抗病毒药物治疗慢性乙型肝炎的效果及对预后的影响

目的分析北京地区抗病毒药物对慢性乙肝患者治疗的现状、疗效及对预后的影响。方法采用回顾性前瞻研究的方法。结果干扰素、拉米夫定抗病毒治疗覆盖率约40％。疗程结束时HBV DNA阴转率拉米夫定组最高，但停药随访时180／220例出现反跳。干扰素组HBeAg血清转换率（22．9％）高于其他组，有统计学意义。干扰素及拉米夫定治疗者病情进展较慢且肝硬化、肝癌发生率明显低于非抗病毒组（P〈0．001）。E系统转换组的并发症和死亡率明显低于非转换组（P〈0．05）。结论北京地区干扰素和拉米夫定抗病毒治疗覆盖率高于其他地区，效果优于其他药物组，但总体疗效仍较低。干扰素等抗病毒治疗能减缓病情进展和减少肝硬化、肝癌的发生率。     

加强慢性乙型肝炎的抗病毒治疗

我国“慢性乙型肝炎防治指南”指出:“慢性乙型肝炎治疗主要包括抗病毒、免疫调节、抗炎保肝、抗纤维化和对症治疗,其中抗病毒治疗是关键,只要有适应证,且条件允许,就应进行规范的抗病毒治疗[1]。”但据调查,我国仅有19%慢性乙型肝炎患者接受抗病毒治疗;45%医务人员不知道慢性乙型肝炎规范化抗病毒治疗;73%医师仅用中成药和保肝降酶药治疗慢性乙型肝炎患者;38%慢性乙型肝炎患者轻信虚假广告。因此,多数慢性乙型肝炎患者未能得到及时、规范的抗病毒治疗,从而延误了病情,甚至发展成为肝硬化和肝细胞癌(HCC)。值得指出的是:我国一方面是大多…     

慢性重型乙型肝炎转归相关因素及抗病毒治疗研究

目的探讨慢性重型乙型肝炎转归的影响因素及抗病毒治疗对其转归的影响。方法应用回顾性研究方法,分析330例慢性重型乙型肝炎患者的年龄、凝血酶原活动度(PTA)、血清中HBeAg、抗-HBe滴度,HBV-DNA定量,有无并发症,抗病毒治疗等因素与转归的关系。结果慢性乙型重型肝炎患者随年龄增加、PTA降低、并发症增多,其死亡率明显增高;慢性乙型重型肝炎患者血清HBV-DNA定量大于1×105拷贝/ml者其死亡率(52.3%)比HBV-DNA小于1×105拷贝/ml的死亡率(32.9%)明显升高;HBeAg,抗-HBe的表达对死亡率无影响;2005年应用拉米夫定抗病毒治疗后慢性乙型重型肝炎HBV-DNA定量大于1×105拷贝/ml的患者其死亡率(30.38%)比2001年未使用抗病毒治疗者(54.64%)明显下降。结论影响慢性乙型重型肝炎预后的因素除年龄、PTA、有较多并发症外,患者血清中高病毒载量是影响其死亡率的关键因素,及时抗病毒治疗可以降低患者的死亡率。     

慢性乙型肝炎抗病毒治疗依从性影响因素分析

目的探讨慢性乙型病毒性肝炎患者用药依从性的影响因素。方法以服药依从性差的32例患者为观察组;服药依从性好的32例患者为对照组。采用Logistic回归分析方法,探索影响慢性乙型肝炎患者服药依从性的因素。结果与服药依从性差的患者相比,服药依从性好的患者组中有乙肝家族史（OR0．042,95％C．I．0．005～0．333）、抗病毒治疗的认知程度高（OR 0．112,95％C．I．0．014～0．872）和“医师告知”详细（OR0．142,95％C．I．0．020～0．993）的出现服药依从性差的危险度均降低。结论有乙肝家族史的患者,可从亲属的诊疗经历中获得经验,而服药依从性较好。此外,医师加强对患者“治疗认知度”的培训,可提高患者抗病毒治疗的依从性。     

HBeAg阴性乙型肝炎ACLF患者的临床特征及抗病毒治疗短期疗效

目的 观察HBeAg阴性乙型肝炎慢加急性肝衰竭患者的临床特征及应用恩替卡韦抗病毒治疗的短期疗效.方法 132例HBeAg阴性和51例HBeAg阳性乙型肝炎慢加急性肝衰竭患者,分为常规治疗组及抗病毒治疗组,抗病毒组在常规内科治疗基础上加用恩替卡韦0.5 mg/d治疗,比较两组患者临床特征、病死率及抗病毒治疗短期疗效差异.结果 与HBeAg阳性组比较,HBeAg阴性组年龄较大(P=0.001),血清HBV DNA定量较低(P=0.001).HBeXS阴性组与HBeAg阳性组肝衰竭分期构成比及常规治疗病死率比较无差异.应用恩替卡韦抗病毒治疗时HBeAg阴性组生存率为54.24%,高于常规治疗组(35.62%),P=0.032,低于HBeAg阳性抗病毒组(80.00%),P=0.004.HBeAg阴性组血清HBV DNA在(3～5)log10拷贝/ml时,抗病毒治疗组生存率为55.56%,高于常规治疗组(20.00%),P=0.011.结论 乙型肝炎慢加急性肝衰竭患者中,常规治疗下HBeAg阴性患者与HBeAg阳性患者的病死率无差异.采用恩替卡韦抗病毒治疗能提高HBeAg阴性患者的生存率.在HBV DNA低水平复制的HBeAg阴性患者中恩替卡韦抗病毒治疗能提高生存率.     

拉米夫定联合胸腺素α1治疗慢性重型乙型肝炎疗效观察

目的研究拉米夫定联合胸腺素α1治疗慢性重型乙型肝炎的疗效、安全性及对预后的影响。方法以我院住院慢性重型肝炎病人为研究对象共慢性重型乙型肝炎89例，分成治疗组55例，对照组34例。对照组采用拉米呋定等支持、保肝综合疗法；治疗组在此基础上加胸腺素α1 1．6mg，每天一次皮下注射，1周后改为每周2次，共24周。治疗过程检测血清总胆红素（TBiL）、丙氨酸氨基转氨酶（ALT）、凝血酶原时间（PTA）、血清白蛋白、乙肝病毒定量、YMDD变异及乙肝血清标志物。结果治疗组总有效率78．2％，死亡12人，病死率21．8％；对照组总有效率47．1％，死亡18人。病死率52．9％，两组比较差异有显著性（P〈0．05）；治疗组治疗后各项生化指标改善均优于对照组（P〈0．05）。治疗1年时治疗组的HBVDNA阴转率及HBeAg阴转率均明显高于对照组（P〈0．05），治疗组YMDD（HBVDNA聚合酶活性区酪氨酸-蛋氨酸-门冬氨酸-门冬氨酸变异）变异数少于对照组，治疗组HbeAg血清转换数高于对照组。治疗组及对照组用药过程未发现明显药物不良反应。结论在综合护肝治疗基础上。联合应用拉米夫定和胸腺素α治疗慢性重型乙型肝炎能减轻肝脏的免疫性损伤，抑制病毒复制，改善肝功能，减少并发症，降低病死率，无明显不良反应，治疗重型肝炎安全、有效。     

早期糖皮质激素联合抗病毒药物治疗重型乙型肝炎病例对照研究

目的 探讨糖皮质激素治疗早期重型乙型肝炎的临床疗效.方法 将56例重型乙型肝炎早期患者随机分为糖皮质激素治疗组(实验组)与常规治疗组(对照组).观察两组治疗前后总胆红素、凝血酶原时间、谷丙转氨酶及并发症发生率的情况.结果 (1)实验组与对照组治疗后ALT均有改善(P＜0.05),两者治疗后感染、出血及肝性脑病等并发症发生无统计学差异(P＞0.05).(2)实验组治疗前后血清总胆红素、凝血功能明显改善(P＜0.05),对照组治疗前后比较总胆红素、凝血功能差异均无统计学意义(P＞0.05),两组治疗后,实验组白细胞明显高于对照组(P＜0.05),但仍在正常值范围之内.结论 在重型乙型肝炎早期,短期、中等剂量使用糖皮质激素对于黄疸下降及凝血功能的改善优于常规治疗,且未增加感染、出血等常见并发症的发生率,但其对临床预后的影响还需进一步深入研究.     

慢性乙型肝炎抗病毒治疗后病毒学应答与特异性细胞免疫的关系

目的探讨阿德福韦酯治疗慢性乙型肝炎（CHB）患者病毒学应答与HBV特异性细胞毒性T淋巴细胞（CTL）的关系。方法51例CHB患者,HBVDNA阳性（HBVDNA≥I×10^4拷贝／ml,HBeAg阳性32例（62．75％）、丙氨酸转氨酶（ALT）〉2×正常值上限（ULN）、人白细胞抗原（HLA）-A2阳性,用阿德福韦酯10mg,口服,每日1次。观察治疗72周后HBVDNA转阴和HBeAg血清学转换与HBV特异性CTL的关系。结果阿德福韦酯治疗72周后,HBVDNA转阴（〈500拷贝／m1）39例（76．47％）,其HBV特异性CTL（0．81％±0．06％）,高于12例（23．53％）的HBVDNA未转阴者（0．66％±0．06％）,t=7．93,P〈0．01,IqBeAg血清学转换8例（25％）,其HBV特异性CTL（0．97％±0．07％）,高于24例（75％）的无HBeAg血清学转换者（0．67％±0．07％）,t=7．61,P〈0．01。结论阿德福韦酯治疗CHB患者病毒学应答和血清学应答与HBV特异性CTL水平升高有关。     

动态观察血清HBV-DNA水平预测干扰素治疗慢性乙型肝炎疗效的意义

目的　研究干扰素 α 2a治疗慢性乙型病毒性肝炎 (慢性乙肝 )期间 ,患者血清中HBV-DNA定量的动态变化与疗效的关系。方法　 5.8例慢性乙肝患者皮下注射干扰素 α-2a3MIU 次 ,每周 3次 ,疗程 6个月。观察患者血清中HBV DNA定量和丙氨酸转氨酶 (ALT)的动态变化。结果　完全有效组治疗 1个月后 ,患者血清中HBV DNA定量显著降低 [(3 99± 0.91)log1.0 ],明显低于部分有效组[(5.6 3± 1.31)log1 0 ]和无效组 [(6.6 9± 1.4 2 )log1 0 ],(P <0.0 5 )。疗效不同的 3组患者经过 1个月的治疗 ,血清中HBV DNA定量分别下降 (2.5 0± 0.4 4 )log1 0 、(1 6 2± 1.12 )log1 0 和 (1 0 5± 1.35 )log1 0 。通过多因素分析 ,用干扰素 α-2a治疗 1个月后患者血清中HBV DNA阴转 ,提示干扰素 α-2a的疗效好 ;治疗前ALT高水平和无家族史也与其疗效好相关。结论　患者治疗 1个月后血清中HBV DNA定量是预测干扰素 α 2a疗效的重要因素     

慢性乙型肝炎的抗病毒治疗

目的 根据慢性乙型肝炎患者的自身情况选择抗病毒药物.方法 查阅国内外相关资料,进行总结分析.结果 干扰素及核苷类似物在临床应用方面日趋成熟.结论抗病毒治疗是慢性乙型肝炎最根本的治疗方法.     

扶正化瘀胶囊联合核苷类抗病毒药物治疗慢性乙型肝炎的meta分析

目的系统评价扶正化瘀胶囊联合核苷类抗病毒药物治疗慢性乙型肝炎的疗效。方法纳入文献中以核苷类抗病毒药物为对照组,以扶正化瘀胶囊联合核苷类抗病毒药物为试验组。由2名研究者独立评价纳入研究的方法学质量,并采用RevMan 5.1软件进行meta分析。结果共纳入17个随机对照试验,合计1 320例慢性乙型肝炎患者,其中对照组636例,试验组684例,1个研究方法学质量为B级,16个研究方法学质量为C级。meta分析结果显示：肝功能4个指标（丙氨酸转氨酶、天冬氨酸转氨酶、总胆红素、白蛋白）在治疗24周时2组无统计学差异（P〉0.05）,进一步治疗到48周时试验组前3个指标明显下降,最后1个指标明显上升（P〈0.05）。肝纤维化指标（透明质酸、Ⅳ型胶原）在治疗24周时2组有统计差异（P〈0.05）,48周时2个指标值进一步降低（P〈0.05）。解剖学指标（门静脉直径）在治疗24周时2组无统计学差别（P〉0.05）,试验组脾脏厚度有明显减小（P〈0.05）,进一步观察48周后发现门静脉直径开始减小（P〈0.05）,而脾脏厚度进一步减小（P〈0.05）。血清病毒学指标（HBeAg阴转率、HBV-DNA阴转率）在治疗24、48周时均无明显改善（P〉0.05）。结论本系统评价结果表明,扶正化瘀胶囊联合核苷类抗病毒药在治疗48周时能明显改善慢性乙型肝炎患者肝功能、肝纤维化、解剖学指标,但对血清病毒学指标无明显改善作用。     

Serum HBeAg quantitation during antiviral therapy for chronic hepatitis B

Hepatitis Be antigen (HBeAg) seroconversion is considered the principal short-term goal of antiviral therapy in chronic hepatitis B. To test whether the pre- and per-treatment HBeAg quantitation has a higher predictive value than that of hepatitis B virus DNA (HBV-DNA) quantitation for the outcome of antiviral therapy in chronic hepatitis B. A quantitative measurement of HBV-DNA and HBeAg (AxSYM HBe 2.0 Quantitative, Abbott Laboratories) was undertaken in serial serum samples from 30 patients with 16-week interferon-α (IFN-α) treatment (follow-up 36 weeks; 14 responders) and from 15 patients with 24-week lamivudine treatment (follow-up 24 weeks; 2 responders). In the group of interferon-treated patients, the median pretreatment HBV-DNA level was significantly lower in responders compared to nonresponders (P = 0.02); the difference in median HBeAg level was not significant. However, the percentage of response was significantly related (P = 0.003) to the magnitude of decline in HBeAg level between the start of therapy and week 4. This phenomenon was not observed for HBV-DNA. Using multivariate analysis, it was found that the fall of HBeAg levels between weeks 0 and 4 was the most important independent predictor of response. In the group of lamivudine treated patients, the rapid decline in HBV-DNA (>90%) in 12 patients at week 4 had no relation to HBeAg seroconversion. In contrast, the fall in HBeAg-level (one patient with >50% reduction at week 4 seroconverted) appears to be predictive. Quantitation of HBeAg at start and early during therapy may have clinically important predictive value for long-term response to antiviral therapy. J. Med. Virol. 53:282–287, 1997. © 1997 Wiley-Liss, Inc.     

Foscarnet therapy in chronic hepatitis B virus E antigen carriers

Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.     

Occult HBV infection may represent a major risk factor of non-response to antiviral therapy of chronic hepatitis C

Occult hepatitis B virus (HBV) infection is common in chronic hepatitis C patient. However, its significance and consequences are still unclear. The aim of this study was to evaluate the prevalence of occult HBV among HCV chronic carriers in France and to assess its impact on liver histology and response to antiviral therapy. To this end a cohort of 203 patients with chronic hepatitis C without hepatitis B surface antigen (HBsAg) has been examined. Serum HBV-DNA was detected using a highly sensitive PCR with primers located in the S and X genes. HBV viraemia levels were further determined by real-time PCR. Results showed that 47 of 203 (23%) patients had occult HBV infection with a low HBV load (10(2)-10(4) copies/ml) but significantly higher HCV-RNA titers (P < 0.05). No significant difference in age, gender, serum ALT level, HCV genotypes, and the presence of anti-HBc was observed between patients with or without HBV-DNA. When compared histologically, patients with occult HBV infection had higher activity (A2-A3 in 53% vs. 38%, P < 0.01) and more advanced fibrosis (60% vs. 33%, P < 0.001) than HBV-DNA negative cases. Sustained response to combination therapy against Chronic hepatitis C was achieved in 11 (28%) of 40 HBV-DNA positive cases, compared with 65 (45%) of the 144 HBV-DNA negative cases (P < 0.05). Among the 144 HBV-DNA negative HCV patients those with genotype 1 responded less frequently to therapy as compared to other genotypes infected patients (38% vs. 55%, P < 0.05). Surprisingly, when considering all patients studied, irrespective to the HBV-DNA status no significant difference was observed in response to combination therapy regarding HCV genotypes (39% vs. 44%, P > 0.05). In conclusion, HBV-DNA is found in 1/4 of French chronic hepatitis C patients regardless of the presence of anti-HBc. Such an occult HBV co-infection is associated with more severe liver disease, higher HCV viral load and decreased response to antiviral therapy irrespective of HCV genotypes.     

Intrahepatic CD8 T-lymphocytes and HBV core expression in relation to response to antiviral therapy for chronic hepatitis B patients

Recognition of HBV-infected hepatocytes by CD8 T-lymphocytes is important for viral clearance. Expression of hepatitis B core antigen (HBcAg) in HBV-infected hepatocytes can trigger this antiviral T-cell response. The intrahepatic CD8 T-lymphocytes and HBcAg expression were investigated in relation to response to antiviral therapy. Forty chronic HBeAg-positive patients treated with either lamivudine (n = 20) or interferon-alpha (n = 20) were investigated. Ten patients from each treatment group exhibited a response. Liver biopsies were carried out before and after therapy. CD8 T-lymphocytes and HBcAg expression were detected by immunohistochemistry. The number of pretreatment intrahepatic CD8 T-lymphocytes was significantly higher in responders (P = 0.008). In responders baseline nuclear HBcAg expression tended to be lower (P = 0.09). Cytoplasmic expression was not significantly different between responders and non-responders (P = 0.46). The number of CD8 T-lymphocytes correlated with cytoplasmic HBcAg (r(s) = 0.31; P = 0.04); CD8 T-lymphocytes were situated in clusters of hepatocytes with cytoplasmic HBcAg. Longitudinal analysis showed a significant reduction of CD8 T-lymphocytes after treatment in responders (P < 0.001). Multivariate analysis revealed pretreatment CD8 T-lymphocytes and age as independent prognostic factors for response (n = 40). The number of pretreatment CD8 T-lymphocytes was the only independent prognostic indicator for response to interferon-alpha (P = 0.03); it was of borderline significance for lamivudine therapy (P = 0.06). It is concluded that the number of pretreatment intrahepatic CD8 T-lymphocytes is an important predictor of response to HBV therapy with either interferon-alpha or lamivudine. Response to therapy led to a significant reduction of intrahepatic CD8 T-lymphocytes. Co-localisation of CD8 T-lymphocytes and HBcAg-positive hepatocytes suggests antiviral activity predominantly at the site of maximum HBV replication.     

核苷类似物抗病毒过程中乙型肝炎表面抗原与DNA复制水平的相关性

目的 监测核苷类似物治疗慢性乙犁肝炎(CHB)的过程中HBsAg及HBV DNA水平的动态变化,并探讨HBsAg滴度与HBV DNA复制水平的相关性.方法 选取57例拉米夫定(LAM)、20例阿德福韦(ADV)抗病毒治疗2年以及23例未使用核苷类似物治疗的CHB患者,所有患者均未进行其它抗病毒药物治疗.于不同时间点采集血清标本,动态监测HBsAg及HBV DNA水平,并分析两者之间的相关性.结果 (1)57例LAM抗病毒治疗的CHB患者中,20例有效应答后出现病毒反弹的患者,在HBV DNA发生剧烈变化的4个时间点.未观察到HBsAg滴度随HBV DNA复制水平的一致变化,无相关性(P>0.05);37例应答良好的患者,可观察到HBsAg水平随HBV DNA复制水平的一致变化,呈正相关(r=0.71,P<0.05).(2)20例ADV抗病毒治疗的CHB患者中,7例有效应答后出现病毒反弹的患者,未观察到HBsAg随HBV DNA水平的一致变化,无相关性(P>0.05);13例应答良好的患者,可观察到HBsAg随HBV DNA复制水平的一致变化,呈正相关(r=0.73,P<0.05).结论 核苷类似物治疗CHB的过程中,对核苷类似物抗病毒治疗有良好应答的患者,HBsAg滴度在一定程度上能反映HBV DNA复制水平,HBsAg滴度与HBV DNA复制水平有相关性.     

Quantitative measurement of hepatitis B virus DNA in different areas of hepatic lobules in patients with chronic hepatitis B

Liver histology in chronic hepatitis B is marked by inflammatory infiltration involving the peripheral zones. The cause of such cellular infiltration remains unknown. The aim of the present study was to investigate the amounts of intrahepatic hepatitis B virus (HBV) DNA separately in the peripheral and central zones, using laser capture microdissection coupled with real-time quantitative polymerase chain reaction. Fourteen patients with chronic hepatitis B were included in the study. Liver biopsy samples were taken and hepatocytes were microdissected separately from peripheral and central zones. DNA was extracted from hepatocytes in each zone and evaluated the amounts of HBV-DNA. Immunohistochemical study for hepatitis B core antigen (HBcAg) was also performed. The amounts of total intrahepatic HBV-DNA in patients positive for hepatitis Be antigen (HBeAg) were greater than those in HBeAg-negative patients. There was no difference in HBV-DNA between the peripheral and central zones. Immunohistochemistry also showed that HBcAg-positive cells were distributed homogeneously in the hepatic lobules. In patients with peripherally predominant HBV-DNA, the serum alanine aminotransferase (ALT) level was lower than in patients with centrally predominant HBV-DNA. HBV-DNA was distributed homogeneously in the hepatic lobules. In patients with lower amounts of HBV-DNA in the peripheral zone, the serum ALT level tended to be higher than in other patients.