修回日期: 2005-04-08
接受日期: 2005-04-09
在线出版日期: 2005-07-28
抗病毒、抗肝纤维化治疗是近年来慢性病毒性肝炎治疗的关键. 单一应用抗病毒药物干扰素对HBV的完全应答约为30-40%, 长效干扰素使疗效及耐受性均有提高;LMV虽系应用广泛的核苷类抗病毒药物, 但最大的问题是需要长期治疗, 而较长时间用药容易产生病毒YMDD变异与耐药; 阿德福韦、恩替卡韦能有效抑制LMV的YMDD变异株复制, 用于LMV治疗出现YMDD变异耐药者. 新的抗病毒治疗策略如联合治疗、序贯治疗以及免疫调节治疗等能否进一步提高疗效有待深入研究. 中医药肝纤维化治疗虽然取得了良好效果, 但迫切需要根据循证医学原理, 深入开展和加强肝纤维化的临床病理研究工作.
引文著录: 姚希贤, 崔东来. 进一步加强慢性肝炎、肝纤维化治疗研究. 世界华人消化杂志 2005; 13(14): 1645-1649
Revised: April 8, 2005
Accepted: April 9, 2005
Published online: July 28, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(14): 1645-1649
- URL: https://www.wjgnet.com/1009-3079/full/v13/i14/1645.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i14.1645
常见的嗜肝病毒有甲、乙、丙、丁、戊五型, 导致慢性化者主为乙型和丙型. 我国乙肝病毒(HBV)人群感染率57.6%, 乙肝表面抗原(HBsAg)阳性者9.75%[1], 全国现症慢性乙型肝炎(简称慢乙肝)约3 000-4 000万, 全球慢性HBV感染者达3.5亿[2]. 成年慢乙肝中40-70%有病毒复制[3-4]和活动性肝炎[5-6], 其中15-20%进展为肝硬化[7-8]. 丙肝病毒(HCV)感染率为3.2%, 慢性化率高达50-85%, 10-30%发展为肝硬化, 3-10%可演变为肝癌[9-11].
对慢乙肝主要采用抗病毒、免疫调节、改善肝功能等, 抗病毒是治疗的关键影响疗效的主要因素是机体对HBV的免疫耐受、共价闭锁环状DNA(cccDNA)难以清除[12-13]以及HBV不断发生变异, 逃逸免疫攻击有关. 随着慢性肝炎病变的发展, 肝脏纤维组织增生益重. 因此, 慢乙肝的治疗仍然是复杂而长期的难题. 为此, 加强慢性肝炎、肝纤维化合理治疗是摆在面前的重要问题.
抗病毒治疗是慢性病毒性肝炎治疗的关键, 目前国内外公认的抗病毒药物有干扰素、拉米夫定(lamivudine, LMV)以及阿德福韦(adefovir, ADV)等, 但尚乏满意疗效. 为此, 应探讨抗病毒治疗新策略.
1.1.1 干扰素(interferon, IFN): 是目前抗病毒有效药物. 对HBV的完全应答为30-40%, 对丙肝病毒(HCV)约为HBV的一半, IFN主要用于病程在半年以上, 有活动性病毒复制和活动性肝病, 丙氨酸氨基转移酶(ALT)升高患者, 剂量宜较大(一般3-5 kU), 疗程不能太短(4-6 mo), 对HBeAg阴性者可能需1年[14-15].IFN对HBV-DNA有报道转阴率为37%, HBsAg转阴率7.8%, 长期治疗可增加患者的生存率, 降低肝癌的发生率[16-21].IFN与LMV相比, 对减少HBV-DNA和ALT复常率方面不及LMV, 但HBeAg血清转换高于LMV, 停药后可继续增加, 很少出现耐药为另一优点. 本药不良反应较多, 肝硬化患者不宜应用. 长效干扰素-聚乙二醇(PEG), 使IFN在血中浓度维持时间延长, 每周给药一次, 副作用减少, 疗效及耐受性提高. PEG-IFN-2a、2b单用于治疗慢性丙型肝炎(简称慢丙肝)完全应答率分别达36-39%和23-25%, 对IFN-a治疗无效或复发患者取得较好疗效[15]. 目前上市的有佩乐能(Peg-intron)和派罗欣(Pegasys), 治疗慢乙肝随机、对照初步结果显示HBV-DNA滴度下降较快, HBeAg血清转换率提高, 伴随着生化及组织学病变改善, 其具体疗效有待进一步评价[22-25].
1.1.2 LMV: 能有效地抑制乙型肝炎病毒复制, 减少血液和肝脏病毒载量, 从而减轻肝脏炎症、坏死和纤维化, 清除HBeAg和促进HBAeg/抗-HBe的血清转换. 连续用药1年, HBV-DNA转阴率可达80%, 而HBAeg/抗-HBe的血清转换率仅16-21%, 但对cccDNA无效, 故停药后HBV-DNA很快恢复阳性. 亚洲一项多中心实验研究表明, 治疗24 mo后HBAeg/抗-HBe转换率高至27%, 36 mo后达40%[26-31]. 治疗前ALT水平是血清转换的重要预测因素. ALT基线水平大于5倍正常值上限的患者, 经LMV治疗12 mo后HBeAg/抗-HBe的血清转换率为38-80%, ALT基线水平在2-5倍正常值上限时, 转换率为5-12%, ALT正常者, 无一例出现血清HBeAg转阴. 因此, 治疗适应证的选择至关重要. 治疗前1 mo至少1-2次, ALT>2×ULN或于既往3-6 mo内ALT反复波动, 至少有1-2次>2×ULN, 可推荐抗病毒治疗; 慢乙肝患者, ALT在1-2×ULN之间是否需治疗, 应做肝活检决定, 如组织学有明显坏死性炎症, 可进行抗病毒治疗, 一般疗效较好. 但对ALT正常的HBV感染者暂不考虑抗病毒治疗[32-34], 此种患者并非不需要治疗, 而是治疗乏效, 罔受可能发生的不良反应所累. 但面对当前众多此类患者, 迫切需要治疗. 有关联用抗病毒、增强免疫功能研究值得引起更多重视.
LMV虽系应用广泛的核苷类抗病毒药物, 但最大的问题是需要长期治疗, 而较长时间用药容易产生病毒YMDD变异与耐药[36], 而使治疗乏效或疗效降低. 研究显示长期治疗未发生YMDD变异者, 组织学改善率为77%, 恶化率很低, 为5%. 一旦发生耐药, 组织学改善率仅45%, 恶化率高达14%, 出现病毒学指标反弹. YMDD变异通常发生在LMV治疗6 mo后, 随治疗时间延长发生率逐渐增高. LMV治疗1、2、3年和4年YMDD变异发生率分别为14%、38%、49%和66%[37]. 因此, 如何减少、延缓LMV耐药也是当前研究的热点问题.
HBV是高变异病毒, 当机体免疫系统对已感染的野生株产生强烈特异性免疫应答后, 野株型HBV复制即被抑制, 变异株的产生可逃逸已形成的抗病毒免疫力攻击并对抗病毒药物产生耐药. HBV前C或/和基本核心启动子(BCP)变异最为常见[38]. 我国HBeAg阴性慢乙肝中38%存在前C终止密码子, 42%有BCP变异, 12%二者共存. 特点是HBsAg持续阳性, HBeAg阴性, 抗HBe阳性, 以PCR法测定HBV-DNA水平高于108-109copies/L, 具有活动性肝病, 易于慢性化或者发生重症肝炎, 对干扰素往往耐药, 治疗难度增大, 亚洲和我国的慢乙肝中约1/5为此类患者. 干扰素治疗此类患者最大的问题是停药后复发, 平均复发率60%. 疗程4-6 mo, 持续应答率10-15%;疗程增至12-24 mo者持续应答率22-30%[39-41].
对有前C区突变的慢乙肝患者, LMV可产生明显治疗反应, 但很难确定其治疗终点, 长期服用可望提高疗效, 但随着LMV治疗时间延长, 耐药变异率也随之增高, 造成治疗困难[42-44].ADV能有效抑制LMV的YMDD变异株复制, 随着血清HBV-DNA的下降, cccDNA也有显著下降, 对LMV治疗出现YMDD变异耐药患者, 应用ADV有良好疗效[45-46]. 恩替卡韦(entecavir)等临床药物的应用将给LMV耐药、治疗失效者带来希望 [47-48], 值得重视.
不同药物同时应用的治疗的策略为联合治疗(combination therapy); 先后应用的治疗策略称为序贯治疗(sequential therapy).
1.2.1 联合治疗: 现有的抗乙肝病毒药物如干扰素、LMV主要作用于cccDNA以下的复制阶段, 单一用于慢乙肝抗病毒治疗, 疗效皆有限. 长疗程应用单一抗病毒药物不仅会增加药物毒性, 而且可能发生病毒变异, 引起耐药. 应用作用于不同病毒复制靶位的抗HBV药的联合治疗可望提高疗效, 但迄今对联合用药优势尚无肯定结论, 持慎重态度者认为联合治疗可能增加药物毒性和治疗费用. 联合治疗方案有: (1)LMV与IFN联用: 二者抗病毒作用环节与机制不同, LMV可控制HBV-DNA迅速降低其水平, IFN治疗创造条件, 一般将之联合用于慢乙肝. 最近欧洲完成了一项多中心随机、双盲、对照IFN联合LMV治疗慢乙肝的临床研究. 治疗52 wk HBeAg/抗HBe血清转换率联合治疗组为29%, 比单用IFN组(19%)和LMV组(18%)为高[48-49]. PEG-IFN与LMV联用的临床试验正在进行中, 初步结果令人鼓舞, 治疗52 wk时, PEG-IFN与LMV联合治疗组持续病毒学应答率显著高于单用LMV组(36% vs 14%), HBV-DNA含量显著降低, YMDD变异显著减少(21% vs 40%)[50-51]. (2)LMV与泛昔洛韦(famciclovir, FCV)以及LMV、百塞诺或苦参素联合治疗等; (3)IFN与利巴韦林(ribavirin, RBV)联合: 可清除HCV感染效果, 对单用IFN无应答、停药后复发者, 本联合治疗往往有效. 同时推荐方案为IFN-a 3-5 kU, 3次/wk, RBV 800-1 200 mg/d, 6 mo以上. (4)LMV、ADV联合用于LMV长期治疗发生耐药者, 疗效较停用LMV, 单一用药为好[52]. 对此, 今后对联合用药应根据循证医学原则, 采用双盲、随机对照临床研究进一步验证.
1.2.2 序贯治疗: 是应用不同有效抗HBV药, 连续、轮换、顺序治疗, 可以维持较长疗程, 防止病毒变异, 减少药物毒性. 新的有效抗HBV药不断开发和应用, 为序贯治疗创造了更好的、可供选择的药物, 是今后值得研究的途径. IFN与核苷类药物的序贯治疗以及LMV与ADV几种核苷类药物的序贯治疗等, 已被证明比单用任何一种药物具有更好疗效. 目前已有不少应用IFN、LMV序贯治疗慢乙肝可以提高疗效, 减少YMDD变异和严重不良反应减少的报道. 当前多用的序贯治疗方案是首用LMV, 如未发生耐药突变, 则继续用药, 如发生了, 则更换为ADV, 从而完成长达数年的长期治疗[53-54].Entecavir能明显抑制HBV复制, 且能改善肝功能和肝组织病变, 国内已完成I、II期临床试验, 准备启动III期临床试验, 有望成为新的有效抗病毒药物[55].
慢乙肝患者多有机体免疫调节障碍, 多表现为CD4+减少, CD8+升高, 二者比值降低, 尤其免疫耐受问题使HBV不易被清除. 研究表明ALT水平高低是反应机体免疫状态的重要指标. 抗病毒治疗出现应答者多伴有ALT升高伴有免疫功能的恢复和增强, 反之, 免疫功能不够强, ALT水平不高, 抗病毒疗效差[56-57]. 因此, 免疫调节治疗有可能在抗病毒治疗中起着举足轻重的作用. 不少研究表明IFN或核苷类药物联用调免药物胸腺肽a1取得了较为良好疗效[41]. 但目前对免疫调节剂的应用还存在不少问题. 首先, 目前虽然免疫调节剂如胸腺肽、胸腺肽a1、胸腺五肽、免疫核糖核酸、胎盘转移因子、左旋咪唑、卡介苗以及中草药制剂甘草酸、苦参素(氧化苦参碱)、猪苓多糖、云芝多糖等, 有一定提高免疫作用, 但除胸腺肽a1、胸腺五肽外, 疗效均有限; 其次, 特异性免疫调节剂如各种治疗性疫苗, 如S和前S2蛋白疫苗、特异性细胞毒性Ｔ淋巴细胞多肽疫苗、HBsAg抗HBs免疫复合物疫苗、HBV特异性核酸疫苗等是较为有希望的免疫调节剂, 亟待深入研究.
肝纤维化是肝脏对慢性损伤的一种修复反应, 是慢性肝病共有的病理改变, 其特征性改变是肝内细胞外基质(ECM)的过多沉积. 研究表明慢性肝炎早期即有纤维组织增生, 随着肝病加重, 肝纤维化程度逐渐加重. 美国著名肝病学家Hans Popper教授提出"谁能阻止或延缓肝纤维化的发生, 谁将治愈大多数慢性肝病".近10多年来, 随肝纤维化发生机制的逐渐阐明, 本病治疗成为可能[58-59], 但当前现代医学对之尚乏良好治疗药物. 近年来, 中西医结合对基因调控、细胞凋亡、信号转导等研究的开展, 极大地拓宽了肝纤维化的治疗途径. 新出现的技术如反义寡核苷酸、核酶、基因导入等显示出令人鼓舞的前景, 但由于其靶向性和可调控性缺陷, 用于体内还有较长一段时间摸索. 中药861合剂(含丹参、桃仁、冬虫夏草、当归), 一方面抑制肝星状细胞(HSC)合成ECM, 又增加HSC表达基质金属蛋白酶(MMPs), 提高其降解活性, 并能促进细胞凋亡. 我们以"淤血"立论重用丹参为主联用一组活血化瘀药组成的"益肝冲剂"-及其新一代中药益肝康以及拆方小复方具有良好地抗肝纤维化作用, 而且早期用药较晚期具有更好疗效[14,60-67]. 但目前抗肝纤维化中药多为体外或动物实验研究, 尚乏基于肝活检的病理组织学随机对照、盲法、多中心、足够病例的临床研究. 因之, 面对本病中医药初步取得良好抗肝纤维化效果, 迫切需要中西医结合根据循证医学原理, 深入开展和加强肝纤维化的临床病理研究工作.
编辑:张海宁
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