HBV感染慢性化的免疫耐受机制

HBV感染机体后,机体抗病毒免疫强度的高低,能否及时、有效、彻底清除病毒可能成为决定急性自限性感染或慢性感染的标志。HBV作为抗原,欲长期持续存在于宿主体内,必须逃避宿主免疫系统的监视与攻击,即造成免疫耐受环境,免疫耐受是HBV感染慢性化最主要的机制。免疫耐受与机体免疫系统发育成熟程度有关。成人、儿童、幼儿感染HBV后分别有5％、30％、95％的患者成为慢性HBV感染者。表明免疫成熟程度是决定HBV持续感染的重要因素。     

中西医治疗慢性HBV感染免疫耐受期的研究概况

<正>据世界卫生组织报道,全球范围内2015年统计慢性HBV感染人数达2.57亿人,每年死于慢性乙型病毒性肝炎的人数达88.7万[1]。我国是世界上HBV感染率最高的国家,感染HBV人口基数大,据统计,我国现有7 000万人处于HBsAg携带状态(患病率5%～6%)[2,3]。因此,慢性HBV感染仍是我国面临的一个重要医疗问题。慢性HBV感染进展有一个过程,发病初期一般为免疫耐受期(慢性HBV携带状态),后再过度到免疫清除期,再者为免疫控制期     

慢性乙型肝炎病毒感染免疫耐受期患者的临床病理特征

目的:了解HBV慢性感染免疫耐受期患者的临床及病理学特征．方法:分析HBV感染不同时期380例患者的年龄、母婴垂直传播感染途径、乙肝家族史、肝细胞内HBsAg、HBcAg表达状况及肝组织病理学特征．结果:HBV慢性感染免疫耐受期患者年龄 16岁以下占61．8％,母婴垂直传播感染者占 55．0％,有乙肝家族史患者占46．6％,免疫耐受期患者89例肝组织内HBcAg阳性表达率 78．7％,均明显高于免疫活动期及感染非活动状态患者(x2=38．73,49．08,17．2,31．69, P<0．01)．免疫耐受期16岁以下的患者肝组织内HBsAg及HBcAg阳性表达率最高,分别占64．3％(45／75)和72．9％(51／79),显著高于免疫活动期和非活动HBV携带状态患者(x2= 17．51,31．17,P<0．001)．免疫耐受期16岁以上的患者肝组织内HBsAg及HBcAg阳性表达率最低,分别占35．7％(25／75)和27．1％(19／70),显著低于免疫活动期和非活动HBV携带状态患者(x2=17．51,x2=31．17,P<0．001)．结论:HBV慢性感染免疫耐受期患者中16岁以下者,母婴垂直传播感染者及乙肝家族史者所占比例明显高;HBV在肝组织复制表达以免疫耐受期患者最多,且16岁以下的患者占多数．     

112例慢性HBV感染免疫耐受期患者肝组织病理学特点

目的探讨处于免疫耐受期慢性HBV感染者的肝组织病理特点。方法回顾性分析112例慢性HBV感染免疫耐受期患者的临床病理资料及其肝组织炎症、纤维化程度以及HBcAg免疫组织化学的特点。结果 112例患者包括肝组织炎症G0期31例、G1期75例、G2期4例、G3～4期2例。肝组织纤维化S0期34例、S1期63例、S2期9例,S3～4期6例。肝组织免疫组织化学HBcAg分布,核型48例、混合型53例,浆型4例、阴性7例。不同性别、年龄组之间及ALT亚组间肝组织病理学差异无统计学意义（χ2分别为0.50、2.62、1.22,P均〉0.05）。结论慢性HBV感染高HBVDNA载量（〉107拷贝/ml）的免疫耐受期患者主要集中在年轻人群,其肝组织炎症及纤维化程度较轻微,HBcAg表达以核型和混合型为主。肝组织病理学损害与性别、年龄,ALT不同亚组间无相关性。     

慢性HBV感染免疫耐受期患者应精准抗病毒治疗

正慢性HBV感染免疫耐受期患者是否应进行抗病毒治疗一直存在争议。当前,国内外各个乙型肝炎指南对免疫耐受期的定义和治疗意见不完全一致,主要体现在HBV DNA不同水平的定义,且大部分指南对HBsAg的滴度无明确界定,因此导致对免疫耐受期的定义并不清晰。目前有研究~([1])认为,慢性HBV感染免疫耐受期患者由于其肝脏内不存在炎症,其ALT是正常的,因此不需要治疗,发生肝癌的可能性比较小~([2])。但也有研究~([3])显示:病毒载量高、转氨酶正常的慢性乙型肝炎(CHB)患者,约20%ALT水平持续正常的CHB患者存在着潜在的肝脏炎症。     

慢性HBV感染免疫耐受期患者应积极抗病毒治疗

正针对慢性HBV感染免疫耐受期(IT-CHB)患者是否积极抗病毒治疗已成为国际关注的热点和难点。近年来大量研究表明,HBV携带者直接发展到肝硬化、HCC而无ALT增高表现的病例明显攀升。因此即使是处于IT-CHB的患者,宜早期开始抗病毒治疗,特别对于HBV DNA高水平的妊娠期患者、年龄30岁慢性HBV感染者及一些特殊人群要高度重视,具体阐述如下,供大家讨论。     

慢性HBV感染免疫耐受期应否治疗?

国际主要指南对慢性HBV感染免疫耐受期的定义不完全一致,但几乎所有指南均不推荐对免疫耐受期慢性乙型肝炎患者启动治疗。本文讨论了关于对HBV感染免疫耐受期患者进行抗病毒治疗的最新证据,以预防其肝硬化和肝细胞癌的发生。     

慢性HBV感染免疫耐受期患者应选择性进行抗病毒治疗

正在HBV高度流行的亚太地区,尤其是我国,HBV感染的主要途径是围产期传播或垂直传播,新生儿或低幼龄儿童在感染HBV后有相当高的比例会发展为慢性感染,进入所谓的"免疫耐受期"[1-2],这一时期可持续几年甚至几十年之久。鉴于HBV免疫耐受期的治疗难度以及目前药物治疗的效果,过去很长一段时期内,国内外大部分指南和专家对免疫耐受期患者不建议抗病毒治疗,认为这一时期肝损伤较轻,疾病进展缓慢,治疗后可能效果不佳。目前为止,免疫耐受的概念仍被大多数学者认同。     

慢性HBV感染合并HIV感染患者治疗研究进展

艾滋病病毒(HIV)与乙型肝炎病毒(HBV)具有相同的传播途径,均可经血液(静脉吸毒和血制品输入)、性接触、母婴垂直传播等途径感染。因此,HIV/HBV共感染情况很常见。随着高效抗逆转录病毒治疗(HAART)的广泛应用,艾滋病患者的病死率和机会性感染等合并症已明显减少,艾滋病患者的生存期明显延长。然而,由HBV共感染引起的慢性肝脏疾病已经成为艾滋病患者死亡的主要因素之     

71例血清ALT正常的慢性HBV感染者临床与肝脏病理特征

目的 了解血清ALT正常的慢性HBV感染者的临床及肝脏病理特征.方法 分析71例血清ALT正常,且HBeAg阳性的慢性HBV感染者的年龄、性别、血清HBV DNA水平、肝脏病理改变等.结果 本组病例中＜30岁者61例(85.92%),≥30岁者10例(14.08%).45.07%感染者母亲HBsAg阳性,所有感染者血清HBVDNA为高水平复制,＞107copies/ml者占78.87%.95.77%感染者肝脏有轻度炎症反应,43.66%有不同程度的纤维化,未发现肝硬化.结论 血清ALT正常、HBeAg阳性的慢性HBV感染者多处于免疫耐受期,肝组织病理损害轻微,但部分患者肝脏有一定程度纤维化,显示ALT虽然正常,肝损伤可能在隐匿中进展.因此,对ALT正常的HBV感染者及早进行肝脏病理检查,有利于判断病情和确定治疗方案.     

难治性慢性乙型肝炎

"难治性慢性乙型肝炎"的定义:符合慢性乙型肝炎的诊断标准,因各种原因/因素导致在现有指南或建议治疗方案指导下,使用了包括核苷(酸)类似物和(或)干扰素在内的抗HBV药物治疗失败或疗效不佳、或不规范抗病毒治疗所致、或已有循证医学依据证实疗效不佳的慢性乙型肝炎.难治性慢性乙型肝炎概念的提出,有利于乙型肝炎患者接受临床规范化...     

血清乙型肝炎病毒DNA定量在慢性乙型肝炎病毒感染的临床意义

目的:测定慢性HBV感染不同状态时血清HBV-DNA水平,阐明其在判断病情和指导治疗中的价值。方法:共90例慢性HBV感染患者接受研究,共中HBeAg阳性无症状携带者(ASC)15例,HBeAg阳性慢性肝炎(CHB)17例,HBeAg阴性CHB14例,HBeAg阴性ASC16例;另有28例HBeAg阳性CHB接受干扰素治疗。血清HBV-DNA浓度测定应用AG-9600Amplisensor荧光PCR定量系统,测定范围定为10~(3.00-9.50)copies/ml。结果:血清HBV-DNA在HBeAg阳性ASC病例最高,达10~(8.46±0.71)copies/ml,其次依次为HBeAg阳性CHB(10~(7.24±0.54) cooies/ml)、HBeAg阴性CHB(10~(6.04±0.69) copies/ml),HBeAg阴性ASC者最低,为10~(3.80±0.71)copies/ml。4组病例相互之间差异在统计学上均有显著意义(P<0.01)。28例BHeAg阳性CHB患者接受干扰素治疗,治疗结束时呈完全应答(CR)者13例,无应答(NR)15例。对13例CR患者继续随访6个月,其中4例血清ALT再升高(复燃)。血清HBV-DNA水平在治疗前,CR不伴ALT复燃组HBV-DNA为10~(3.44±0.43)copies/ml,明显低于CR伴ALT复燃组(10~(6.84±0.51))(P<0.01)和NR组(10~(7.18±0.66))(P<0.01)。结论:测定血清HBV-DNA水平有助于鉴别慢性HBV感染的不同状态;在HBeAg阳性CHB病例,干扰素治疗结束时,检测HBV-DNA水平对于判断疗效有指导价值,HBV-DNA低于104copies/ml往往能取得持久疗效。     

Role of occult hepatitis B virus infection in chronic hepatitis C

The development of sensitive assays to detect small amounts of hepatitis B virus(HBV) DNA has favored the identification of occult hepatitis B infection(OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV(HBs Ag) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody(antiHBc) in serum of HBs Ag-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C(CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma(HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.     

Natural history of chronic hepatitis B virus infection: New light on an old story

Chronic hepatitis B virus (HBV) infection is one of the most common persistent virus infection in man. It causes significant morbidity and mortality, and therefore is important. Extensive studies on clinicopathologic studies and long-term follow up on hepatitis B surface antigen (HBsAg) carriers have largely disclosed the natural history of chronic HBV infection. The infection easily becomes chronic when contracted in early infancy. As high as 90% of babies born to HBV carrier mothers will also become HBsAg carriers. Once chronic infection is established, it is refractory, and HBsAg carriage usually persists for life. However, the chronic infection is not monotonous, it actually evolves from an HBV replicative phase to a non-replicative phase. The host responds differently and with more complexity in different phases. The virus-host interactions, divided into three phases, virus tolerance, virus clearance and residual HBV integrated phases, result in a heterogeneous variety of hepatic lesions. The first two phases occur when HBV is actively replicating, and the last corresponds to the non-replicative phase. The high HBV level (and hence HBV gene products) renders the host's immune system tolerant to the virus, and the infected host does not exert an effort to get rid of the virus. At this stage, the liver is nearly normal, and the host is asymptomatic. However, later in the replicative phase, the HBV replication begins to wane, and the immune tolerance is no longer maintained. Hepatitis B core antigen/hepatitis B e antigen (HBcAg/HBeAg)-specific cellular immune responses result in lysis of the infected liver cells; the liver then begins to have active disease as revealed by the presence of lobular hepatitis. The asymptomatic carrier may then start to have symptoms of hepatitis. After a variable period, usually in years, the host eventually gets rid of active viral replication and only residual incomplete HBV genome integrated to host chromosomes is found. The carrier is now HBeAg negative/anti-HBe positive, serum HBV DNA decreases to very low levels, and the disease becomes qulescent at this stage. The outcome of the host is determined by the hepatic lesions caused by HBV-host interactions mentioned above, with cirrhosis and hepatocellular carcinoma (HCC) as the major sequelae of chronic HBV infection. Although HCC is usually preceded by HBV-induced cirrhosis, this is not always the case. Cirrhosis and HCC may develop independently, with cirrhosis as the most important precipitating factor or cofactor of HCC. A significant proportion of HBsAg carriers, particularly the males, will eventually die of these sequelae.     

慢性乙型肝炎的治愈现状

慢性乙型肝炎（chronic hepatitis B, CHB）是一种广泛的全球感染性疾病,是肝细胞癌和肝衰竭的主要原因。目前可以通过接种乙型肝炎疫苗降低CHB的新发感染率,主要的治疗方法是通过聚乙二醇化干扰素α和核苷（酸）类似物抑制病毒,延缓CHB患者的疾病进展,但不能治愈CHB。如何清除稳定的DNA中间体共价闭合环状DNA,以及如何恢复肝脏微环境中疲惫的免疫系统是目前面临的挑战。为此肝病学者们不断探索新的靶标和药物,研究通过针对HBV生活周期不同阶段的药物联合疗法实现持久功能性治愈。本文将对目前CHB的多种治疗策略以及正在研发的新靶标和新药物进行回顾。     

Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy

BACKGROUND AND AIM: A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD: We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS: The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION: Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.     

慢性乙肝病毒携带者中医证候分布规律调查及病机探讨

目的:研究慢性乙肝病毒(HBV)携带者的中医证候分布规律及病机.方法:选择3 000例慢性HBV携带者,分别填写中医证候调查表,进行辨证分析.结果:慢性HBV携带者分为10种证型,10种证型及出现频数所占百分比分别为:肾虚型(31.90％)、脾虚型(20.41％)、肝气郁结型(16.92％)、肝胃不和型(8.60％)、肝胆湿热型(7.37％)、肝阴虚型(6.59％)、湿热中阻型(5.96％)、湿困中焦型(4.58％)、肝血虚型(4.05％)、血瘀阻络型(1.55％).肾虚型又分为肾阳虚型、肾阴虚型、肾气虚型和肾精不足型,分别占总频次的9.45％、9.38％、12.30％、0.08％,脾虚型又分为脾气虚型和脾阳虚型,分别占总频次的16.28％和4.12％.兼证以肝胆湿热和湿热中阻为主.结论:慢性HBV携带者的最主要中医证型是肾虚型和脾虚型,其病机为疫毒内伏,脾肾亏虚,正气不足,无力鼓邪外出.     

Long-term clinical impact of occult hepatitis B virus infection in chronic hepatitis B patients

BACKGROUND/AIMS: Long-term clinical outcomes of occult hepatitis B virus (HBV) infection were studied. METHODS: Fifteen chronic hepatitis B patients were monitored for a median of 4.4 years (range 0.9-15.3) after hepatitis B surface antigen (HBsAg) seroclearance. Serum HBV DNA was measured by real-time detection polymerase chain reaction. Thirteen patients underwent liver biopsies at the end of follow-up and liver histology was evaluated by Ishak score. Liver HBV DNA was also measured for 12 patients. RESULTS: At the end of follow-up, HBV viremia was absent in 13 (87%) patients, and antibody titers to hepatitis B core antigen showed an inverse correlation with time from HBsAg seroclearance (r=-0.554; P=0.0040). However, all patients retained liver HBV DNA and tested positive for the covalently closed circular HBV DNA replicative intermediate. The hepatic HBV DNA loads had no relation to liver histology. Paired biopsies from 11 patients disclosed that each necroinflammatory score significantly improved after HBsAg seroclearance. Amelioration of liver fibrosis was also evident in eight (73%) patients (P=0.0391 by signed rank test). CONCLUSIONS: A long-standing but strongly suppressed HBV infection may confer histological amelioration after HBsAg seroclearance.     

Reactivation of hepatitis B virus during interferon‐free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co‐infection

Direct‐acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti‐HBe hepatitis during interferon (IFN)‐free DAA therapy in HBV/HCV co‐infected patients with inactive HBV. A 69‐year‐old male patient was diagnosed with chronic hepatitis due to HBV/HCV co‐infection with serum levels of alanine aminotransferase (ALT) of 94 U/L, HCV RNA of 4.2 log IU/mL and HBV DNA of 2.5 log copies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core‐related antigen (3.1 log U/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237 U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0 log copies/mL at that time. The treatment was stopped due to suspicion of drug‐induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti‐HCV DAA therapy and the commencement of anti‐HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co‐infection.