucleic acid polymers has been excluded in vitro,8 and the induction of the intracellular innate immune response has been ruled out in primary hepatocytes.9 In view of the likely accumulation of HDV viral components inside hepatocytes, indirect antiviral effects might be considered—eg, inhibition of viral replication induced by the large isoform of the HDV antigen.10 Studies that investigate intrahepatic viral markers are required to clarify the mechanism by which serum HDV RNA is decreased. The results of Bazinet and colleagues' study indicate that some degree of control of HBsAg secretion is necessary to maintain a virological response after treatment withdrawal because HDV rebound occurred only in patients in whom HBsAg loss was not achieved.

Although the results of the study by Bazinet and colleagues must be interpreted with caution, they indicate that nucleic acid polymers might represent a promising new therapy that provides effective, long-lasting, and safe control of chronic hepatitis D infection.

StephenW

www.natap.org

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核酸聚合物：D型肝炎急需的希望？

柳叶刀胃肠病学和肝病学 - * Dulce Alfaiate，弗朗切斯科黑人
日内瓦大学病理与免疫学系，
日内瓦1211，瑞士（DA）;和胃肠病科
和肝病学和临床病理学，大学医院
日内瓦，瑞士日内瓦（FN）


在Lancet胃肠病学和肝病学中，Michel Bazinet及其同事1描述了用核酸聚合物REP 2139和聚乙二醇干扰素α-2a联合治疗慢性乙型肝炎病毒患者的安全性和有效性的2期临床试验的结果（HBV）和丁型肝炎病毒（HDV）共同感染。

慢性丁型肝炎被认为是治疗慢性病毒性肝炎最严重和最困难的形式。尽管全世界估计有15-20万人受到影响，但常常在贫困的环境中，慢性丁型肝炎治疗的资源分配低于其他类似患病率的慢性感染.2目前，聚乙二醇化干扰素α-2a是唯一的批准的慢性丁型肝炎治疗方案，由于已知的药物安全问题，只有少数患者符合资格.3此外，应答率较差，后期复发较为常见，突出表明迫切需要新的治疗策略.4

核酸聚合物在实验模型和概念验证临床试验中都显示出抗HBV的抗病毒活性.5所提出的作用机制涉及抑制病毒进入，最重要的是阻断乙型肝炎病毒表面抗原（HBsAg）的释放和亚病毒颗粒的分泌，从而能够恢复宿主对病毒的免疫应答.5因为HDV是一种有缺陷的病毒，它也依赖于HBsAg的装配，并假设使用亚病毒颗粒分泌途径来出口，6这些分子是非常有吸引力的候选靶向HDV。

在Bazinet及其同事的这项原理验证试验中，共有112名患者（均无肝硬化）接受REP 2139，首先作为单药治疗15周，然后再与聚乙二醇化干扰素α-2a联合使用15周，接着使用33周聚乙二醇干扰素α-2a单药治疗过程。 REP 2139单药治疗结束时观察到HBsAg浓度和HDV RNA均显着下降，在停药后1年内大多数患者仍保持稳定。尽管在一些患者中诱导了显着的丙氨酸转氨酶闪光，但这种方案似乎相对安全，这可能限制了治疗肝硬化患者的适用性。虽然这些结果看起来很有希望，但是对这些分子的更全面的评估有必要验证它们的使用。

首先，这项不受控制的研究结果必须通过随机对照试验加以证实，该试验至少包括聚乙二醇化干扰素α-2a单药治疗组。事实上，尽管所有患者在治疗前都有1年以上的HDV感染，并且HDV RNA和HBsAg浓度的下降速度比疾病的自然病程中预期的要快，但抗乙型肝炎核心抗原的IgM抗体数据分别为不提供。因此，不能排除某些入选患者自发清除的长期急性HDV感染的可能性。

其次，必须认真排除晚期复发的可能性，这不仅仅是因为它们在接受聚乙二醇化干扰素α-2a治疗的慢性丁型肝炎感染患者中很常见，4也是因为在作者之前关于REP 2139疗效的研究中7在患有慢性HBV感染的患者中，停药后123周发生复发，支持暂时性，不完全病毒清除的可能性。长期随访也可以调查与肝内病毒产物积聚有关的并发症风险。
除了临床意义之外，这项研究提出了关于核酸聚合物对HDV生命周期影响的有趣问题。在大多数患者中，在引入聚乙二醇化干扰素α-2a之前观察到血清HDV RNA急剧下降，这与所提出的核酸聚合物抑制HBsAg组装和排出一致，尽管这种作用机制仍有待在HDV感染的情况。更重要的是，在一些患者中，无论HBsAg下降如何，在引入聚乙二醇化干扰素α-2a后出现的丙氨酸转氨酶浓度增加之前，HDV RNA降低发生，这表明受感染细胞的实质性裂解是不太可能的解释。此外，体外排除核酸聚合物对HDV复制的直接抑制[8]，原代肝细胞中排除了细胞内先天免疫应答的诱导[9]。鉴于肝细胞内HDV病毒组分可能积累，间接可考虑抗病毒作用 - 例如抑制由HDV抗原的大型同种型诱导的病毒复制[10]。研究肝内病毒标志物的研究需要阐明血清HDV RNA降低的机制。 Bazinet及其同事的研究结果表明，HBsAg分泌的某种程度控制对于治疗停药后维持病毒学应答是必要的，因为HDV反弹仅发生在HBsAg消失未达到的患者中。

尽管Bazinet及其同事的研究结果必须谨慎解读，但他们指出，核酸聚合物可能是一种有前途的新疗法，可提供对慢性丁型肝炎感染的有效，持久和安全的控制。