抗HBV特异性主动免疫疗法对标准乙型肝炎疫苗免疫无应答者免疫效果分析

目的探讨抗HBV特异性主动免疫疗法对标准重组乙型肝炎(乙肝)疫苗无应答者的免疫效果。方法按0-1-6月方案把472例出生时未接种乙肝疫苗、学龄期常规接种乙肝疫苗无应答者分为2组:主动免疫组106例,为抗HBV主动免疫疗法组,采用乙肝疫苗联合IL-2及MG-CSF行三角肌肌内注射;单用组366例,为单用标准乙肝疫苗注射。结果第一针免疫后7个月,主动免疫组抗HBs的阳性率88.0%,明显高于单用组56.8%(P<0.05);抗HBs滴度主动免疫组为276.7±46.3mIU/ml,明显高于单用组184.6±36.6mIU/ml(P<0.01);免疫后的抗HBs阳性率与家中是否有HBV感染者无关(P<0.05)。结论抗HBV特异性主动免疫对初次免疫无应答者的再次免疫有一定的疗效。     

抗HBV特异性主动免疫疗法联合干扰素抗乙型肝炎病毒的临床研究

目的探讨抗 HBV 特异性主动免疫疗法(主动免疫)和干扰素(IFN)联合使用,观察其抗乙型肝炎病毒的效果。方法应用前瞻性随机分组的方法,对180例未经治疗的慢性乙型肝炎患者分3组进行观察,每组60例,A 组:(主动免疫联合IFN),主动免疫每月1次,α-1b-IFN 5MU,每周3次;B组:α-1b-IFN 5MU,每周3次;C 组:对照组。总疗程为12个月。分别于治疗后第3、6、9、10、11、12个月和随访半年时抽血检查,并观察各组 HBV DNA 复制水平、HBeAg、肝功能变化。结果 A 组有显著的抗病毒效果,显著高于 B 组和 C 组,直至治疗结束后6个月,均显示出极好的抑制 HBV 复制和持续的丙氨酸氨基转移酶复常效果(34.0±1 1.4)U/L 对(86.4±31.4)U/L,P<0.01。A 组与 B 组比较,治疗结束6个月,病毒负荷量(11.02±1.52)×10~5copies/ml 对(77.98±3.12)×10~5 copies/ml,P<0.01,差异有显著性。结论抗 HBV 特异性主动免疫疗法联合α-1b 干扰素的应用,具有显著增加抗病毒效果,特别是停药后持续抗病毒及肝功能持续正常的疗效更为显著。     

重组乙肝疫苗联合干扰素对慢性乙型肝炎患者抗HBV及改善肝功能的临床研究

目的通过重组乙肝疫苗联合干扰素抗HBV研究,探讨其治疗乙型肝炎的可行性及作用机制。方法两组慢性乙型肝炎患者均常规给予保肝降酶药物,联合组每周3次肌注IFNα2b3MU,另加重组乙肝疫苗20μg每月1次三角肌处肌注,疗程为6个月。对照组只单独肌注IFNα2b,分别观察其抗HBV及改善肝功能情况。结果联合组抗HBV及改善肝功能效果与对照组比较有显著差异。结论重组乙肝疫苗联合干扰素抗HBV显示出良好的治疗前景。     

HBV携带者中抗-TB治疗所致肝损伤的临床分析

目的研究HBV携带者中结核杆菌(TB)感染者抗-TB治疗所致肝损伤的临床及组织学特点.方法105例结核杆菌(TB)感染者,其中HBV携带者45例,非HBV携带者60例,均进行抗-TB治疗6mo～8mo;前2mo四联用药,异烟肼、利福平、吡嗪酰胺及乙胺丁醇,后4mo～6mo两联用药,异烟肼和利福平.男选择60例HBV携带者,无结核杆菌感染,未用药,作为对照组.所有病例均在治疗前检查肝功能、HBV标记物、腹部B超检查,HBV标记物阳性的,进行HBVDNA滴度测定.治疗后,每2wk～4wk复查上述指标肝功能异常者,再复查1次,谷丙转氨酶(ALT)仍高于正常上限1.5倍以上者作为观察对象,部分做肝穿刺行组织学检查.肝功能异常者,ALT≥3倍正常值的,暂停用抗-TB治疗,其中HBVDNA滴度高于1000ng/L的,给予拉米扶啶治疗加保肝治疗,其余的仅给予保肝治疗.结果结核杆菌(TB)感染者合并HBV携带者(A组)、TB感染者不合并HBV携带者(B组)、单纯HBV携带者(C组)肝功能异常者发生率分别为44.4%,13.3%,16.6%;发病年龄A组较B组年轻,P<0.05;e抗原转阴率,A组为20%,C组为10%;HBVDNA滴度增高时易出现肝功能异常;A组肝组织损伤较B,C两组严重;给予拉米扶啶治疗的10例患者肝功能正常后,再给予抗-TB治疗仅1例出现轻度肝功能异常.结论HBV感染可增加抗-TB药物治疗的肝毒性,尤其在HBVDNA滴度较高时(>1000ng/L),加用抑制HBV复制的药物可减少肝损伤的发生率;抗-TB治疗后HBeAg转阴率略增加,可能与肝细胞损伤后病毒ccDNA负荷量减少有关.     

苦参素胶囊对HBeAg阴性、HBV DNA阳性慢性乙型肝炎患者HBV DNA阴转的影响

目的:探讨苦参素胶囊对HBeAg阴性而HBV DNA阳性的慢性乙型肝炎患者HBV DNA阴转的影响.方法:根据肝功能有无异常、HBV DNA的对数值是否＜6进行分层,并按2∶1的比例随机分组:治疗组69例,口服苦参素胶囊200mg 参柴颗粒5g,对照组33例,仅口服参柴颗粒5g,均每日3次,3个月1个疗程,连续治疗2个疗程.分别于治疗前、治疗3个月末、治疗6个月末及停药后6个月各检测1次HBV DNA、HBV-M.结果:治疗3个月、6个月及随访6个月的HBV DNA阴转率:①治疗组分别为23.19%、44.93%、50.72%,较对照组的12.12%、21.21%、24.24%要高,P值分别为0.293、0.036、0.02;②HBV DNA对数值＜6的患者中,治疗组分别为26.92%、53.85%、61.54%,明显较对照组的8.00%、20.00%、24.00%要高,P值分别为0.106、0.011、0.004;③肝功能异常的患者中,治疗组分别为37.93%、65.52%、79.31%,明显较对照组的14.29%、28.57%、42.86%要高,P值分别为0.22、0.051、0.041.结论:苦参素胶囊对此类患者中HBV DNA对数值＜6的患者或/和肝功能异常者能产生较好的抗HBV作用,疗程延长到6个月,疗效更明显,停药后仍有持久疗效.     

拉米夫定联合其他药物对HIV/HBV合并感染者的抗HBV效果分析

目的探讨拉米夫定对人免疫缺陷病毒(HIV)/乙型肝炎病毒(HBV)合并感染者的抗HBV疗效,为合理选择HIV/HBV合并感染者的抗病毒方案提供依据。方法 A组60例HIV/HBV合并感染者使用拉米夫定(300mg qd)+齐多夫定(300mg bid)+依非维仑(600mg qd)抗病毒治疗。B组60例为初治的慢性乙型肝炎(CHB)患者,使用3TC(100mg qd)。两组患者治疗前均进行HBV DNA定量、HBV血清标志物(HBVM)定量检测、HBV YMDD变异检测。所有患者均在治疗后每3个月检测1次HBVM、HBV DNA及肝功能,治疗观察满2年。比较两组患者治疗后HBV DNA的阴转率。结果 A组患者治疗后HBV DNA的阴转率均较B组高(P0.05);治疗满96周,A组患者仍保持100%的HBV DNA阴转率。结论 HIV/HBV合并感染者使用含3TC(不含替诺福韦TDF)的抗病毒治疗方案,显示出良好的抗HBV效果,且未发生高耐药的表现。     

4药联合治疗慢性乙型肝炎320例临床分析

目的探讨4药联合治疗慢性乙型肝炎(CHB)的临床疗效。方法选择CHB患者640例,随机分为2组。对照组患者口服拉米夫定100mg/d;治疗组患者在口服拉米夫定(100mg/d)基础上加服苦参素0.3g,3/d,并同时给予抗HBV特异性主动免疫疗法,1套/月,肌内注射,疗程均为6个月。结果治疗组患者血清AST下降、HBeAg阴转率、HBeAg血清转换率优于对照组(P<0.05)。结论4药联合治疗CHB可改善肝功能,增强抗HBV作用,值得临床进一步研究应用。     

慢性HBV感染免疫治疗新进展

慢性HBV感染有发展为肝硬化和肝细胞癌高风险.IFN-α、拉米夫定、阿德福韦、恩替卡韦是目前批准用于HBV感染的治疗药物.这些药物是防止慢性HBV感染者发展为肝硬化和肝细胞癌的唯一策略.然而,以发生HBeAg血清转换、血清丙氨酸转氨酶正常和血清HBVDNA水平转阴作为评价疗效标准,这些药物的治疗效率仅占接受治疗者的20%-30%.应用拉米夫定或阿德福韦长期治疗可能导致药物耐药,从而导致延长了应用其他核苷类似物治疗的期限.目前抗病毒治疗的缺陷使我们有必要寻找更好的治疗策略.而提高慢性HBV感染者病毒特异性T细胞活性的特异性和非特异性免疫治疗策略为抗HBV感染提供了新的治疗方向.这些免疫治疗策略包括,过继性HBV免疫、PEG干扰素和治疗性疫苗等.     

北京地区HIV/HBV合并感染者与HBV单独感染者中HBV基因型分布

目的比较北京地区艾滋病病毒(HIV)/乙型肝炎病毒(HBV)合并感染者和HBV单独感染者中HBV基因型分布是否存在差异,分析两组人群中基因型相关的基本临床特征差异。方法收集2016年7月至2017年12月在北京地坛医院门诊和住院处就诊的慢性乙型肝炎患者共1 453例,分为HIV/HBV合并感染组和HBV单独感染组,通过测序来鉴定HBV基因型。结果共343例分型成功。其中,HIV/HBV合并感染者75例,HBV-B型占40.0%(30例),HBV-C型占60.0%(45例);HBV单独感染者268例,HBV-B型占27.6%(74例),HBV-C型占72.4%(194例)。在HBV单独感染者中,HBV-C型患者的丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)处于异常水平比率及乙型肝炎病毒e抗原(HBeAg)阳性率明显高于HBV-B型患者;而在HIV/HBV合并感染者中,HBV-B、C型患者的ALT、AST水平及HBeAg阳性率无显著差异。在两组人群中,HBV-B型患者在年龄、ALT、AST水平上无显著差异;HBV-C型患者在性别、年龄、ALT水平上存在显著差异。结论北京地区HIV/HBV合并感染者和HBV单独感染者中HBV基因型分布存在差异。HBV-C型患者的肝功能损害程度重于HBV-B型,HIV/HBV合并感染可能对肝功能造成一定的影响。     

慢性HBV感染免疫耐受期应重新评估诊断标准并将研究重点着眼于>35岁人群

正慢性HBV感染可导致肝硬化和肝癌。我国目前20岁以上的人群慢性HBV感染率超过5%~([1])。其中,慢性HBV感染免疫耐受期感染者,即HBeA g阳性、高病毒载量(HBV DNA 106IU/ml)、肝功能正常者是否应该抗病毒治疗的问题引发广泛讨论,既有学者推荐抗病毒治疗,也有不同建议,或者提出需要对免疫耐受期的肝功能指标进行个体化或精准治疗。现有抗HBV治疗药物,     

Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy

Reactivation of the hepatitis B virus (HBV) is a well-described complication among cancer patients undergoing cytotoxic chemotherapy. Mutations in the preC/C and the preC promoter regions of HBV have been reported in some patients who developed this condition. A G-to-A mutation at nt 1896 in the preC/C region (HBeAg negative/ anti-HBe positive) has been associated with more severe liver disease than that caused by wild type virus. In addition, it has been suggested that patients with these mutations may be more likely to reactivate than those with the wild type virus. Whether or not such mutations were present before the commencement of or developed during the course of cytotoxic chemotherapy is not known. In this study, 28 cancer patients (consisting of 14 consecutive patients who developed HBV reactivation and another 14 who had no reactivation during cytotoxic chemotherapy) are reported. The objectives were firstly, to determine the prechemotherapy HBeAg status and nucleotide sequences of the preC/C and preC promoter regions of HBV in order to determine if these parameters affected the rate of reactivation, and secondly, for those who developed reactivation, to determine whether the mutations were present before chemotherapy or developed during, possibly as a result of, cytotoxic chemotherapy. HBV DNA was amplified by PCR and nucleotide sequencing performed on samples taken prior to chemotherapy and at the time of reactivation. Results revealed that 16 of the 28 patients were HBeAg negative/anti-HBe positive. Of these 16, four (57%) of the seven patients who had nt 1896 mutation, but only one (17%) of the six who had the wild type HBV genome, developed reactivation. Three had no detectable HBV DNA. In the majority of cases, the type of virus, i.e. wild/mutant at preC/C, that was detected during the reactivation was identical to that detected in the pretreatment samples. With respect to the preC promoter region, the two commonest mutations detected were at nt 1762 (A to T) and nt 1764 (G to A). When this region was translated into amino acid sequences, stop codons leading to truncated X protein at carboxyl terminus were found in four patients, three of whom developed HBV reactivation. We conclude that chronic HBV carriers who are HBeAg negative/anti-HBe positive with nt 1896 mutation (G to A) may be more likely to develop HBV reactivation during cytotoxic chemotherapy than those with the wild type virus. Cytotoxic chemotherapy does not appear to select out mutant HBV, or to be consistently mutagenic in patients who develop HBV reactivation. The occurrence of stop codons in the amino acid sequences of the X protein in three patients who developed HBV reactivation, including one who was detected only at the time of reactivation, is of particular interest, as such mutant viruses remain replication competent.     

乙型肝炎病毒的基因变异及其临床意义

乙型肝炎病毒(hepatitis B virus,HBV)感染仍是世界范围内的公共健康问题.HBV为一嗜肝细胞DNA病毒,不仅可以引起隐匿性、急性和慢性病毒性肝炎,还与肝硬化和肝细胞癌的发生发展密切相关.HBV基因组易发生变异,并在长期进化过程中不断积累,形成了具有种族和地域差异的HBV基因型、基因亚型和准种,与HBV感染的发生、发展和治疗等密切相关.     

HBV NAT positive [corrected] blood donors in the early and late stages of HBV infection: analyses of the window period and kinetics of HBV DNA

BACKGROUND AND OBJECTIVES: The Japanese Red Cross (JRC) carries out nucleic acid amplification testing (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1) by using a multiplex (MPX) reagent. Screening is undertaken on serologically negative units. In this study we characterized HBV NAT-positive donations individually and analysed the window period and kinetics of HBV DNA, during acute infection, in follow-up studies. MATERIALS AND METHODS: Two hundred and seventy-seven HBV DNA-positive donations have been identified in Japan since the introduction of NAT screening of 50-donation minipools. The viral loads and genotypes of these HBV DNA-positive donations were characterized. The doubling time and half-life of HBV was estimated from the data of 123 follow-up donors. The sensitivity of the NAT system (based on 50-donation minipools) was compared with the sensitivities of the enzyme immunoassay (EIA) and the chemiluminescence immunoassay (CLIA). Samples that were CLIA negative, but with > 10(4) copies/ml of HBV DNA, were analysed by sequencing the hepatitis B surface antigen (HBsAg) region. RESULTS: Out of 277 HBV NAT-positive samples, 125 (45%) were found to have an increasing viral load and 45 (16%) a decreasing viral load. Forty per cent of HBV NAT-positive samples with an increasing viral load, and 33% of those with a decreasing viral load, were negative when tested by using the CLIA. No mutations related to escape mutants were found in the samples that were CLIA negative but with HBV DNA loads of > 10(4) copies/ml. The median HBV doubling time was 2.6 days (n = 93, 1.3-15.2 days) and the half-life was 1.6 days (n = 55, 0.9-6.3 days). Some kinetic difference was observed between genotypes A and B. CONCLUSIONS: HBV NAT screening detected HBV DNA in both early (the so-called serological window period) and late stages of acute HBV infection.     

Hepatitis B virus surface protein mutations clustered mainly in CTL immune epitopes in chronic carriers: results of an Iranian nationwide study

Mutations within the coding region of hepatitis B surface antigen (HBsAg) have been found naturally in chronic carriers. To characterize the mutations of HBsAg from Iranian chronic carriers who were vaccine and/or medication naive. The surface genes from 360 patients were amplified and directly sequenced. The distribution of amino acid substitutions was classified according to different immune epitopes of the surface protein. All isolates belonged to genotype D . 222 (61.6%) of 360 patients contained at least one amino acid substitution. 404 (74.5%) of 542 amino acid changes occurred in different immune epitopes of HBsAg, of which 112 (27.7%) in 32 residues of B‐cell epitopes (62 in the ‘a’ determinant); 111 (27.4%) in 32 residues of T helper; and 197 (48.7%) in 32 residues inside cytotoxic T lymphocyte (CTL) epitopes. One Th (186–197) and two CTL (28–51 and 206–215) epitopes were found to be hotspot motifs for the occurrence of 213 (52.7%) substitutions. 20 stop codons were identified in different epitopes. There was a significant association between amino acid substitutions and anti‐HBe seropositivity; however, the correlation between such changes with viral load and ALT levels was not significant. In chronic hepatitis B virus(HBV) carriers, positive selection in particular outside the ‘a’ determinant appeared to exert influence on the surface proteins. These changes could be immune escape mutations naturally occurring due to the host immune surveillance especially at the T‐cell level.     

HBV前C区1896点突变株与野生株感染患者临床特点分析

目的探讨乙型肝炎病毒(HBV)前C区1896位点突变株感染的临床特点及其对干扰素治疗的反应差异。方法采用PCR法检测HBV感染者HBV前C区1896点突变,同时检测HBV M和血生化指标。结果HBV前C区1896位点突变株感染病人和野生株感染病人ALT水平分别为268.42±243.76U/L和186.78±142.75U/L,AST为279.66±241.11U/L和172.33±157.27U/L,SB为164.36±114.28μmol/L和82.83±64.39μmol/L,ALB为36.04±5.36g/L和43.27±6.17g/L(P<0.05);HBeAb阳性者和HBeAg阳性者中突变株感染占77.2%和11.3%(P<0.05);慢性重型肝炎组、肝硬化组突变株检出率分别为68.57%和44.23%,明显高于慢性肝炎轻中度组和慢性乙型肝炎重度组的25.47%和40.29%(P<0.01)。HBeAg阳性组和HBeAb阳性组突变株感染对干扰素治疗应答率分别为28.6%和20.8%,明显低于野生株感染者的44.0%和37.5%(P<0.05)。结论HBV前C区1896位点突变株感染普遍存在,突变株...     

e抗原阴性和阳性慢性乙型肝炎患者血清HBVDNA定量与肝组织病理学关系

目的研究HBeAg阴性和阳性慢性乙型肝炎（以下简称慢乙肝）患者血清HBVDNA定量与肝组织炎症活动度及纤维化程度的关系。方法选取慢乙肝患者68例,行肝穿刺病理检查,并检测血清HBVDNA定量,按照HBeAg阴性和阳性分组,进行相关性检验。结果HBeAg阴性患者血清HBVDNA定量与肝组织炎症活动度及纤维化程度之间呈明显正相关,r分别为0．706、0．689,P均小于0．05;HBeAg阳性者血清HBVDNA定量与肝组织炎症活动度及纤维化程度之间均无相关性,r分别为-0．119、-0．096,P均大于0．05。结论血清HBVDNA定量可作为HBeAg阴性慢乙肝患者肝组织损伤程度的预测指标之一。     

乙型肝炎患者YMDD变异57例临床分析

目的探讨HBV发生YMDD变异的相关因素。方法对57例HBVYMDD变异的慢性乙型肝炎患者的临床特点进行回顾性分析。结果57例HBV发生YMDD变异的肝炎患者中,42例(73.7%)使用过拉米夫定,3例(5.3%)使用过干扰素,12例(21.0%)从未使用过抗病毒药物。HBVYMDD变异的肝炎患者,经积极治疗,预后良好。结论HBV发生YMDD变异主要与使用拉米夫定有关,亦存在自然变异。因此,使用拉米夫定一定要严格掌握适应证,在抗病毒治疗前应检测YMDD变异,指导选择使用抗病毒药物。     

HBV宫内感染机制及基因的影响

乙型肝炎是一个世界性公共卫生问题。我国地处乙型肝炎高发区，人群中HBsAg阳性率高达10％以上。近年来的研究表明HBV宫内感染是HBV主要传播途径，亦是造成我国人群中大量乙肝病毒慢性感染者的主要原因，但对宫内感染机制尚无全面系统的研究。现将HBV宫内感染机制及易感因素的近期研究成果综述如下。