从1例慢性乙型肝炎患者治疗过程分析慢性乙型肝炎的治疗策略

一、病例 患者男,47岁.从1981-2003年因ALT升高、HBsAg(+),HBeAg(+)、抗-HBc(+)在本院诊断为病毒性乙型肝炎.患者共住院治疗4次,住院期间先后给予一般保肝药物治疗、聚肌胞治疗,1997年肝功能正常且排除肝硬化后开始用干扰素(IFN)抗病毒治疗.给予基因工程干扰素α-2b(购自美国先灵葆雅公司)3 MU,隔天1次;2003年,改用注射用重组人干扰素α-2b(购自深圳海王英特尼公司)3 MU,隔天1次.     

干扰素在治疗慢性乙型肝炎中的应用

干扰素的发现及应用是抗病毒治疗的一个里程碑，“迄今为止，没有任何一项科学发现象干扰素这样对病毒性肝炎的治疗产生如此重大的影响”（引自2007年美国肝病年会宣传手册）。干扰素作用广泛，具有其抗病毒、抗增殖、抗肘瘤以及免疫调节活性。根据其受体不同可将干扰素分为I型（α和β）和Ⅱ型（γ），用于治疗慢性乙型肝炎的主要是干扰素α。1995年聚乙二醇化干扰素（PEG-IFN）研制威功，其优越的药代动力学和药效学特性给慢性乙型肝炎的治疗带来重大进展。[第一段]     

用拉米夫定治疗对干扰素α无应答的慢性乙型肝炎患者

目的探讨拉米夫定对干扰素α治疗无应答的慢性乙型肝炎的疗效。方法经重组干扰素α-1b 5MU治疗无应答的慢性乙型肝炎35例为治疗组,选择同期未接受抗病毒治疗的慢性乙型肝炎35例为对照组。两组患者均给予拉米夫定100 mg口服每天一次,疗程2年以上,观察两组患者的肝功能、HBV标志及YMDD变异的发生率。结果拉米夫定治疗两年后,治疗组ALT复常率、HBeAg阴转率、HBeAg血清转换率、HBVDNA阴转率分别为85.71%、68.57%、42.86%和74.29%,显著高于对照组的65.71%、42.86%、20.00%和51.43%,两组比较,有显著性差异（P〈0.05）。拉米夫定治疗两年后,治疗组YMDD变异的发生率为8.57%,显著低于对照组的37.14%（P〈0.01）。结论拉米夫定可显著提高干扰素α无应答慢性乙型肝炎的抗病毒疗效,并明显降低拉米夫定YM-DD耐药变异的发生率。     

干扰素联用苦参素治疗慢性乙型肝炎的疗效观察

目的观察干扰素联用苦参素治疗慢性乙型肝炎的疗效。方法设置观察组和对照组，观察组用塞诺金（a2b干扰素）和博尔泰力联用，对照组单用干扰素。结果治疗6个月和1年后复查，观察组HBV-DNA及HBeAg阴转率均明显高于对照组（P〈0．01）。结论提示干扰素联用苦参素治疗慢性乙型肝炎有协同作用，值得在临床推广使用。     

聚乙二醇干扰素α-2a联合短程拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效

目的 探讨通过短程联合拉米夫定以提高聚乙二醇干扰素α-2a 疗效的新治疗方法.方法 所有患者以聚乙二醇干扰素α-2a 135μg开始治疗,在治疗12周时,若HBV DNA或HBeAg转阴,继续单独使用干扰素治疗至52周(A组),未达到上述条件者(B组)分为B1组及B2组,B1组短程联合拉米夫定治疗12周后继续干扰素治疗并完成52周疗程,B2组继续单独用干扰素治疗并完成52周疗程.符合正态分布的计量资料采用t检验;符合偏态分布的计量资料用中位数(全距)表示,采用秩和检验.结果共有58例患者入组,8例患者在治疗12周时出现HBV DNA或HBeAg转阴,单用干扰素完成52周疗程,治疗结束时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为8/8、6/8、0/8及8/8.B1组患者24例,治疗52周时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为50%(12/24)、38%(9/24)、4%(1/24)及63%(15/24);B2组患者26例,治疗52周时HBV DNA转阴率、HBeAg血清学转换率,HBsAg转阴率及ALT复常率分别为31%(8/26)、27%(7/26)、O(0/26)及35%(9/26).结论 聚乙二醇干扰素α-2a治疗取得早期应答的患者治疗52周的应答率高;通过对早期疗效不佳的患者短程联合拉米夫定治疗,可提高干扰素的疗效,但有待更大样本量的随机临床试验证实.     

慢性乙型肝炎的联合抗病毒治疗

全球约有3.5亿人感染乙型肝炎病毒(HBV).目前抗HBV的主要药物有干扰素(IFN)、拉米夫定(LAM)和阿德福韦(ADV)等,现就有关药物的联合治疗作一简述.     

重组人干扰素α-1b治疗慢性乙型肝炎导致白癜风1例

1.病历资料:患者男,12岁,汉族,因体检时发现HBsAg阳性,肝功能异常1个月,于2008年12月1日入院.患者有慢性乙型肝炎家族史.体温36.4℃,脉搏82次/min,呼吸19次/min,血压100/75 mm Hg(1 mmHg=0.133 kPa),皮肤、巩膜无黄染,未见肝掌、蜘蛛痣,皮肤黏膜未见异常,双肺及心脏正常,腹部平软,无压痛,肝脾未触及,肝区有叩击痛,移动性浊音阴性,双下肢无水肿,生理反射正常.入院时肝功能检查ALT 74.0 U/L,AST 60.0 U/L,总胆红素8.3 μmol/L,白蛋白44.1 g/L,球蛋白30.1 g/L.     

聚乙二醇干扰素α-2a联合短程拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效

Objective To investigate the efficacy of by combining a 12-week course of lamivudine in those HBeAg-positive hepatitis B patients receiving peginterferon alfa-2a (peg-IFN α-2a) therapy. Methods A total of 58 patients initiated a 52-week course of peginterferon alfa-2a were enrolled and divided into 3 groups. The patients with HBV DNA undetectable or HBeAg negative at week 12 were divided into group A, in this group treatment continued to week 52 with peg-IFN α -2a alone; The rest paitents were divided into group Bl and B2, in group Bl, lamivudine was combined at a course of 12 weeks, while in group B2 treatment continued to week 52 with peg-IFN α -2a alone. Clinical responses were assessed at week 52. Results 8 out of 58 patients achieved undetectable HBV DNA or HBeAg loss at week 12 and divide into group A. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100% (8/8) respectively at the end of treatment. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100%(8/8) respectively at the end of treatment. The rest 50 patients without early response to peg-IFN α -2a at week 12 were divided into group Bl (24 patients enrolled) and B2 (26 patients). At the end of treatment, the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate in Group B1 were 50% (12/24), 38% (9/24), 4% (1/24) and 63% (15/24) respectively, and 31% (8/26), 27% (7/26), 0% (0/26) and 35% (9/26) respectively in group B2. Conclusions Those patients with early responses to peg-IFN α -2a therapy can achieve high clinical responses at the end of 52-week treatment. The combining therpay of lamivudine for a course of 12-weeks can improve the clinical responses for the patients without early responses to peg-IFN α-2a.     

聚乙二醇干扰素α-2a联合短程拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效

Objective To investigate the efficacy of by combining a 12-week course of lamivudine in those HBeAg-positive hepatitis B patients receiving peginterferon alfa-2a (peg-IFN α-2a) therapy. Methods A total of 58 patients initiated a 52-week course of peginterferon alfa-2a were enrolled and divided into 3 groups. The patients with HBV DNA undetectable or HBeAg negative at week 12 were divided into group A, in this group treatment continued to week 52 with peg-IFN α -2a alone; The rest paitents were divided into group Bl and B2, in group Bl, lamivudine was combined at a course of 12 weeks, while in group B2 treatment continued to week 52 with peg-IFN α -2a alone. Clinical responses were assessed at week 52. Results 8 out of 58 patients achieved undetectable HBV DNA or HBeAg loss at week 12 and divide into group A. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100% (8/8) respectively at the end of treatment. In this group the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate were 100% (8/8), 75% (6/8), 0% (0/8) and 100%(8/8) respectively at the end of treatment. The rest 50 patients without early response to peg-IFN α -2a at week 12 were divided into group Bl (24 patients enrolled) and B2 (26 patients). At the end of treatment, the HBV DNA loss rate, HBeAg seroconversion rate, HBsAg loss rate and ALT normalization rate in Group B1 were 50% (12/24), 38% (9/24), 4% (1/24) and 63% (15/24) respectively, and 31% (8/26), 27% (7/26), 0% (0/26) and 35% (9/26) respectively in group B2. Conclusions Those patients with early responses to peg-IFN α -2a therapy can achieve high clinical responses at the end of 52-week treatment. The combining therpay of lamivudine for a course of 12-weeks can improve the clinical responses for the patients without early responses to peg-IFN α-2a.     

干扰素联合拉米夫定治疗70例慢性乙型肝炎临床观察

干扰素及拉米夫定是目前国内外公认的治疗慢性乙型肝炎最为有效的药物之一。我院采用α-1b干扰素与拉米夫定联合治疗慢性乙型肝炎取得了一定效果，现总结报告如下。     

恩替卡韦初治慢性乙型肝炎耐药1例报道

<正>恩替卡韦(ETV)自2006年在我国正式上市以来,其抑制HBV作用强且耐药发生率低,因而在慢性乙型肝炎患者中得到广泛应用。目前,国内关于恩替卡韦耐药的报道较少。我们在临床工作中收治1例初治的慢性乙型肝炎患者在抗病毒治疗半年时出现病毒学反弹,并经检测证实发生了恩替卡韦基因型耐药,现报道如下。1病例摘要     

慢性乙型肝炎患者抗病毒治疗中的病毒准种演变

目的 探讨拉米夫定耐药后换用恩替卡韦补救治疗的慢性乙型肝炎患者的病毒准种演变.方法 提取1例慢性乙型肝炎患者治疗中的7个不同时间点(0、24、48、60、72、96、152周)血清中的HBV DNA,巢式聚合酶链反应法扩增HBV DNA聚合酶基因逆转录酶区,克隆测序法对逆转录酶区氨基酸替换形式及准种分布进行分析,并采用扩增耐药突变系统聚合酶链反应法对患者病毒种群中野毒株与病毒总量进行定量检测.结果 患者在治疗过程中主要存在rtM204V、rtL180M+rtM204V和rtM204I 3种拉米夫定耐药相关的病毒株变异形式,各病毒株所占比例不断发生变化,基线时HBV野毒株为优势病毒株,在病毒学突破时,种群中全部为耐药突变株;换用恩替卡韦治疗后,随着病毒载量的下降,拉米夫定耐药突变株被抑制,野毒株在种群中比例逐渐上升,并成为优势病毒株(79.3%).扩增耐药突变系统聚合酶链反应检测结果显示,在基线和发生病毒学突破时,野毒株在种群中的比例分别为68.55%和0.21%,换药治疗后24周,野毒株比例开始上升,此后野毒株占种群的比例波动于16.01%～26.93%.结论 慢性乙型肝炎患者在核苷(酸)类药物序贯治疗过程中,HBV种群的准种分布一直处于动态变化中.不同的HBV准种演变模式可能在恩替卡韦补救治疗中对恩替卡韦耐药发生的作用也不相同.

Abstract：

Objective To investigate the evolution of hepatitis B virus (HB V) quasispecies in one patient during lamivudine (LAM) monotherapy and switching to entecavir (ETV) rescue treatment. Methods Serum samples were taken at seven different time points during antiviral therapy (0, 24, 48, 60, 72, 96,152 weeks, respectively), the HBV DNA polymerase gene was amplified, cloned and sequenced to analyze the amino acid substitutions within HBV DNA polymerase gene and distribution of virus quasispecies. Quantitative detection of the HBV wild strains and total virus was performed by amplification refractory mutation system real-time PCR (ARMS-PCR). Results Three mutation patterns detected during antiviral therapy in the patient: rtM204V, rtM204V+rtL180M and rtM204I. The HBV quasispecies were found always in dynamic variation. The HBV populations were completely replaced with the LAM-resistant variants when the viral breakthrough was encountered during LAM monotherapy. Interestingly, the wild-type variants presented gradually dominant (79.3%) with the decline of HBV DNA load after switching to ETV rescue administration. ARMS-PCR results showed that the wild-type variants account ed for 68.55% of the HBV populations at baseline and this proportion declined to 0.21% when the viral breakthrough emerged under LAM therapy. The wild-type variants gradually increased from week 24 after switching to ETV rescue therapy and the proportion of HBV wild-type variants in the population fluctuated between 16.01% to 26.93%. Conclusions The distribution of virus quasispecies were always in dynamic variation during sequential therapy with nucleotide analogs in chronic hepatitis B patients. Different patterns of dynamic HBV quasispecies may have different contribution in ETV resistance in LMV refractory patients with ETV administration.     

Short-term intravenous interferon therapy for chronic hepatitis B

AIM：To investigate the therapeutic efficacy of short- term, multiple daily dosing of intravenous interferon （IFN） in patients with hepatitis B e antigen （HBeAg）-positive chronic hepatitis B.
METHODS：IFN-β was intravenously administered at a total dose of 102 million international units （MIU） over a period of 28 d in 26 patients positive for HBeAg and HBV-DNA. IFN-beta was administered at doses of 2 MIU and 1 MIU on d 1, 3 MIU twice daily from d 2 to d 7, and 1 MIU thrice daily from d 8 to d 28. Patients were followed up for 24 wk after the end of treatment. RESULTS：Six months after the end of the treatment, loss of HBV-DNA occurred in 13 （50.0%） of the 26 patients, loss of HBeAg in 9 （34.6%）, development of anti-HBe in 10 （38.5%）, HBeAg seroconversion in 8 （30.8%）, and normalization of alanine aminotransferase （ALT） levels in 11 （42.0%）.
CONCLUSION：This 4-wk long IFN-β therapy, which was much shorter than conventional therapy lasting 12 wk or even more than 1 year, produced therapeutic effects similar to those achieved by IFN-α or pegylated- IFN-α （peg-IFN）. Fewer adverse effects, greater efficacy, and a shorter treatment period led to an improvement in patients＇ quality of life. IFN-β is administered intravenously, whereas IFN-α is administered intramuscularly or subcutaneously. Because both interferons are known to bind to an identical receptor and exert antiviral effects through intracellular signal transduction, the excellent results of IFN-β found in this study may be attributed to the multiple doses allowed by the intravenous route.     

慢性乙型肝炎抗病毒优化治疗策略的新认识

2005年版《慢性乙型肝炎防治指南》[1](简称《指南》)与2010年版《指南》[2]的一个显著差异,是关于慢性乙型肝炎(CHB)的治疗目标.前者提出最大限度地长期抑制或消除HBV,减轻肝细胞炎症坏死及肝纤维化,延缓和阻止疾病进展,减少和防止肝脏失代偿、肝硬化、肝细胞癌(HCC)及其并发症的发生,从而改善生活质量和延长生存时间;而后者删去了"消除HBV"的提法.记得在2005年版《指南》起草过程中还在讨论究竟用"清除(eradication)"还是"消除(elimination)"的表述,而现在较为保守的"消除"也删掉了,可见专业学术界对关于CHB抗病毒治疗疗程的看法更加趋于延长[1].     

慢性乙型肝炎患者病毒准种特性的初步研究

目的 探讨慢性乙型肝炎(CHB)患者血清中乙型肝炎病毒(HBV)是否存在准种特性,并初步了解HBV准种的复杂性和遗传差异性。 方法用多聚酶链反应(PCR)技术从1例CHB患者血清中扩增HBV整个PreC/C基因区,然后用T载体克隆PCR产物,从转化阳性的克隆中随机选出34个克隆进行核酸序列分析。结果在34个测序克隆中发现存在28种不同的序列,序列间差异性介于0.2％～2.1％。变异位点分布于整个区域。所有序列nt1896位均无变异。 结论 在CHB患者体内HBV存在复杂的准种特性。     

慢性乙型肝炎抗病毒优化治疗策略浅淡

慢性乙型肝炎患者在适宜时机进行抗病毒治疗的必要性和疗效已得到国内外专家一致认同.经过10余年的临床实践探索,伴随欧洲、亚太地区,美国和我国《慢性乙型肝炎防治指南》的相继出台和不断完善,有关抗病毒治疗策略已越趋于成熟[1-5].2010年底,我国出台的《慢性乙型肝炎防治指南》(下文简称《指南》)在综合国内外指南基础上,逐步突显出中国指南的特色.尤其是慢性乙型肝炎治疗中优化治疗策略的提出,为进一步全面规范慢性乙型肝炎的抗病毒治疗登上了一个新的台阶.在解读2010版《指南》过程中,我们将自己对慢性乙型肝炎抗病毒优化治疗策略的认知作如下浅析,供广大专家参考指正.     

慢性乙型肝炎初治患者的抗病毒优化治疗

近十几年来,慢性乙型肝炎的抗病毒治疗研究取得了令人瞩目的进展,随着核苷(酸)类似物等药物的逐个研发和争相面市,临床获益甚多.这些药物能有效抑制病毒复制,从而控制疾病进展,显著改善预后,大大降低了与HBV感染相关的肝硬化和肝癌的发生率.但在经历了这段快速发展之后,相关研究的步伐明显减缓,很久没有听见能让人振奋的喜讯,当前正面临着抗病毒治疗发展的"瓶颈",期待有新的突破.以往的新药临床研究基本上按单药、方案不变的原则设计,临床治疗方案也按这种研究结果推荐,尽管大多数患者能受益,但也有少数应答不佳的患者因没有可供及时和有效调整的方案导致治疗失败或中断治疗.而且,以往大多数研究注重治疗过程中是否应答,继续治疗是否维持应答,并不注重停药后是否持续应答,于是强调长期治疗.因此,目前抗病毒治疗的现状可被简单概括为"三易三难",即"用药容易停药难,病毒控制容易免疫控制难,标准治疗容易个体化治疗难",克服"三难"、突破"瓶颈"是当前面临的主要任务,是研究的热点,可能的解决途径之一是深入进行"优化治疗"的研究.     

拉米夫定联合胸腺肽加乙肝疫苗治疗慢性乙型肝炎的临床观察

目的观察拉米夫定联合胸腺肽加乙肝疫苗治疗慢性乙型肝炎的临床效果。方法100例未曾接受过抗病毒治疗的慢性乙型肝炎患者随机分为治疗组和对照组,治疗组50例,给予拉米夫定100mg,每日一次口服,同时乙肝疫苗10μg皮下注射,每两周一次,胸腺肽20mg肌肉注射,隔日一次,共计26周,随后继续使用拉米夫定和乙肝疫苗26周,总疗程52周;对照组给予拉米夫定100mg·d-1,疗程52周。结果治疗结束时治疗组ALT下降、HBeAg/抗-HBe血清转换率明显高于对照组,差异有显著性(P<0·01),但HBVDNA下降差异无显著性(P<0·01),停药后随访6月、12月,治疗组ALT及HBVDNA下降、HBeAg/抗-HBe血清转换率明显高于对照组比,差异有显著性(P<0·01)。治疗组的完全应答率与对照组比,差异有高度显著性(P<0·01)。结论拉米夫定联合胸腺肽加乙肝疫苗能明显提高临床疗效及HBeAg/抗-HBe血清转换率及HBVDNA阴转率,且无明显毒性反应。     

慢性乙型肝炎抗病毒药物治疗的评价

本文对慢性乙型肝炎抗病毒芗治疗的应答反应作一评价。单一治疗：干扰素－α：治疗前血清ALT水平升高者,30％－40％患者对治疗呈完全应答反应,HBV携带者或免疫耐受者对治疗无效;拉米夫定：能明显抑制BV复制,但HBeAg转阴者少,停药后HBV－DNA迅速反跳,延长治疗时间可引起YMDD变异;治疗前血清ALT水平在正常上限5倍以上者,60％患者呈完全应答反应;法昔洛维：抑制HBV复制作用弱,且较短暂,长期用药可引起基因突变,发生耐药性。联合治疗：拉米夫定－干扰素、拉米夫定－法昔洛维／阿地洛维、强的松－拉米夫定／干扰素等联合应用。联合治疗可降低HBV负荷,改善CD4＋－T细胞功能及减少耐药性。