乙型肝炎治疗：我们现在所知道的以及还有待研究的内容。

StephenW

Hepatol Commun. 2018 Nov 15;3(1):8-19. doi: 10.1002/hep4.1281. eCollection 2019 Jan.
Hepatitis B Treatment: What We Know Now and What Remains to Be Researched.
Suk-Fong Lok A1.
Author information
Abstract

Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, two types of treatment, interferons (IFNs) and nucleos(t)ide analogues (NAs), have been approved. These treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. However, these treatments do not eliminate the virus, and the risk of HCC remains. This review article summarizes current knowledge about the safety, efficacy, and clinical indications of hepatitis B treatment. It also discusses limitations of existing treatment, gaps in knowledge, and feasibility of a hepatitis B cure.

PMID:
    30619990
PMCID:
    PMC6312657
DOI:
    10.1002/hep4.1281

StephenW

Hepatol Commun。 2018年11月15日; 3（1）：8-19。 doi：10.1002 / hep4.1281。 eCollection 2019年1月
乙型肝炎治疗：我们现在所知道的以及还有待研究的内容。
Suk-Fong Lok A1。
作者信息
抽象

慢性乙型肝炎病毒（HBV）感染仍然是全球主要的健康负担。 目前，已经批准了两种类型的治疗，干扰素（IFN）和核苷（t）ide类似物（NAs）。 这些治疗方法可有效抑制HBV复制，降低肝硬化，肝功能衰竭，肝细胞癌（HCC）和死亡的风险。 然而，这些治疗并没有消除病毒，并且HCC的风险仍然存在。 本综述文章总结了目前关于乙型肝炎治疗的安全性，有效性和临床适应症的知识。 它还讨论了现有治疗的局限性，知识差距以及乙型肝炎治愈的可行性。

结论：
    30619990
PMCID：
    PMC6312657
DOI：
    10.1002/ hep4.1281

StephenW

Recent studies suggest paradoxically that, for patients who are HBeAg‐negative who had been virally suppressed for >2 to 3 years, withdrawal of an NA may be associated with a higher rate of HBsAg loss compared to those who continued the NA.39-41 This has led the APASL and EASL guidelines to include a provision for such an approach as long as patients agree to close monitoring after treatment is discontinued. However, outcomes, including risks of hepatic decompensation, frequency of monitoring, and criteria for resuming treatment, need to be studied in larger cohorts before this approach is widely adopted.

The reason for a higher rate of HBsAg loss after NA withdrawal is unclear. It has been postulated that viral relapse after a long duration of virus suppression may mimic acute hepatitis B, provoking a rigorous immune response to HBV leading to HBsAg loss. Among patients who experienced clinical relapse, one study found that those who did not resume treatment had a higher rate of HBsAg loss than those who did, suggesting that HBsAg loss is more likely to occur if immune clearance is allowed to proceed and not be curbed too soon. However, overly rigorous or prolonged immune lysis of infected hepatocytes can result in liver failure. Moreover, this same study showed that patients who had no viral relapse and those who had viral but not clinical relapse had higher rates of HBsAg loss than those who had clinical relapse, indicating that hepatitis flares are not required for HBsAg loss.40
最近的研究表明，对于HBeAg阴性且病毒被抑制超过2至3年的患者，与继续使用NA的患者相比，撤销NA可能与较高的HBsAg丢失率相关.39-41这导致APASL和EASL指南包括这种方法的规定，只要患者同意在停止治疗后进行密切监测。然而，在广泛采用这种方法之前，需要在更大的队列中研究结果，包括肝功能失代偿的风险，监测频率和恢复治疗的标准。

NA停药后HBsAg丢失率较高的原因尚不清楚。据推测，长期病毒抑制后病毒复发可能模拟急性乙型肝炎，引起对HBV的严格免疫反应，导致HBsAg丢失。在经历过临床复发的患者中，有一项研究发现那些没有恢复治疗的患者HBsAg丢失率高于那些患者，这表明如果允许进行免疫清除并且不被抑制，则更有可能发生HBsAg丢失。不久。然而，感染的肝细胞的过度严格或延长的免疫裂解可导致肝衰竭。此外，同样的研究表明，没有病毒复发的患者和病毒复发但未复发的患者HBsAg丢失率高于临床复发患者，表明HBsAg丢失不需要肝炎发作.40

StephenW

Future of HBV Treatment

The availability of a simple, safe, and highly effective cure for hepatitis C has reenergized the search for a cure for hepatitis B. However, as described earlier, a sterilizing cure with elimination of both cccDNA and integrated HBV DNA may not be possible. Instead, experts agree that a functional cure akin to spontaneous HBsAg loss in patients with chronic HBV infection may be a realistic goal.3 The endpoint would be HBsAg loss accompanied by HBeAg loss and undetectable HBV DNA in serum, but HBV DNA may persist in the liver as integrated HBV DNA and as transcriptionally inactive cccDNA. Progression of liver disease would be halted, and over time fibrosis would regress and the incidence of HCC would decrease. Whether seroconversion to hepatitis B surface antibody is necessary to prevent HBsAg seroreversion remains to be determined. This functional cure is currently achievable in a small percentage (<10%) of patients after IFN or NA therapy. The vision for the future is to deploy a combination of antiviral drugs directed against new targets and immunomodulatory therapies to restore innate as well as adaptive immune responses with the goal of achieving HBsAg loss in a higher percentage (>50%) of patients after a finite course (≥2 years) of treatment. These new strategies may or may not include IFN or NAs.

New antiviral drugs in clinical trials include entry receptor inhibitors, capsid assembly modifiers, RNA interference, and nucleic acid polymers.3 To date, capsid assembly modifiers have shown promising results, but the effect on HBsAg levels has been modest and there is a concern for antiviral drug resistance. RNA interference has been shown to result in >1 log decrease in HBsAg levels, but it has to be administered as injections and there is a concern for off‐target effects. Studies of nucleic acid polymers have shown a high rate of HBsAg loss, but the design of those studies is complex, the exact mechanism of action of nucleic acid polymers is unclear, and marked ALT flares were observed in a high percentage of patients; thus, safety needs to be established and efficacy needs to be confirmed. To date, studies of immune modulatory therapies, including therapeutic vaccines to stimulate T‐cell response and toll‐like receptor agonists to enhance innate immune response, have had limited success. Given the recent success of immune therapies in oncology, enthusiasm for immune modulatory therapies, including check‐point inhibitors and engineered T cells, remains high. A major concern of immune modulatory therapies is uncontrolled immune activation leading to fatal hepatitis flares or extrahepatic organ damage.

Major challenges with developing new drugs for hepatitis B include safety (given the excellent safety profile of NAs), ease of administration (NAs are taken as pills once a day), and cost (ETV and TDF are both off patent). However, given the high global burden of hepatitis B, the desire to achieve a “cure” with a finite course of therapy, and the need to effectively control HBV replication at an early stage of chronic HBV infection, it is hoped that there will be sufficient interest and commitment from the pharmaceutical industry and the scientific community to work together to make an HBV cure a reality in the not too distant future.
HBV治疗的未来

对丙型肝炎的简单，安全和高效治疗的可用性重新激发了寻找乙型肝炎的治疗方法。然而，如前所述，消除cccDNA和整合的HBV DNA的消毒治疗可能是不可能的。相反，专家们认为慢性HBV感染患者的自发性HBsAg丢失的功能性治疗可能是一个现实的目标.3终点是HBsAg丢失伴有HBeAg丢失和血清中检测不到的HBV DNA，但HBV DNA可能持续存在于血清中。肝脏作为整合的HBV DNA和转录无活性的cccDNA。肝病的进展将停止，并且随着时间的推移纤维化将退化并且HCC的发病率将降低。是否需要血清转化为乙型肝炎表面抗体以防止HBsAg血清转换仍有待确定。目前，这种功能性治愈在IFN或NA治疗后的一小部分（<10％）患者中是可实现的。未来的愿景是部署针对新靶点和免疫调节疗法的抗病毒药物组合，以恢复先天性和适应性免疫应答，目标是在有限的患者中实现更高百分比（> 50％）的HBsAg损失。当然（≥2年）治疗。这些新策略可能包括也可能不包括IFN或NA。

临床试验中新的抗病毒药物包括进入受体抑制剂，衣壳组装修饰剂，RNA干扰和核酸聚合物.3迄今为止，衣壳组装修饰剂已显示出有希望的结果，但对HBsAg水平的影响不大，并且存在一个问题。抗病毒药物耐药性。已显示RNA干扰导致HBsAg水平降低> 1log，但它必须作为注射剂施用，并且存在脱靶效应的担忧。对核酸聚合物的研究表明HBsAg损失率很高，但这些研究的设计很复杂，核酸聚合物的确切作用机制尚不清楚，并且在高比例的患者中观察到明显的ALT突发;因此，需要建立安全性并且需要确认疗效。迄今为止，免疫调节疗法的研究，包括用于刺激T细胞应答的治疗性疫苗和用于增强先天免疫应答的Toll样受体激动剂，已经取得了有限的成功。鉴于最近肿瘤学免疫疗法的成功，对免疫调节疗法（包括检查点抑制剂和工程化T细胞）的热情仍然很高。免疫调节疗法的主要问题是不受控制的免疫激活，导致致命的肝炎突发或肝外器官损伤。

开发乙型肝炎新药的主要挑战包括安全性（鉴于NAs的优良安全性），易于给药（每天一次服用NAs）和成本（ETV和TDF均未获得专利）。然而，鉴于乙型肝炎的全球负担很高，希望通过有限疗程实现“治愈”，并且需要在慢性HBV感染的早期阶段有效控制HBV复制，希望会有制药业和科学界有足够的兴趣和承诺共同努力，在不久的将来使HBV治愈成为现实。

StephenW

https://aasldpubs.onlinelibrary. ... l/10.1002/hep4.1281