慢性乙型肝炎免疫治疗进展

目前核苷和核苷酸类药物及IFNα对慢性乙型肝炎(CHB)患者的治疗效果仍有限,因此,开发更有效的治疗策略来提高CHB的疗效至关重要。介绍了CHB的免疫治疗,包括治疗性疫苗(蛋白类疫苗、DNA疫苗、树突状细胞疫苗)和细胞调节治疗。认为免疫治疗是治疗HBV感染的一个很有前景的治疗方案。随着对HBV感染后临床转归机制的进一步深入研究,CHB的免疫治疗研究也取得了显著进展。     

免疫调节剂在慢性乙型肝炎治疗中的应用进展

乙型肝炎病毒(HBV)感染患者使用抗病毒药物能够控制病毒复制和延缓肝硬化的进展,但无法实现慢性乙型肝炎(CHB)的彻底治愈.免疫调节治疗通过打破CHB患者对HBV的免疫耐受及恢复免疫功能失调,有望实现CHB完全治愈.目前用于治疗CHB的免疫调节剂包括RIG-1激动剂、TLR激动剂、免疫检查点抑制剂、治疗性疫苗、细胞凋亡...     

慢性乙型肝炎免疫治疗新策略

慢性乙型肝炎(CHB)是全球重要的传染病之一,目前主要的治疗药物为干扰素与核苷和核苷酸类药物,具有较好疗效,但尚未达到彻底清除人体内HBV的最终目标。因此,探索治疗新策略以及研发新的治疗药物有重要意义。HBV的持续感染与机体内免疫状态密切相关,目前研究表明免疫治疗有助于实现彻底治愈CHB。结合CHB患者的免疫状态,综述了Toll样受体激动剂、细胞治疗、治疗性疫苗等免疫治疗新策略的研究进展。     

靶向适应性免疫治愈慢性乙型肝炎策略及进展

慢性乙型肝炎(CHB)是全球重大公共卫生问题,虽然直接抗病毒药物可以控制HBV复制但难以实现治愈CHB。宿主适应性免疫应答在清除HBV过程中发挥关键作用,通过重建患者适应性免疫有望实现CHB的功能性治愈。治疗性疫苗、细胞免疫治疗、免疫检查点阻滞、T淋巴细胞代谢重编程、中和抗体靶向适应性免疫治疗乙型肝炎的策略取得较大进展。总结了近年来上述乙型肝炎的疗法。     

阿德福韦酯对慢性乙型肝炎患者外周血H B c A g特异性CTL的影响

目的: 探讨阿德福韦酯(ADV)对慢性乙型肝炎(CHB)患者外周血中HBcAg特异性CTL数量的影响.方法: 选择应用ADV治疗48 wk的HLA-A2阳性CHB患者11例作为研究对象, 应用Tetramer流式细胞技术检测治疗前后P BMC中的HBcAg特异性CTL细胞频率.结果: HBcAg特异性CTL为0.074%-0.937%.CHB患者体内的特异性CTL频率远低于急性乙型肝炎. 经ADV治疗CHB患者48 wk后, 其BcAg特异性CTL较治疗前无明显变化;亚组分析也表明无论治疗48 wk后HBV DNA是否转阴、ALT是否恢复正常, 对特异性CTL均无影响.结论: 应用ADV治疗48 wk, 对CHB患者体内HBcAg特异性CTL细胞频率无明显影响.     

恩替卡韦治疗慢性乙型肝炎研究进展

慢性乙型肝炎(CHB)是我国常见多发病,目前尚无特效治疗手段,公认有效的抗病毒药物有两类,即干扰素类及核苷(酸)类似物,后者是近10 a来研究的热点.目前,核苷(酸)类似物已有拉米夫定(LVD)、阿德福韦(ADV)、恩替卡韦(ETV)和替比夫定4个品种用于CHB治疗[1],其中ETV是2005年美国食品药品管理局批准治疗CHB的核苷(酸)类似物.现结合文献对ETV治疗CHB的研究进展介绍如下.     

拉米夫定联合干扰素延长疗程对e抗原阳性慢性乙型肝炎患者表面抗原转换的作用

慢性乙型肝炎(CHB)的治疗,目前有两类抗病毒药物--核营(酸)类似物单用存在耐药问题、单药干扰素(IFN)的疗效有限.本研究回顾性探讨拉米夫定(LAM)联合IFN治疗CHB的疗效,分析其可能的作用机制.     

拉米夫定联合干扰素延长疗程对e抗原阳性慢性乙型肝炎患者表面抗原转换的作用

慢性乙型肝炎(CHB)的治疗,目前有两类抗病毒药物--核营(酸)类似物单用存在耐药问题、单药干扰素(IFN)的疗效有限.本研究回顾性探讨拉米夫定(LAM)联合IFN治疗CHB的疗效,分析其可能的作用机制.     

拉米夫定联合干扰素延长疗程对e抗原阳性慢性乙型肝炎患者表面抗原转换的作用

慢性乙型肝炎(CHB)的治疗,目前有两类抗病毒药物--核营(酸)类似物单用存在耐药问题、单药干扰素(IFN)的疗效有限.本研究回顾性探讨拉米夫定(LAM)联合IFN治疗CHB的疗效,分析其可能的作用机制.     

拉米夫定联合干扰素延长疗程对e抗原阳性慢性乙型肝炎患者表面抗原转换的作用

慢性乙型肝炎(CHB)的治疗,目前有两类抗病毒药物--核营(酸)类似物单用存在耐药问题、单药干扰素(IFN)的疗效有限.本研究回顾性探讨拉米夫定(LAM)联合IFN治疗CHB的疗效,分析其可能的作用机制.     

Therapeutic vaccination for chronic hepatitis B: A systematic review and meta‐analysis

Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines + standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow‐up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow‐up, when comparing therapeutic vaccines vs no therapy, RD = 0.01, 95% CI ?0.05 to 0.07, and when comparing therapeutic vaccines + standard of care vs standard of care, RD = 0.03, 95% CI ?0.03 to 0.09. For HBVDNA reduction at the end of follow‐up, when comparing therapeutic vaccines vs no therapy, RD = ?0.03, 95% CI ?0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD = 0.15, 95% CI 0.02‐0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow‐up for therapeutic vaccines + standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection.     

Current and novel modalities for management of chronic hepatitis B infection

Over 296 million people are estimated to have chronic hepatitis B viral infection (CHB), and it poses unique challenges for elimination. CHB is the result of hepatitis B virus (HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV. Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA. Functional HBV “cure” is the durable loss of hepatitis B surface antigen (HBsAg), with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment. The currently approved therapies are nucleos(t)ide analogues, interferon-alpha, and pegylated-interferon. With these therapies, functional cure can be achieved in < 10% of CHB patients. Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV. Novel therapies may allow efficient control of CHB. They include direct acting antivirals and immunomodulators. Reduction of the viral antigen load is a crucial factor for success of immune-based therapies. Immunomodulatory therapy may lead to modulation of the host immune system. It may enhance/restore innate immunity against HBV (as toll-like-receptors and cytosolic retinoic acid inducible gene I agonist). Others may induce adaptive immunity as checkpoint inhibitors, therapeutic HBV vaccines including protein (HBsAg/preS and hepatitis B core antigen), monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV. Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure. Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage. The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues. Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.     

Restoration in vitro of impaired T-cell responses in patients with chronic hepatitis B by autologous dendritic cells loaded with hepatitis B virus proteins (R2)

BACKGROUND: The purpose of the present paper was to investigate dendritic cell (DC) and T-cell functions in patients with chronic hepatitis B (CHB) and determine whether therapeutic DC vaccines could restore T-cell function in those patients in vitro. METHODS: Twelve patients with CHB and 10 normal control subjects with positivity for antibodies to hepatitis B surface and core antigens (anti-HBs and anti-HBc positivity) were enrolled in the present study. Phenotype analysis and allogeneic mixed lymphocyte reaction assay of DC from CHB patients and normal controls were made in the absence or presence of a cocktail of cytokines: interleukin-1beta (IL-1beta), prostaglandin E(2) (PGE(2)), IL-6 and tumor necrosis factor-alpha (TNF-alpha). Autologous T-cell proliferation assays and the enzyme-linked immunospot (ELISPOT) method for detecting interferon-gamma (IFN-gamma)-producing CD8(+) T cells were used to evaluate the efficacy of DC loaded in vitro with HBsAg or HBcAg. RESULTS: The DC from CHB patients had a lower expression of costimulatory molecules CD80, CD86 and impaired allogeneic mixed lymphocyte reaction capacity compared to those from normal controls. However, the impaired DC function could be restored partially by cytokine cocktail supplemented in vitro. Mature DC loaded with HBsAg or HBcAg showed a greater capacity for autologous T-cell proliferation and antigen-specific IFN-gamma production than immature DC. Moreover, as a DC -loading antigen, HBcAg was more immunogenic than HBsAg. CONCLUSIONS: The impaired function of DC in patients with CHB may be restored by supplementation in vitro with a cocktail of cytokines, and therapeutic DC vaccines might be effective to treat CHB infection in humans.     

慢性乙型肝炎治疗新药相关研究进展及思考

慢性乙型肝炎是全球最重要的健康负担之一,每年导致80多万乙型肝炎病毒相关死亡病例。迄今为止,由于肝细胞核内共价、闭合、环状DNA的存在,还没有办法清除感染细胞内的乙型肝炎病毒,从而达到完全治愈的目标。乙型肝炎新药研究的进展让人们看到了乙型肝炎表面抗原转阴的希望。临床治愈目标的达到将有助于减少慢性乙型肝炎患者发生肝硬化、肝癌和其他严重并发症的风险。本文从慢性乙型肝炎的基础研究、治愈策略、新药进展、未来期望等方面,阐述了慢性乙型肝炎研究领域非常重要的一些问题,旨在抛砖引玉,给慢性乙型肝炎的研究提供思路。     

Specific CD8~+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

Hepatocellular carcinoma(HCC), chronic hepatitis B(CHB) and chronic hepatitis C(CHC) are characterized by exhaustion of the specific CD8~+ T cell response. This process involves enhancement of negative costimulatory molecules, such as programmed cell death protein-1(PD-1), cytotoxic T-lymphocyte antigen-4(CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8~+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4(tremelimumab and ipilimumab) and PD-1(nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.     

Hepatitis B in the Greater San Francisco Bay Area: an integrated programme to respond to a diverse local epidemic

Although chronic hepatitis B (CHB) affects approximately 2 million United States residents, there is no systematic screening of at-risk individuals, and most remain unaware of their hepatitis B virus (HBV) infection. Unmonitored and untreated, CHB results in a 25-30% risk of death from liver cancer and/or cirrhosis, inflicting an increasing healthcare burden in high-prevalence regions. Despite high prevalence in immigrant Asians and Pacific Islanders, among whom CHB is a leading cause of death, community and healthcare provider awareness remains low. Because safe and effective vaccines and effective antiviral treatments exist, there is an urgent need for integrated programmes that identify, follow and treat people with existing CHB, while vaccinating the susceptible. We describe an extant San Francisco programme that integrates culturally targeted, population-based, HBV screening, vaccination or reassurance, management and research. After screening over 3000 at-risk individuals, we here review our operational and practical experience and describe a simple, rationally designed model that could be successfully used to greatly improve the current approach to hepatitis B while ultimately reducing the related healthcare costs, especially in the high-risk populations, which are currently underserved.     

Dendritic cells from chronic hepatitis B patients can induce HBV antigen-specific T cell responses

AIM: To determine whether dendritic cells (DCs) from chronic hepatitis B patients could induce HBV antigen-specific T cell responses or not. METHODS: DCs were generated from peripheral blood mononuclear cells of patients with chronic hepatitis B (CHB) infection and healthy donors. We compared the phenotypes of these DCs and their ability to secrete cytokines and to participate in mixed lymphocyte reactions. In addition, autologous lymphocytes were cultured with DCs loaded with HBV core region peptide HBcAg8-27, an epitope recognized by cytotoxic T lymphocytes (CTL), and bearing human leucocyte antigen (HLA)-A2 for 10 d. Cytokine secretion and lytic activity against peptide-pulsed target cells were assessed. RESULTS: DCs with typical morphology were generated successfully by culturing peripheral blood mononuclear cells (PBMCs) from CHB patients with AIM-V containing GM-CSF and IL-4. Compared with DCs from normal donors, the level of CD80 expressed in DCs from CHB patients was lower, and DCs from patients had lower capacity of stimulate T cell proliferation. When PBMCs isolated from patients with chronic or acute hepatitis B infection and from normal donors were cocultured with HBcAg18-27 peptide, the antigen-specific memory response of PBMCs from acute hepatitis B patients was stronger than that of PBMCs from chronic hepatitis B patients or normal donors. PBMCs cocultured with DCs treated with HBcAg18-27 CTL epitope peptide induced an antigen-specific T cell reaction, in which the level of secreted cytokines and lytic activity were higher than those produced by memory T cells. CONCLUSION: DCs from patients with CHB can induce HBV antigen-specific T cell reactions, including secretion of cytokines essential for HBV clearance and for killing cells infected with HBV.     

Cellular immune responses in hepatitis B virus e antigen negative chronic hepatitis B

The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-gamma (IFN-gamma) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-gamma producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-gamma assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.     

Management of chronic hepatitis B before and after liver transplantation

Liver transplantation remains the only curative option for eligible patients with complications of chronic hepatitis B (CHB) infection, including severe acute hepatitis flares, decompensated cirrhosis, and hepatocellular carcinoma. In general, all patients with CHB awaiting liver transplantation should be treated with oral nucleos(t)ide analogs (NAs) with high barriers to resistance to prevent potential flares of hepatitis and reduce disease progression. After liver transplantation, lifelong antiviral therapy is also required to prevent graft hepatitis, which may lead to subsequent graft loss. Although combination therapy using NA and hepatitis B immune globulin (HBIG) has been the regimen most widely adopted for over a decade, recent studies have demonstrated that newer NAs with low rates of resistance are effective in preventing graft hepatitis even without the use of HBIG, achieving excellent long term outcome. For patients without pre-existing resistant mutations, monotherapy with a single NA has been shown to be effective. For those with resistant strains, a combination of nucleoside analog and nucleotide analog should be used. To date, clinical trials using therapeutic vaccination have shown suboptimal response, as CHB patients likely have an immune deficit against HBV epitopes. Future strategies include targeting different sites of the hepatitis B replication cycle and restoring the host immunity response to facilitate complete viral eradication.     

Restoring homeostasis of CD4~+ T cells in hepatitis-B-virusrelated liver fibrosis

Immune-mediated liver injury is widely seen during hepatitis B virus(HBV) infection. Unsuccessful immune clearance of HBV results in chronic hepatitis and increases the risk of liver cirrhosis and hepatocellular carcinoma. HBV-related liver fibrosis(HBVLF),occurring as a result of HBV-induced chronic hepatitis,is a reversible,intermediate stage of chronic hepatitis B(CHB) and liver cirrhosis. Therefore,defining the pathogenesis of HBVLF is of practical significance for achieving better clinical outcomes. Recently,the homeostasis of CD4+ T cells was considered to be pivotal in the process of HBVLF. To better uncover the underlying mechanisms,in this review,we systematically retrospect the impacts of different CD4+T-cell subsets on CHB and HBVLF. We emphasize CD4+ T-cell homeostasis and the important balance between regulatory T(Treg) and T helper 17(Th17) cells. We discuss some cytokines associated with Treg and Th17 cells such as interleukin(IL)-17,IL-22,IL-21,IL-23,IL-10,IL-35 and IL-33,as well as surface molecules such as programmed cell death protein 1,cytotoxic T lymphocyte-associated antigen 4,T cell immunoglobulin domain and mucin domain-containing molecule 3 and cannabinoid receptor 2 that have potential therapeutic implications for the homeostasis of CD4+ T cells in CHB and HBVLF.