聚乙二醇干扰素α-2a治疗多种核苷和核苷酸类药物耐药慢性乙型肝炎的效果观察

目的观察聚乙二醇干扰素(PEG-IFN)α-2a治疗对多种核苷和核苷酸类药物(NAs)耐药的HBe Ag阳性慢性乙型肝炎(CHB)患者的疗效。方法选取武警上海市总队医院2009年8月-2014年2月住院及门诊的对多种NAs耐药的HBe Ag阳性CHB患者120例,根据治疗方法不同将患者分为2组,每组60例。治疗组患者全部停用NAs,改用PEG-IFNα-2a治疗48周;对照组患者维持原有NAs治疗方案不变,加用PEG-IFNα~(-2)a治疗48周。观察治疗24、48周及停药后24周时乙型肝炎血清学标志物及HBV DNA变化情况。计数资料组间比较采用χ~2检验,计量资料组间比较采用t检验。结果 2组患者均取得了较为满意的疗效,治疗第24、48周及停药后24周时2组的血清HBe Ag阴转率、HBe Ag转换率、HBV DNA阴转率以及HBs Ag阴转率相比,差异均无统计学意义(P值均0.05)。PEG-IFNα-2a治疗过程中出现的不良反应包括发热、头痛、注射部位炎症、腹泻、中性粒细胞减少、贫血及抑郁,情况均不严重。结论 PEG-IFNα-2a治疗对多种NAs耐药的CHB安全有效,并可考虑直接换用PEG-IFNα-2a继续抗病毒治疗。     

自体细胞因子诱导的杀伤细胞治疗慢性乙型肝炎患者的临床观察

目的观察自体细胞因子诱导的杀伤细胞(CIK)治疗慢性乙型肝炎(CHB)患者的疗效及安全性,探索CHB治疗的新策略。方法收集2009年12月1日至2012年12月1日南京军区福州总医院收治的84例CHB患者,称为CIK治疗组,采集其外周血单个核细胞,在体外经干扰素γ、白细胞介素2、抗CD3单克隆抗体等细胞因子诱导成CIK,分次自体回输,观察治疗前及治疗后12、24、48周患者肝功能、HBV血清标志物变化及HBV DNA水平;50例接受恩替卡韦(ETV)治疗的患者作为对照组,称为ETV治疗组。将两组HBe Ag阳性和HBe Ag阴性患者分组进行比较分析,同时对不良反应和肾功能进行评估。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验。结果随着观察时间延长,CIK治疗组无论是HBe Ag阳性患者还是HBe Ag阴性患者,其ALT水平均降低,其中HBe Ag阳性患者治疗12、24周时与ETV治疗组相比,两组差异均具有统计学意义(t值分别为5.03、4.72,P值均0.01);CIK治疗组在不同时间点的HBe Ag阴转率和血清转换率均高于ETV治疗组,其中治疗24周和48周时两组间的HBe Ag阴转率差异均有统计学意义(χ2值分别为6.85、4.83,P值均0.05)。无论是HBe Ag阳性还是HBe Ag阴性,在治疗12、24、48周后,CIK治疗组的HBV DNA阴转率均低于ETV组,尤其两组HBe Ag阳性患者的HBV DNA阴转率差异均有统计学意义(χ2值分别为45.62、26.89、12.54,P值均0.01),但随着观察时间延长,CIK治疗组HBV DNA阴转率逐渐升高。结论 CIK治疗CHB后在48周随访观察期内是安全有效的。虽然与ETV治疗相比,HBV DNA下降水平较低,但治疗后随着观察时间的延长,HBe Ag阴转率和血清转换率明显高于ETV治疗组,提示CIK治疗后可能存在持久的免疫应答效应。     

恩替卡韦治疗慢性乙型肝炎的疗效观察

目的评价恩替卡韦治疗慢性乙型肝炎(CHB)患者96周的疗效。方法收集2011年7月-2014年7月在江苏省泰兴市人民医院门诊和住院的62例CHB患者,给予恩替卡韦0.5 mg/d抗病毒治疗96周。所有病例分为两组,HBe Ag阳性组患者43例,HBe Ag阴性组患者19例。其中HBV DNA106拷贝/ml患者38例,HBV DNA106拷贝/ml患者24例。比较两组治疗24、48及96周的疗效。计数资料组间比较采用χ2检验。结果在治疗24、48、96周时,HBe Ag阳性组患者HBV DNA阴转率分别为34.88%、65.12%、74.42%,明显低于HBe Ag阴性组的78.95%、89.47%、100%,差异均有统计学意义(P值分别为0.003、0.047、0.038)。两组患者的ALT复常率差异均无统计学意义(P值分别为0.102、0.779、0.638)。在38例HBV DNA载量106拷贝/ml和24例HBV DNA载量106拷贝/ml的两组中,治疗24、48、96周时,两组患者HBV DNA阴转率差异均有统计学意义(34.21%vs70.83%、57.89%vs 95.83%、76.32%vs 95.83%,P值分别为0.005、0.001、0.002);两组患者ALT复常率差异均无统计学意义(P值分别为0.940、0.150、0.280)。结论恩替卡韦治疗CHB有很好的抗病毒活性,在抑制病毒复制的同时能改善肝功能。     

替比夫定联合阿德福韦酯与PEG-IFN联合恩替卡韦治疗慢性乙型肝炎的效果比较

目的观察替比夫定联合阿德福韦酯与PEG-IFNα-2a联合恩替卡韦治疗HBe Ag阳性的高病毒载量的慢性乙型肝炎患者的疗效差异。方法选取2012年11月-2015年11月在青岛市第六人民医院就诊的HBe Ag阳性、高病毒载量的慢性乙型肝炎初治患者共80例,随机分成两组,每组40例。A组为替比夫定联合阿德福韦酯抗病毒组,B组为PEG-IFNα-2a联合恩替卡韦抗病毒组。观察两组患者分别服药12、24、48周时生化学、病毒学及血清学转换率有无差异。观察两组患者病毒耐药率及不良反应发生情况。计量资料组间比较采用t检验,计数资料组间比较采用χ~2检验。结果两组患者在12、24、48周时病毒学、生化学应答率差异均无统计学意义(P值均0.05)。12、24周时两组血清学转换率无明显差异,而48周时B组HBe Ag阴转率及血清学转换率均高于A组且差异均有统计学意义(45.0%vs 67.5%,22.5%vs 45.0%,χ~2值分别为4.114 3、4.528 3,P值均0.05)。B组患者出现的不良反应高于A组。结论 PEG-IFNα-2a联合恩替卡韦和替比夫定联合阿德福韦酯均可有效抑制高载量HBV DNA的复制,延缓病情进展,实现HBe Ag的血清学转换。但两种方案各有利弊,需根据临床实际情况加以选择。     

聚乙二醇干扰素α-2a治疗HBeAg阳性慢性乙型肝炎患儿的疗效观察

目的研究聚乙二醇干扰素(PEG-IFN)α-2a治疗HBe Ag阳性的慢性乙型肝炎(CHB)患儿的疗效。方法随机入组的来自昆明市第三人民医院31例2~16岁儿童CHB患儿,按年龄分为小龄组(2~6岁,n=17)及大龄组(7~16岁,n=14)。所有患儿均接受PEG-IFNα-2a治疗(首剂104μg/m2,1次/周,逐渐增加剂量至135μg/周),疗程24~72周不等。研究过程中监测ALT、HBV DNA、HBV血清学标志物及HBs Ag定量水平等指标,比较两年龄组在不同时间点的生化学、病毒学、血清学应答,分析疗效与年龄、疗程及治疗过程中HBs Ag定量水平动态变化的关系及安全性。计量资料组间比较采用t检验,计数资料比较采用χ2检验。结果小龄组与大龄组各时间点的生化学、病毒学应答方面差异均无统计学意义(P值均>0.05)。治疗24周时小龄组的HBs Ag阴转率明显高于大龄组(41.2%vs 7.1%;χ2=4.644,P<0.05);治疗52及72周时小龄组的HBs Ag定量水平分别为129.22±78.99和51.80±31.54 IU/ml;大龄组患儿52及72周HBs Ag定量水平分别为4677.12±2557.85和1031.37±546.37 IU/ml,与基线相比小龄组患儿52及72周HBs Ag定量水平下降幅度显著高于大龄组,差异有统计学意义(t值分别为2.25、2.23,P值均<0.05)。治疗52周,小龄组与大龄组HBV DNA阴转率、HBe Ag阴转率、HBe Ag血清学转换率、HBs Ag清除率与血清学转换率均有增加的趋势,但差异均无统计学意义(P值均>0.05)。延长治疗至72周的患儿HBV DNA阴转率100%,HBe Ag血清学转换率为80%,HBs Ag血清学转换率为60%。25例停药随访的患儿均无复发。研究中常见的不良反应为流感样症状、血象改变、食欲下降。治疗前后身高、体质量与同龄儿童差异无统计学意义。结论对于小儿CHB而言,PEG-IFNα-2a是可选治疗方案,PEG-IFNα-2a的疗效与患儿年龄和疗程有关。年龄越小,HBs Ag定量水平下降幅度越大,HBs Ag阴转率越高;延长疗程可提高疗效。治疗过程中HBs Ag定量水平变化具有预测疗效的价值。儿童应用安全性较好。     

聚乙二醇干扰素α加用阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的效果观察

目的评价聚乙二醇干扰素(PEG-IFN)α治疗HBe Ag阳性慢性乙型肝炎(CHB)患者12/24周联合阿德福韦酯(ADV)的疗效。方法回顾性收集2009年10月~(-2)014年1月在福建医科大学附属第一医院接受PEG-IFNα治疗12周,HBV DNA≥105拷贝/ml的HBe Ag阳性CHB患者。根据治疗方案分为12周联合ADV组(A组,n=36)、24周联合ADV组(B组,n=19)及PEGIFNα单药治疗组(C组,n=19),比较治疗48周联合应答率,并分析影响疗效的因素。多组间比较采用单因素方差分析,计数资料比较采用χ~2检验,疗效预测采用受试者工作特征曲线和Cox多因素回归分析。结果治疗48周时,A组的联合应答率为27.78%(10/36),高于B组5.26%(1/19)和C组5.26%(1/19)(P值均为0.045);12周的HBe Ag下降值、24周HBe Ag下降值和24周HBV DNA下降值预测联合应答的阴性预测值分别为90.0%、94.44%和94.55%。24周HBV DNA水平103拷贝/ml和24周HBe Ag下降值1.06 log10S/CO是联合应答的独立预测因素。结论 PEG-IFNα治疗12周HBV DNA仍≥105拷贝/ml的HBe Ag阳性CHB患者,联合ADV可以提高48周联合应答率。24周HBe Ag下降值和24周HBV DNA下降值预测联合应答的阴性价值高。     

非酒精性脂肪性肝病对慢性乙型肝炎肝纤维化及α-干扰素抗病毒疗效的影响

目的探讨非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)对慢性乙型肝炎(chronic hepatitis B,CHB)肝纤维化及α-干扰素抗病毒疗效的影响。方法回顾性分析2011年1月-2013年12月湖北医药学院附属人民医院经α-干扰素抗病毒治疗的85例CHB初治患者的临床资料,其中53例为单纯CHB,32例经B超诊断为CHB合并NAFLD。所有患者均采用干扰素α1b抗HBV治疗,比较两组在第12、24、48周时ALT复常率、HBV DNA阴转率、HBe Ag阴转率及血清转换率。结果单纯CHB组年龄、体质量指数(BMI)、腰围、血脂(TC、TG)、空腹血糖(FBG)、尿酸(UA)及肝纤指标(HA、LN、PcⅢ)均明显低于CHB合并NAFLD组(P0.05),而高密度脂蛋白(HDL)高于CHB合并NAFLD组(P0.05)。治疗第48周时,单纯CHB组ALT复常率和HBV DNA阴转率分别为60.4%和66.0%,明显高于CHB合并NAFLD组的37.5%和40.6%,差异有统计学意义(P0.05)。两组在第12、24周的ALT复常率、HBV DNA阴转率及第12、24、48周时HBe Ag阴转率和HBe Ag转换率差异均无统计学意义(P0.05)。结论 NAFLD对CHB肝纤维化及α-干扰素抗病毒疗效具有一定的影响。     

IFN-α 1b治疗核苷（酸）类似物经治未达满意终点的CHB多中心疗效分析

目的评估序贯联合重组人干扰素α1b（IFN-α1b）治疗核苷（酸）类似物（NAs）经治HBe Ag阳性CHB患者48周的疗效与安全性。方法 159例NAs治疗12-36个月HBV DNA检测不到但未发生血清学应答的HBe Ag阳性CHB患者,77例接受序贯联合IFN-α1b治疗48周,82例继续NAs单药治疗48周。基线和治疗期间每12周进行生物化学、病毒学和血清学评估。计量资料采用t检验,计数资料采用χ^2检验。结果治疗48周,试验组HBe Ag低于检测下限和转换率分别为21.74%和20.29%,对照组HBe Ag低于检测下限和转换率分别为5.63%和5.63%,差异有统计学意义（χ^2=7.738、6.709,P〈0.05）。试验组和对照组HBs Ag清除率分别为7.25%和0%,差异有统计学意义（χ^2=5.335,P〈0.05）。试验组和对照组病毒学反弹率分别为0%和4.22%,差异无统计学意义（χ^2=2.979,P〉0.05）。无论是试验组还是对照组,HBs Ag基线水平高的患者（〉2000 IU/ml）的HBe Ag血清学转换率高于基线水平低（≤2000 IU/ml）的患者;差异无统计学意义（χ^2=2.833、0.147,P〉0.05）。HBs Ag下降幅度与HBe Ag下降幅度具有相关性（r=0.606）。NAs基础治疗时间可能对序贯联合干扰素后的HBe Ag低于检测下限和转换有一定影响,但无论基础治疗时间长短,序贯联合干扰素均可增加HBe Ag应答率。结论序贯联合IFN-α1b有助于提高NAs经治未达满意治疗终点的HBe Ag阳性CHB患者的血清学应答率。     

联合治疗策略在应答不佳/耐药HBeAg阳性慢性乙型肝炎患者中的临床研究

目的比较采用聚乙二醇干扰素(pegylated interferon,Peg-IFN)+核苷(酸)类似物[nucleos(t)ide analogues,NAs]和NAs+NAs二种方案治疗NAs治疗应答不佳/耐药的HBe Ag阳性慢性乙型肝炎(chronic hepatitis B,CHB)的疗效和安全性,探求具有停药终点的优化治疗方案。方法选择NAs抗病毒治疗应答不佳/耐药的HBe Ag阳性CHB患者110例,根据既往NAs用药史、耐药检测结果及个人意愿,采用Peg-IFN+NAs(IFN组)或NAs+NAs(NA组)进行抗病毒治疗。比较2组在治疗48周和96周时完全病毒学应答(HBV DNA20 IU/ml)率、HBe Ag血清学转换率及HBs Ag清除/血清学转换率。结果 IFN组58例,NA组52例,2组分别有45例和42例完成96周疗程。在治疗48周IFN组和NA组完全病毒学应答率分别为96.55%(56/58)和67.31%(35/52);96周分别为100%(45/45)和71.43%(30/42),IFN组均高于NA组(P值均为0.001)。IFN组在治疗48周和96周HBe Ag血清学转换率(20.69%、46.67%)高于NA组(5.77%、21.43%),差异有统计学意义(P=0.023、0.013)。24、48、96周时IFN组HBs Ag水平明显低于NA组。截至96周IFN组8例(17.78%)HBs Ag清除,其中3例(6.67%)发生HBs Ag血清学转换。NA组在治疗96周出现1例(2.38%)HBs Ag清除。IFN组的HBs Ag清除率高于NA组(P=0.045)。结论对于NAs治疗应答不佳/耐药的CHB患者,采用Peg-IFN+NAs和NAs+NAs的治疗方案均可有效抑制病毒复制;在HBe Ag血清学转换及HBs Ag清除方面,Peg-IFN+NAs联合治疗方案更具优势。采用以IFN为基础的联合治疗可使NAs应答不佳/耐药患者获得可靠的停药终点。     

急性乙型肝炎与慢性乙型肝炎急性发作的临床特征比较

目的探讨鉴别急性乙型肝炎(AHB)和慢性乙型肝炎(CHB)急性发作的临床特征。方法回顾性分析2014年6月~(-1)2月在复旦大学附属公共卫生临床中心就诊的96例AHB和124例CHB急性发作患者的临床资料。计量资料组间比较采用MannWhitney U检验,计数资料组间比较采用χ~2检验。结果 AHB和CHB急性发作在发病年龄和性别方面差异无统计学意义,男性发病率高于女性。AHB以性接触和医源性传播为主,而CHB急性发作以母婴垂直传播为主。基线ALT水平≥1072 U/L诊断AHB的敏感性和特异性分别为78.6%和79.2%;抗-HBc-Ig M滴度≥13.6 S/CO诊断AHB的敏感性和特异性分别为94.5%和89.3%。入院2周时AHB组HBs Ag、HBe Ag和HBV DNA较基线的下降值均显著高于CHB急性发作组且差异有统计学意义(P值均0.05)。入院第8周时AHB患者HBs Ag阴转率、抗-HBs阳转率、HBe Ag阴转率、抗-HBe阳转率和HBV DNA阴转率均显著高于CHB急性发作患者(P值均0.05)。结论明确传播途径、基线高ALT水平和抗-HBc-Ig M水平、快速HBV DNA阴转和HBV血清学标志物转换均有助于AHB和CHB急性发作的鉴别诊断。     

病原未定型肝炎的临床研究

目的探讨病原未定型肝炎的临床特征。方法以43例慢性乙型肝炎和30例急性乙型肝炎为对照组,对62例病原未定型肝炎患者进行临床分析,比较病原未定型肝炎的流行病学、临床表现、实验室检查及肝组织学改变。结果62例病原未定型肝炎患者发病以冬末及春季多见;发病年龄以青、中年(18岁~50岁)占92.2%;临床表现有急性和慢性,多数症状轻、肝病体征少;血清转氨酶水平呈轻、中度升高;肝活检组织病理学显示炎症轻;绝大多数预后良好。结论病原未定型肝炎的致病因子仍不清楚。     

Histological evolution of chronic hepatitis C. Factors related to progression

We have evaluated the histological progression of liver disease in 29 untreated patients with chronic hepatitis C. All patients were positive to antibodies to hepatitis C virus by ELISA2 and RIBA2. Two liver biopsies were carried out for each patient, with an interval ranging between 12 and 126 months (mean 50.2±30.7). In all cases the usual histological classification was applied and the histological activity index scoring system according to Knodell et al. was determined. Fifteen cases worsened (51.7%), 12 cases showed no histological changes (41.4%) and two patients improved (6.9%). Cirrhosis was found in five patients (18.5%) in the second liver biopsy. Epidemiological, clinical, biochemical and histological parameters were compared between the group without histological progression and the group with impairment in liver histology. Factors related to histological worsening were: more advanced age (p=0.002), high levels of aspartate aminotransferase (p=0.04), high global histological activity index (p=0.03) and piecemeal necrosis and bridging necrosis scores (p=0.02) at first biopsy. The histological activity index can be applied to assess the natural history of chronic viral hepatitis, and is a good tool to evaluate the prognosis. Thus chronic hepatitis C virus infection is a histologically progressive disease in at least half the cases.     

Absence of anti-LKM-1 antibody in hepatitis C viral infection in the United States of America

Summary. Several studies from Europe have observed a relationship between hepatitis C virus infection and anti-liver/kidney microsome-1 (anti-LKM-1) positive chronic hepatitis. It has been suggested that hepatitis C may induce an autoimmune phenomenon that leads to the development of a specific type (type II anti-LKM-1 positive) autoimmune chronic hepatitis. We evaluated 204 sera from patients with well-documented hepatitis C infection from two centres in the United States of America and compared them with sera from 428 French patients from three centres. We evaluated the serological prevalence of anti-smooth muscle antibodies, anti-nuclear antibodies, anti-liver cytosol antibodies, and anti-mitochondrial antibodies subtype anti-M₂ in patients with chronic hepatitis C. The two groups were matched in their ages, gender, mode of transmission of hepatitis C infection and severity of liver disease. Anti-LKM-1 was not observed in the patients from the USA at a time when it was noted in 3.7% of French patients. There were no differences, however, in the expression of other auto-antibodies, which were often in low titres. Absence of anti-LKM-1 in USA sera in comparison with French sera suggests that there may be differences in induction of anti-LKM-1 related to environmental and/or host genetic factors, and/or genomic variation in the hepatitis C virus.     

Detection of HBV core promoter and precore mutations helps distinguish flares of chronic hepatitis from acute hepatitis B

Background and Aim: Acute exacerbation of chronic hepatitis B has to be distinguished from acute hepatitis, because treatment strategies differ between them. Methods: Mutations in the core promoter and precore region of hepatitis B virus (HBV) were determined in 36 patients with acute exacerbation of chronic hepatitis B, in whom alanine aminotransferase (ALT) increased above 500 IU/L, as well as the 36 patients with acute hepatitis. Results: Mutations in the core promoter (A1762T/G1764A) and precore region (G1896A) were more frequent in patients with acute exacerbation of chronic hepatitis than acute hepatitis (81% vs 19%; P < 0.0001 and 58% vs 6%; P < 0.0001, respectively). Of the 19 patients with mutations in both the core promoter and precore region, 17 (89%) had acute exacerbation of chronic hepatitis. In contrast, among the 32 patients with the wild‐type for both the core promoter and precore region, 29 (89%) developed acute hepatitis. By multivariate analysis, the double mutation in the core promoter was predictive of acute exacerbation in chronic hepatitis with the highest odds ratio at 26.4. Conclusions: In patients with hepatitis B having ALT levels >500 IU/L, mutations in the core promoter and precore region are useful in distinguishing acute exacerbation of chronic from acute HBV infection. Detection of these mutations would be useful for commencing prompt antiviral treatments on patients with acute exacerbation of chronic hepatitis for a better prognosis.     

A case of transfusion-acquired hepatitis C

Summary The Blood Transfusion Service introduced screening for Hepatitis C antibody (HCV) in September 1991. This is done by second generation enzyme linked immunosorbent assay (ELISA) tests. We present a case of post-transfusion hepatitis C hepatitis in a patient with myeloma. Infection was acquired before screening was introduced. Both the patient and the infected blood donor were diagnosed using ELISA assays and the polymerase chain reaction (PCR). In this way we prevented the blood donor from spreading the virus via subsequent blood donations. There were some interesting discrepancies in the HCV assays. Blood samples, when tested by different methods, gave both positive and negative results. The results also varied according to when the blood samples to be tested were taken. The case illustrates the importance of confirming positive results and that no single laboratory test is entirely satisfactory in diagnosing HCV infection.     

The medical impact of hepatitis D virus infection in Asia and Africa; time for a reappraisal

Although hepatitis D is believed to be an important medical problem in Africa and many areas of Asia, the geographical distribution and prevalence rates of infection with the hepatitis D virus (HDV) vary considerably, are often inconsistent and sometimes conflicting. Discrepancies may depend on methodological problems, primarily on different modalities of patients' recruitment; these are analysed in this mini‐review, in order to provide a uniform clinical approach when testing patients with chronic HDV disease.