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发表于 2008-10-31 20:33
对慢性乙型肝炎病毒（HBV）感染成功进行抗病毒治疗的报道出现于30年前。在过去10年中其研究进展显著加快。然而，复杂性也随之出现了。现在对HBV感染千变万化的临床表现的了解，比抗病毒治疗时代初期多多了。对何人进行治疗、何时治疗和如何治疗变得越来越复杂。
病毒学、流行病学因素和自然病史
HBV是一种DNA病毒，经皮肤、性行为传播和围产期（母婴间）传播。在美国有125万人感染HBV，全世界有3.5亿到4亿人感染HBV。每年HBV感染导致4000～5500名美国人死亡，全世界每年有100万人死于肝硬化、肝衰和肝细胞癌。
临床重要的病毒蛋白有包膜蛋白——乙型肝炎表面抗原（HBsAg）；一个结构性核衣壳核心蛋白——乙型肝炎核心抗原（HBcAg）；一个可溶性核衣壳蛋白——乙型肝炎e抗原（HBeAg）。血清HBeAg是HBV感染的标志物，抗HBsAg抗体表明（病人）复原。血清活动性病毒复制的标志物——HBeAg——与血清HBV-DNA水平≥100,000～1,000,000IU/ml并存。HBV依赖一种逆转录病毒复制方法（从RNA反转录成DNA）；由于HBV在肝细胞核内建立了稳定持久的共价闭合环状DNA（cccDNA），并且HBV-DNA整合至宿主的基因组内，因此较难根除HBV感染。
从急性HBV感染至慢性HBV感染的进展，受病毒感染时人的年龄影响；在高患病率（例如亚洲）国家和低患病率（例如西方）国家间，年龄亦与HBV感染的2种不同的临床表现有关。在远东地区，于围产期获得的HBV感染，免疫系统不能识别出病毒和宿主之间的差异，并出现高水乎的免疫耐受。对肝细胞膜上的HBV蛋白的细胞免疫反应（与急性肝炎有关）不出现。超过90%的感染者出现慢性感染，通常是终身感染。相反，在西方，多数急性HBV感染发生在青春期和青年期，因为行为和环境有利于血源性感染的传播，例如性活动、注射毒品和职业暴露。在有免疫能力的成年人中，对肝细胞表达的“外源性”HBV蛋白的强细胞免疫反应，导致临床上明显的急性肝炎，后者影响全部感染者的感染清除（大约1%的感染者除外）。
在围产期感染时对HBV建立的免疫耐受性很强并可持续终身，但不是完全的免疫耐受；可出现低水平的肝损伤，这占男子终身肝病死亡危险的40%。妇女的这一危险比男子低。所谓的免疫耐受期发生在出生后最初数十年，虽然HBV复制水平高，但HBV相关肝损伤极轻。免疫清除期伴有活动性肝病发生在以后数十年。这一分期分类反映在生命早期获得的慢性HBV感染的自然史中，早期免疫耐受相对较高，以后免疫耐受相对较低。但此种分类方法不能解释某些病人在表观免疫耐受期存在的显著肝损伤和纤维化或在慢性HBV感染后期的免疫清除期有坏死性炎症静止的现象。
HBeAg状态可区别另外2类慢性HBV感染。HBeAg反应性慢性HBV感染伴有高水平的HBV复制；从HBeAg阳性感染转为抗体（抗HBe）阳性感染的自发性血清转化，与HBV复制减少和临床改善同时发生。在HBeAg阴性慢性HBV感染中，前核心区或核心启动子基因突变妨碍或减少HBeAg的合成，HBeAg阴性慢性HBV感染是病人比例增加的原因。HBeAg阴性的慢性HBV感染病人趋向于有进行性肝损伤，波动性丙氨酸转氨酶（ALT）活性，HBV-DNA水平比HBeAg反应性HBV感染病人低；但他们没有治疗引起的HBeAg血清转化，后者是持久反应，允许病人停用抗病毒治疗。
8个HBV基因型——及不同基因型的临床转归差异——被识别。例如A基因型病人较易发生干扰素引起的HBeAg血清转化；而B基因型病人中发生HBeAg血清转化和疾病发展较慢者比C基因型病人常见。但这些差异没有得到充分确立以指导治疗。
活动性病毒复制促进HBV感染的肝病进展，反映在血清HBV-DNA水平超过阈值，大约为1,000～10,000IU/ml。对于血清HBV-DNA水平<1,000IU/ml和ALT水平始终正常者，考虑是非活动性病毒携带者，其临床进展危险低。虽然再活动罕见，但其可能自然发生或在免疫抑制时发生。尽管围产期感染可在生后最初几十年导致高水平的HBV复制，且没有明显肝损伤，但最终进展为肝硬化和肝细胞癌的危险与长期保持的HBV-DNA水平成正比。
抗病毒治疗的目标
因为临床和组职学改善伴随HBV复制减少一起出现，所以预期减少HBV复制的干预措施可以限制进展性肝病，改善慢性HBV感染的自然病史。然而实际上，HBV感染的严重转归是在数十年内逐渐形成的，但抗病毒治疗的临床试验只持续1～2年，很少达5年。因此采用在时间有限的临床研究中可获得的替代终点。这些终点是血清学终点【即HBeAg转阴或血清转化，通常反映为过渡到非活动性HBV携带状态；并且，在少数病例中，出现HBsAg转阴或血清转化（代表血清学恢复）】、病毒学终点【即HBV-DNA水平减少一个log10或HBV-DNA降至测不出的水平（<10～100IU/ml）】、生化终点（即血清ALT水平恢复正常）和组织学终点（即坏死性炎症分级改善和纤维化分期改善）。一个疗程抗病毒治疗可使疗效在治疗停止后继续保持，但更常见的是，必须继续治疗才能保持取得的疗效。
抗病毒药
在美国有6个药被许可用于治疗HBV感染：干扰素α、聚乙二醇干扰素、拉米夫定、阿德福韦、恩替卡韦、替比夫定和替诺福韦。干扰素需每天注射或每周注射3次。它已被长效聚乙二醇干扰素取代，后者只需每周注射1次。
治疗1年通常使血清HBV-DNA水平减少3.5～6.9log10（在13%～95%的病人中血清HBV-DNA水平不能被聚合酶链反应检出），使38%～79%的病人ALT水平恢复正常，38%～74%的病人有组织学改善，12%～27%的病人出现HBeAg血清转化；药物抑制HBV-DNA的作用越强越常获得临床终点（也许HBeAg血清转化除外）。在口服药中（各种口服药的耐药谱不同），核苷类似物阿德福韦和替诺福韦与拉米夫定、替比夫定或恩替卡韦无交叉耐药性。在治疗第一年可不考虑阿德福韦的耐药性，但至4年末耐药性接近30%。阿德福韦治疗拉米夫定耐药的HBV感染非常有效。在现有药物中，阿德福韦的应用有限，因为阿德福韦抑制HBV-DNA水平的效能最弱、起效最慢；其诱导HBeAg血清转化的可能性最低；导致“原发性无应答”（即在20%～50%的病人中，不能使HBV-DNA水平减少2log10）的可能性最大。
在获得HBeAg血清转化后巩固治疗6～12个月或更久，大约可使80%的HBeAg阴性口服用药者获得持久应答，但除极少数HBeAg阴性病人外通常全部复发。因为应答并不总是持久的，治疗后需仔细监测病人判断其是否出现复发（特别要观察肝硬化病人在洽疗后出现的罕见的、严重的、有时可导致病人死亡的恶化），并重新开始治疗。因此，在没有出现HBeAg血清转化的病人中，接近全部HBeAg阴性病人和大约80%的HBeAg阳性病人在第一年后应继续用核苷和核苷酸治疗；如病人无耐药性，这种治疗通常可维持临床疗效。
成功的抗病毒治疗可延缓肝纤维化的发展速度，甚至可逆转肝硬化，改善病人的生存率。与聚乙二醇干扰素不同，口服用药对干扰素治疗无应答的病人有效，它可安全有效地用作肝脏失代偿病人的补救治疗（延缓或避免肝移植）；并在晚期纤维化和肝硬化病人中，口服药可预防肝脏失代偿。因此，口服核苷和核苷酸类似物的问世已挽救了很多HBV感染病人的生命，使美国每年等待肝移植的病人数减少了30%（2000年等待肝移植的病人有586例，2006年降至406例）。
聚乙二醇干扰素的副作用包括流感样症状、骨髓抑制、抑郁、焦虑、自身免疫性疾病，特别是自身免疫性甲状腺炎，病人需要密切的临床和实验室监测。即使长期应用，多数口服药的副作用可以接受，但因为阿德福韦和替诺福韦有肾毒性作用，在核苷酸治疗期间应定期监测肾功能。临床前啮齿类动物毒性研究显示，恩替卡韦用量高于人类30～40倍，与产生肺、脑和肝肿瘤相关，这在较高等物种中没有观察到。替比夫定似乎也能引起病人为数不多的主要毒性副作用，虽然治疗2年后，替比夫定组病人的3级和4级肌酸激酶水平升高比拉米夫定组病人常见，但外周神经病变是使用替比夫定引起的。
用聚乙二醇干扰素治疗1年，病人的HBeAg血清转化率比用口服药治疗1年者高；但口服药通常使用1年以上，治疗2年末可获得相似的HBeAg血清转化率（约为30%），治疗5年时接近约50%。同样，较早的研究提示，基于干扰素治疗的1年HBsAg血清转化率比口服药的高。然而，聚乙二醇干扰素与某些更有效的新型口服药的HBsAg转阴率相似。此外。在西方病人（不是亚洲病人）中，病人成功地获得HBeAg血清转化和停止治疗后，用拉米夫定治疗者的HBsAg血清转化率（在一项小样本研究中，3年为20%）似乎与干扰素治疗者的相似。在自发的、干扰素诱导的或口服药诱导的HBeAg血清转化病人中，其cccDNA减少相似。
另外2个口服药治疗HBV感染似乎有效，但还没获FDA批准，它们是恩曲他滨和克拉夫定，恩曲他滨的结构、疗效和耐药性与拉米夫定相似，它与拉米夫定相比似乎并无优势。克拉夫定与其他口服药不同之处是停药后仍可抑制HBV-DNA达数月。但临床前研究提示，克拉夫定对HBV-DNA的抑制作用和诱导HBeAg血清转化方面没有其他口服药有效。
对抗病毒药的耐药性
在聚乙二醇干扰素治疗期间，病人似乎没有出现耐药性。L-核苷（例如拉米夫定和替比夫定）与HBV-DNA聚合酶C结构域的YMDD基序（酪氨酸、蛋氨酸、天冬氨酸、天冬氨酸）出现突变相关，与聚合酶A和B结构域出现上游代偿性突变相关，在它们的共同作用下其疗效降低。核苷类似物（阿德福韦和替诺福韦）与聚合酶B和D结构域出现突变相关。虽然对拉米夫定的耐药性已高至足以限制其临床应用，但病毒对环戊基鸟嘌呤类似物（恩替卡韦和替诺福书》的耐药性仍低。药物耐药性最终降低药物的疗效，并在晚期肝硬化病人和在肝移植后病人中诱发肝脏失代偿。此外，因为数种口服药之间存在交叉耐药性，对一种药出现耐药性（例如拉米夫定）以后就无法选择其他治疗（例如替比夫定和恩替卡韦，见下文）。因为治疗1～2年后出现的耐药性，替比夫定没有被广泛用于治疗慢性HBV感染。对核苷酸耐药者用核苷治疗有效，反之亦然。恩替卡韦（剂量为1mg）被批准用于治疗拉米夫定耐药的HBV感染，但至1年末7%的病人出现恩替卡韦耐药性，2年末耐药病人为16%，3年末为35%，4年末为43%。有专门的检测方法可用于检测此突变，但通常可根据取得早期病毒学疗效后，以HBV-DNA增加>1log10，确定是否出现了耐药性（如没有不坚持用药，这在临床试验中占经治病人的30%），尤其是同时有ALT水平开高时。对抗HBV感染病毒药的耐药性在其他文章中已有较详细报道。
应答的预测因素
对疗效最有预测性的因素包括高ALT水平、低HBV-DNA水平、轻度－中度组织学活动性和分期。基因型与自发性（基因型B>C）HBeAg和HBsAg血清转化频率和聚乙二醇干扰素α-2b相关性（基因型A>B>C>D）HBeAg和HBsAg血清转化率相关，但它与口服药造成的HBV-DNA抑制程度无相关性。在口服药临床试验中，事件数太少不能确定基因型对HBeAg血清转化的影响，口服药治疗期间HBV-DNA抑制的速度和程度可预测治疗1年末获得的病毒学、血清学、生化学和组织学益处。三种口服药的耐药基因屏障低——拉米夫定、替比夫定和较小程度上阿德福韦。对于拉米夫定和替比夫定而言，其最初治疗半年末的残留HBV-DNA水平与治疗1年末的耐药频率成反比。阿德福韦治疗1年末的DNA水平与第2年治疗末的耐药发生率成反比。对拉米夫定、替比夫定和阿德福韦耐药有利的其他因素包括高基线HBV-DNA和长期治疗。
联合治疗
在未经治疗的HBV感染病人中联合应用现有抗病毒药不能增加疗效。虽然联合应用聚乙二醇干扰素和拉米夫定可使治疗期间的HBV-DNA额外减少1～2个log10，但联合治疗没有出现持久的治疗后益处。同样，联用替比夫定和拉米夫定的抗病毒作用并未超过单用替比夫定而获得额外抗病毒作用。联合应用耐药谱不同的药应该能减少耐药性的出现，但在恩替片韦或替诺福韦治疗最初数年内耐药发生率极低，由此证明先行联合治疗超过直接单药治疗的优势将受到挑战。事实上，出现耐药性后追加第二个补充药是非常成功的策略。因为缺乏资料支持未经治疗的病人用联合治疗的效果优于单药治疗，目前的治疗指南不建议用联合疗法，除非耐药可诱发或加重肝衰的病人（例如失代偿性肝硬化或肝移植后）。在经治疗的有耐药性HBV感染病人中，现有资料支持追加而非改用第二个耐药谱不同的药物。
HIV和HBV混合感染
《新英格兰医学杂志》最近发表了对HIV和HBV混合感染病人的抗病毒治疗综述。此类病人中的持久应答罕见，通常需无限期连续治疗。很多HBV感染的治疗药对HIV亦有治疗作用，HIV和HBV对这些药的单药治疗很快出现耐药性。因此，对于大多数批准的抗HBV感染药，不要将其单独用于治疗HIV和HBV混合感染。对于混合感染病人，如需要治疗其HIV感染或HIV和HBV感染，建议用2个抗HBV药。对于需治疗HBV感染但不需要治疗HIV感染的混合感染病人，应选用无抗HIV作用或抗HIV作用不大的抗病毒药，但除了干扰素，现有药都有抗HIV作用（例如拉米夫定、恩替卡韦、替诺福韦和恩曲他滨）或在理论上可导致对药物（即阿德福韦和替比夫定）交叉耐药的HIV突变。因此，同时联用抗逆转录病毒治疗较可取。
抗病毒治疗的适应证
数个专业团体和一个美国肝病学家团体（得到一家制药公司无限制性资金支持）发表了关于慢性HBV感染病人的抗病毒治疗建议。这些建议中权威性和影响力最大、最新的是美国肝病研究学会的实用指南。
对于HBeAg反应性慢性HBV感染，抗病毒治疗的适应证是ALT水平>正常上限的2倍，HBV-DNA>20,000IU/ml的病人；ALT水平升高的病人其HBeAg、生化和组织学应答更有可能持久。如不给予病人抗病毒治疗，随访1年期间大约1/4病人的纤维化进展。治疗的适应证非常明确，不一定要做治疗前肝活检，有黄疸或肝脏失代偿其他证据的病人应紧急开始治疗。对于HBV-DNA水平>20,000IU/ml，但ALT水平≤正常上限2倍的HBeAg阳性病人（在围产期获得性感染的年轻亚洲人中常见），疾病在最初数十年进展有限，此时HBV-DNA水平高，伴随生化静止，基线组织学分级和分期往往较低，ALT水平已正常或接近正常。虽然关于此类病人的治疗存在争议，但此类病人获得生化应答和HBeAg血清学应答的机会很小，给予他们抗病毒治疗很少能获得任何近期的临床好处；临床监测足以及时发现活动性肝病的出现，并给予相应的治疗。因此，不建议常规给这些病人抗病毒治疗，除非他们有进展的危险因素【即>40岁，有肝细胞癌家族史，ALT水平>正常范围（最高可达正常上限的2倍）】。在这些情况下，应考虑肝活检，应开始治疗中度－重度的坏死性炎症或纤维化。
ALT水平>正常上限2倍，HBV-DNA水平>20,000IU/ml的HBeAg阴性的慢性HBV感染病人有抗病毒治疗适应证，病人不一定选择做肝活检。如果ALT水平持久≤正常上限的1～2倍，HBV-DNA水平>2,000IU/ml，不会常规建议给予病人抗病毒治疗；应考虑肝活检，中度－重度坏死性炎症或纤维化应做治疗。非活动性HBV携带者（即ALT水平持久正常，HBV-DNA水平≤2,000IU/ml者）无抗病毒治疗适应证。转变至此状态是多数治疗成功病人达到的临床终点。然而，与其他慢性HBV感染病人一样，非活动性HBV携带者可能在停用免疫抑制治疗过程中出现严重的HBV重激活。因此，建议在开始免疫抑制治疗或细胞毒化疗前先给1个核苷或核苷类似物治疗。
在用口服药治疗HBeAg阳性的慢性HBV感染期间，可将HBeAg转阴（最好采用血清转化）作为转折点，达转折点后可停治疗，治疗应至少继续6个月。对于围产期获得性HBV感染的病人，治疗应继续≥1年。在此种巩固治疗后，超过以80%的病人可获得持久应答。对于HBeAg阴性慢性HBV感染，不存在HBeAg应答的机会；虽然一小部分病人出现持久病毒学应答，但绝大多数病人需无限期治疗以维持临床益处。
有代偿性肝硬化和HBV-DNA水平可检出的病人（不依赖于HBeAg状态），适合进行抗病毒治疗以预防疾病进展；如果病人HBV-DNA水平>2,000IU/ml建议给予其治疗，但如果HBV-DNA水平<2,000IU/ml，只有ALT升高的病人才接受治疗。对于失代偿性肝硬化和HBV-DNA水平可检出的病人，医生应与肝移植中心协作对其进行治疗。对于HBV-DNA水平检不出的肝硬化病人，建议对其观察而不给予治疗。失代偿肝硬化病人应转诊至移植中心。
在开始治疗后6个月内HBV-DNA水平降低不足2log10的（“原发性无应答”）病人应改用另一种药。对于拉米夫定耐药的病人，可能的选择是改用或加用阿德福韦或改用恩替卡韦。因为从拉米夫定改为阿德福韦有可能导致病人生化学恶化，以后可出现阿德福韦耐药。已不建议将拉米夫定改为阿德福韦，应将这种核苷酸加到核苷治疗中。尽管已批准用双倍剂量（1mg）恩替卡韦治疗拉米夫定耐药病人，但在用恩替卡韦病人中，恩替卡韦耐药性已很可观。因此，在拉米夫定耐药病人中没有广泛使用恩替卡韦。目前，替诺福韦已被批准，它可能会取代阿德福书对核苷耐药病人进行治疗。在不符合抗病毒治疗标准的病人和在成功地完成抗病毒治疗的病人中，应密切进行临床和实验室监测，观察可能出现的重激活。
如上所述，不推荐联合治疗作为未经治病人的最初抗病毒治疗。但接受过治疗的耐药件HBV感染者可以选择。
因为对某些口服药治疗6个月的病毒学应答，可预测有益转归，减少1年的耐药性，接受艾德尼克斯（Idenix）制药公司和诺华制药公司无限制性资助的一组专家建议，基于24周残留的HBV-DNA水平，采用“路线图”方法管理口服抗病毒药治疗慢性HBV感染。在24周取得完全病毒学应答的病人（即测不出残留HBV-DNA），达到预期治疗转归（即HBeAg血清转化和维持HBV-DNA在检测限下水平）的可能性高，不太可能出现耐药性，因此，建议继续用同一药进行单药治疗。在24周，用耐药基因屏降低的药（例如拉米夫定）取得部分病毒学应答（即残留HBV-DNA<2,000IU/ml）的病人，应加一个无交叉耐药性的药（例如核苷酸）预防耐药性。对于24周病毒学应答不充分（即HBV-DNA残留水平争≥2,000IU/ml）的病人，建议改用疗效更大的药，如果有的话（按照美国肝病研究协会目前指南的建议）或加第二个无交叉耐药性的药。因为阿德福韦降低HBV-DNA的速度比其他药慢，还因为第24周的转折点不能预测第48周的转归，建议阿德福韦给药时间选择的决策点是48周而不是24周。
由于对恩替卡韦的耐药基因屏障非常高，几乎全部病人的HBV-DNA水平下降非常迅速，因此不建议中途改变治疗方案。
但支持这一路线图方法的最令人信服的资料来自拉米夫定和替比夫定的临床试验，由于它们的耐药频率高，这些药不优先用作一线治疗。我预计作用更强、抑制更快和耐药倾向更小的恩替卡韦和替诺福韦将替代拉米夫定、替比夫定和阿德福韦，24周（或较晚时间点）的中间决策可能不重要。但建议在治疗期间监测血清HBV-DNA水平，建议在应答不充分病人中改变治疗。
药物选择
现在有这么多强效药治疗HBV感染，使医师面临众多令其困感的选择。在口服药中，拉米夫定和替比夫定的耐药率较高，限制了其应用。现在替诺福韦获准后，可能取代阿德福韦。因此，在口服药中，恩替卡韦或替诺福韦用作一线治疗较适宜。
口服药是治疗失代偿慢性HBV感染和预防晚期肝纤维化和肝硬化病人肝脏失代偿的唯一选择。但对于未经治疗的代偿性病变病人，建议用聚乙二醇干扰素和口服药，现在的指南不认为孰优孰劣。是使用一个限定疗程的副作用大的聚乙二醇干扰素注射还是在多数病人中用耐受性好、疗程更长（有时是无限期的）的口服药治疗，对此仍有争议。
支持将聚乙二醇干扰素作为一线治疗的理由是治疗48周有价值，不产生耐药性和在一个疗程治疗后产生持久HBeAg和HBsAg应答的高度可能。但在多数研究中，基于干扰素治疗在高水平HBV病毒血症病人中的疗效欠佳，与多数口服药相比，干扰素抑制HBV-DNA较不明显。赞成用口服药的医师强调病毒抑制的深度与良好的血清学、生化和组织学转归直接相关，HBV-DNA抑制与耐药性的出现间呈负相关。与用拉米夫定治疗1年相比，用聚乙二醇干扰素治疗1年更有可能获得持久HBeAg、HBsAg和HBV-DNA应答。但用较长疗程的口服药可获得相同的疗效，作用更强的新型口服药可在1年获得相似的HBsAg应答，没有干扰素和注射相关的副作用，也无需较贵的实验室监测和临床监测。此外，新型口服药治疗数年不伴有耐药性或耐药性可忽略不计。此外，在HBeAg阴性病人中，少数病人用干扰素治疗后HBV-DNA抑制作用较持久，随时间推移HBV-DNA抑制作用逐渐减弱。因为聚乙二醇干扰素对低水平HBV-DNA、高水平ALT和A基因型病人往往更有效，有些专家赞成这些病人的一线治疗用聚乙二醇干扰素。但在HBV-DNA水平低、ALT水平高的病人中，口服药亦更有效。此外，在终局性临床试验中，A基因型有利于对聚乙二醇干扰素α-2b（但不是聚乙二醇干扰素α-2a）产生HBeAg应答；聚乙二醇干扰素α-2b研究没有纳入只用核苷的治疗组。在所有可能性中，A基因型有利丁HBeAg血清转化，与采用的治疗类型无关。最后，因为在有限的治疗期内有获得临床终点的适度优势，一此专家主张将聚乙二醇干扰素作为较年轻病人的一线治疗，以避免对他们治疗很多年。但初始聚乙二醇干扰素治疗只使一小部分病人不必长期口服治疗，在较年轻病人中耐受性同样重要（如不更重要的话）。最终，令人信服的论据既支持注射药，又支持口服药，选择常常取决于医师和病人的偏好。
结论
最近有了疗效更好，耐药倾向更小的抗病毒药可采用治疗HBV感染。大量资料支持高水平HBV复制与慢性HBV感染的晚期后果有联系，越来越多的证据说明，通过治疗显著并持久地抑制HBV-DNA，对减慢和逆转慢性HBV感染进展很重要。我们可以期望将来抗病毒药治疗方案可提高疗效，不产生耐药性，药物联合治疗将促进这一发展。面临的挑战是开发较短时的治疗方案，并有更持久的临床转归；在HBV感染时，当疾病活动的伤害性最重时，对病人更精确地进行靶向治疗，尤其对于围产期感染的病人。
作者：美国波士顿马萨诸塞总医院胃肠病科 尤勒斯·L·丁斯泰格
译者：中国医学论坛报 蒋鸿鑫
备注：所有HBV-DNA水平的单位是IU/ml，这是世界卫生组织（WHO）采用的国际通用标准，目的是为了减少HBV-DNA测量中实验室间和试验间的差异。在较早的文献和发表的指南中，HBV-DNA水平的单位为拷贝/ml。因为IU/ml与拷贝/ml的单位换算因子约为5.6（1IU/ml约为5.6拷贝/ml），以拷贝/ml为单位的治疗阈值是以IU/mI为单位的5倍。
N Engl J Med. 2008 Oct 2;359(14):1486-500.
Drug Therapy: Hepatitis B virus infection.
Dienstag JL.
Gastrointestinal Unit (Medical Services), Massachusetts General Hospital, and Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School, Boston 02114, USA.
Reports of successful antiviral therapy for chronic hepatitis B virus (HBV) infection appeared three decades ago,1 and during the past decade, progress has accelerated dramatically. Along with progress, however, has come complexity. So much more is known now than at the dawn of the antiviral era about the protean clinical expressions of HBV infection that determining whom, when, and how to treat has become progressively more challenging.
Virologic and Epidemiologic Factors and Natural History
HBV, a DNA virus transmitted percutaneously, sexually, and perinatally, affects 1.25 million persons in the United States and 350 to 400 million persons worldwide. HBV infection accounts annually for 4000 to 5500 deaths in the United States and 1 million deaths worldwide from cirrhosis, liver failure, and hepatocellular carcinoma.2,3,4,5,6
Viral proteins of clinical importance include the envelope protein, hepatitis B surface antigen (HBsAg); a structural nucleocapsid core protein, hepatitis B core antigen (HBcAg); and a soluble nucleocapsid protein, hepatitis B e antigen (HBeAg). Serum HBsAg is a marker of HBV infection, and antibodies against HBsAg signify recovery. A serum marker of active viral replication, HBeAg, is accompanied by serum levels of HBV DNA that are 100,000 to 1 million IU per milliliter or higher. HBV relies on a retroviral replication strategy (reverse transcription from RNA to DNA),7 and eradication of HBV infection is rendered difficult because stable, long-enduring, covalently closed circular DNA (cccDNA) becomes established in hepatocyte nuclei and HBV DNA becomes integrated into the host genome (Figure 1).
Figure 1. Steps of HBV Replication.
The hepatitis B virus (HBV) establishes covalently closed circular DNA (cccDNA) as a durable miniature chromosome in the host nucleus and relies on a retroviral strategy of reverse transcription from RNA to negative-strand DNA. The steps of HBV replication targeted by nucleoside and nucleotide analogues that are used to treat chronic HBV infection are shown. ER denotes endoplasmic reticulum, and HBsAg hepatitis B surface antigen.
Progression from acute to chronic HBV infection is influenced by the patient's age at acquisition of the virus; age is also related to a dichotomy in the clinical expression of HBV infection between high-prevalence (e.g., Asian) and low-prevalence (e.g., Western) countries (Figure 2). In the Far East, where HBV infection is acquired perinatally, the immune system does not recognize a difference between the virus and the host, and high-level immunologic tolerance ensues. The cellular immune responses to hepatocyte-membrane HBV proteins that are associated with acute hepatitis do not occur, and chronic, usually lifelong infection is established in more than 90% of persons who are infected. In contrast, in the West, most acute HBV infections occur during adolescence and early adulthood because of behaviors and environments that favor the transmission of bloodborne infections, such as sexual activity, injection-drug use, and occupational exposure. In immunocompetent adults, a strong cellular immune response to "foreign" HBV proteins expressed by hepatocytes results in clinically apparent acute hepatitis, which, in all but approximately 1% of persons infected, affects clearance of the infection.5,6,8
Figure 2. Clinical and Epidemiologic Correlations in HBV Infection.
The clinical expression of HBV infection depends on the time of life when the infection is acquired. In Asian countries with a high prevalence of HBV infection, HBV is acquired perinatally from infected mothers. It is not accompanied by acute hepatitis, but it results in chronic infection in more than 90% of patients. Later in life, cirrhosis and hepatocellular carcinoma account for up to a 40% lifetime risk of death. In contrast, in Western countries with a low prevalence of HBV infection, HBV is rarely acquired perinatally but instead is acquired during adolescence and early adulthood; infections acquired in adulthood usually cause a clinically apparent acute hepatitis, but progression to chronic hepatitis is rare, as is the risk of hepatocellular carcinoma.
Immunologic tolerance to HBV established during perinatal infection is profound and lifelong, but not complete; a low level of liver injury occurs and accounts for up to a 40% lifetime risk of death from liver disease among men.9 This risk is lower among women.9 A so-called immune-tolerant phase occurs in the early decades of life, with negligible HBV-associated liver injury despite high-level HBV replication. An immune-clearance phase occurs in the later decades of life with active liver disease. This categorization of phases reflects relatively higher immunologic tolerance early and relatively lower tolerance later in the natural history of chronic HBV infection acquired early in life.5,6,10 Such categorization, however, does not explain the presence of substantial liver injury and fibrosis during the apparent immune-tolerant period in some patients11,12 or the presence of necroinflammatory quiescence during the immune-clearance phase later in the course of chronic HBV infection.
The HBeAg status distinguishes two additional categories of chronic HBV infection. HBeAg-reactive chronic HBV infection is accompanied by high-level HBV replication, and spontaneous seroconversion from HBeAg-positive to antibody (anti-HBe)–positive infection coincides with a reduction in HBV replication and clinical improvement.13,14,15 HBeAg-negative chronic HBV infection, in which precore or core-promoter gene mutations preclude or reduce the synthesis of HBeAg, accounts for an increasing proportion of cases.16 Patients with HBeAg-negative chronic HBV infection tend to have progressive liver injury, fluctuating alanine aminotransferase (ALT) activity, and lower levels of HBV DNA than patients with HBeAg-reactive HBV infection; however, they cannot have treatment-induced HBeAg seroconversion, a durable response that may permit the discontinuation of antiviral therapy.
Eight HBV genotypes - and differences in clinical outcome according to genotype - are recognized.17,18,19 For example, patients with genotype A are more likely to undergo interferon-induced HBeAg seroconversion20; HBeAg seroconversion and slower disease progression are more frequent in patients with genotype B than in patients with genotype C.19 These differences, however, are not sufficiently established to guide management.
The progression of liver disease in HBV infection is fostered by active virus replication, reflected by the presence in serum of an HBV DNA level above a threshold of approximately 1000 to 10,000 IU per milliliter. Persons with a serum HBV DNA level below 1000 IU per milliliter and a normal ALT level consistently are considered to be inactive carriers with a low risk of clinical progression,21 although, rarely, reactivation can occur spontaneously or with immunosuppression.22,23 Although perinatal infection can result in high-level HBV replication without substantial liver injury in the early decades of life, ultimately the risk of progression to cirrhosis and hepatocellular carcinoma is proportional to the level of HBV DNA maintained persistently over time.24,25
Goals of Antiviral Therapy
Because clinical and histologic improvement accompanies reductions in HBV replication, interventions that reduce HBV replication are expected to limit progressive liver disease and improve the natural history of chronic HBV infection. Practically, however, serious outcomes of HBV infection evolve over decades, whereas clinical trials of antiviral therapy are limited to 1 to 2 years and, rarely, up to 5 years. Therefore, surrogate end points that are achievable during time-limited clinical trials are used. These end points are serologic (i.e., HBeAg loss or seroconversion, usually reflecting a transition to inactive HBV carriage, and, more rarely, HBsAg loss or seroconversion, representing serologic recovery), virologic (i.e., a log10 reduction in the HBV DNA level or suppression of HBV DNA to an undetectable level [<10 to 100 IU per milliliter]), biochemical (i.e., normalization of the serum ALT level), and histologic (i.e., improvement in the necroinflammatory grade and stage of fibrosis).5,6 A course of antiviral therapy may lead to responses that are sustained after treatment withdrawal; more commonly, therapy must be continued to maintain responses achieved during therapy.
Antiviral Drugs
Seven drugs are licensed in the United States for the treatment of HBV infection: interferon alfa,26,27,28,29 pegylated interferon alfa-2a,30,31 lamivudine,32,33,34,35,36 adefovir,37,38,39,40,41 entecavir,42,43,44,45,46 telbivudine,47,48,49 and tenofovir50,51 (Table 1 and Table 2).5,6,52 The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting pegylated interferon, which is injected once weekly.
Table 1. Currently Used or Approved Antiviral Therapies for HBeAg-Positive Chronic HBV Infection in Patients Who Have Not Received Treatment.
Table 2. Currently Used or Approved Antiviral Therapies for HBeAg-Negative Chronic HBV Infection in Patients Who Have Not Received Treatment.
As shown in Table 1 and Table 2, treatment for 1 year generally results in the reduction of serum HBV DNA levels by 3.5 to 6.9 log10, a level of serum HBV DNA that is undetectable by polymerase chain reaction in 13 to 95% of patients, normalization of the ALT level in 38 to 79% of patients, histologic improvement in 38 to 74% of patients, and HBeAg seroconversion in 12 to 27% of patients; drugs that suppress HBV DNA more profoundly more often achieve clinical end points (except perhaps HBeAg seroconversion). Among the oral agents, which differ in resistance profile, the nucleotide analogues adefovir and tenofovir are not cross-resistant with lamivudine, telbivudine, or entecavir. Adefovir resistance is negligible during the first year of therapy but approaches 30% by the end of 4 years. Adefovir is very effective in lamivudine-resistant HBV infection.37,38,39,40,53,54,55 Limiting its appeal among the available drugs, adefovir is the least potent, the slowest to suppress HBV DNA levels, the least likely to induce HBeAg seroconversion, and the most likely to result in "primary nonresponse" (i.e., failure to achieve a reduction in the HBV DNA level of 2 log10 in 20 to 50% of patients56).
Consolidation treatment for 6 to 12 months or more after HBeAg seroconversion achieves a durable response in approximately 80% of HBeAg-positive patients who have received oral agents,57,58,59 whereas all but a small minority of HBeAg-negative patients usually have a relapse after therapy.31,60 Because responses are not always durable, careful post-treatment monitoring is required to identify relapse (especially rare, severe, and sometimes fatal post-treatment flares in patients with cirrhosis) and to reinstitute therapy. Thus, nearly all HBeAg-negative patients and approximately 80% of HBeAg-positive patients who do not undergo HBeAg seroconversion should continue nucleoside or nucleotide therapy after the first year; in the absence of resistance, such therapy generally maintains clinical effectiveness.39,40,45,61,62,63
Successful antiviral therapy retards hepatic fibrosis,33,37,38,64,65 even reverses cirrhosis,66,67 and improves survival.68,69,70 Unlike pegylated interferon, oral agents are effective in patients who previously did not have a response to interferon,33,35,37,42,44 can be used safely and effectively as salvage therapy in patients with hepatic decompensation (delaying or averting liver transplantation),71,72,73,74 and, in patients with advanced fibrosis and cirrhosis, may prevent hepatic decompensation.75 Thus, the introduction of oral nucleoside and nucleotide analogues has been lifesaving in HBV infection, paralleling a 30% reduction (from 586 patients in 2000 to 406 patients in 2006) in the number of patients listed for liver transplantation annually in the United States.76
The side effects of pegylated interferon include flulike symptoms, marrow suppression, depression and anxiety, and autoimmune disorders, especially autoimmune thyroiditis; close medical supervision and laboratory monitoring are required. Most oral agents have an acceptable side-effect profile even after extended use,39,40,45,77 but because adefovir and tenofovir may cause nephrotoxic effects, periodic monitoring of renal function during nucleotide therapy is advisable.39,40 In preclinical rodent-toxicology studies, doses of entecavir that were 30 to 40 times higher than those that were used in humans were associated with lung, brain, and liver tumors, which have not been observed in higher species (e.g., rabbits and dogs).42,44,45 Telbivudine, too, appears to cause few major toxic side effects, although grade 3 and 4 elevations in levels of creatine kinase were more common in patients treated with telbivudine than in patients treated with lamivudine after 2 years of therapy,48 and peripheral neuropathy has been attributed to telbivudine.
Treatment with pegylated interferon for 1 year is more likely to result in HBeAg seroconversion than is treatment with an oral agent for 1 year30; however, oral agents are usually administered for more than 1 year and achieve similar rates of HBeAg seroconversion (approximately 30%) by the end of 2 years, approaching approximately 50% at 5 years.45,49,61,63 Similarly, earlier studies suggested that rates of HBsAg seroconversion at 1 year are higher for interferon-based therapy than for oral agents.26,30,31 However, rates of HBsAg loss are similar between pegylated interferon and some of the newer, more potent oral agents (Table 1 and Table 2).45,51 In addition, after successful HBeAg seroconversion and cessation of therapy in Western (not Asian) patients, patients who have received lamivudine appear to have rates of HBsAg seroconversion (20% at 3 years in one small study) that are similar to those achieved after interferon therapy.58,68,78,79 Reductions in cccDNA are similar in patients with spontaneous, interferon-induced, or oral-agent–induced HBeAg seroconversion.80
Two other oral agents that appear to be efficacious against HBV but are not yet approved by the Food and Drug Administration are emtricitabine and clevudine. Emtricitabine, which is similar in structure, efficacy, and resistance profile to lamivudine,81 appears to confer no advantage over lamivudine. Clevudine is distinguished from other oral agents by its sustained suppression of HBV DNA for several months after cessation of therapy.82,83,84 However, preliminary clinical trials suggest that clevudine is less potent than other oral agents in suppressing HBV DNA and inducing HBeAg seroconversion.83,84
Resistance to Antiviral Drugs
Resistance does not appear to emerge during pegylated interferon therapy. L-nucleosides (e.g., lamivudine and telbivudine) are associated with the emergence of mutations in the YMDD motif (tyrosine, methionine, aspartate, aspartate) of HBV DNA polymerase domain C and with upstream compensatory mutations in polymerase domains A and B that, collectively, reduce treatment efficacy. The nucleotide analogues (adefovir and tenofovir) are associated with mutations in polymerase domains B and D. Although resistance to lamivudine is sufficiently high to limit its clinical impact, resistance to the cyclopentyl guanine analogue entecavir and tenofovir remains low (Table 1 and Table 2). Ultimately, drug resistance reduces drug effectiveness66,75 and may precipitate hepatic decompensation in patients with advanced cirrhosis and after liver transplantation. In addition, because of cross-resistance between several of the oral agents, the emergence of resistance to one drug (e.g., lamivudine) eliminates the option for subsequent treatment with others (e.g., telbivudine and entecavir [see below]). Because of 1-to-2–year treatment-emergent resistance,49 telbivudine has not been widely used for the treatment of chronic HBV infection. The nucleotides are effective in nucleoside resistance and vice versa.54,55,85 Entecavir, at a dose of 1 mg, is approved for lamivudine-resistant HBV; however, entecavir resistance emerges in 7% of patients at the end of year 1, in 16% of patients at the end of year 2, in 35% of patients at the end of year 3, and in 43% of patients at the end of year 4.86,87 Specialized assays are available to detect these mutations. However, the emergence of resistance can usually be detected by an increase in HBV DNA of greater than 1 log10 after an initial virologic response (in the absence of nonadherence,88 which accounts for breakthrough in 30% of patients treated in clinical trials5), especially when accompanied by an elevation in the ALT level. More detailed overviews of antiviral resistance in HBV infection appear elsewhere.6,89,90,91,92
Predictors of Response
Factors that are most predictive of a response include a high ALT level, a low HBV DNA level, and mild-to-moderate histologic activity and stage.93,94 The genotype is associated with higher frequencies of spontaneous (B>C)19,95 and pegylated interferon alfa-2b–related (A>B>C>D) HBeAg and HBsAg seroconversion,20,96 but it does not correlate with the degree of HBV DNA suppression associated with the oral agent.97 In clinical trials of oral agents, numbers of events were too small to determine the influence of the genotype on HBeAg seroconversion. The rapidity and profundity of HBV DNA suppression during oral-agent therapy is predictive of the virologic, serologic, biochemical, and histologic benefit at the end of 1 year of therapy.5,48,52,98,99 Three oral agents have low genetic barriers to resistance - lamivudine, telbivudine, and, to a lesser degree, adefovir. In lamivudine and telbivudine, the level of residual HBV DNA at the end of the first half-year of therapy is inversely proportional to the frequency of drug resistance by the end of the year of therapy. In adefovir, the level of residual DNA at the end of a full year is inversely proportional to the frequency of drug resistance by the end of the second year. Other factors favoring resistance to lamivudine, telbivudine, and adefovir include high baseline HBV DNA and treatment of long duration.6,89,90,91,92
Combination Therapy
Combinations of available antiviral drugs for HBV infection in patients who have not received treatment do not increase efficacy. Although combinations of pegylated interferon and lamivudine yielded a reduction in HBV DNA of an extra 1 to 2 log10 during therapy, the combination did not result in a durable post-therapy benefit.30,31 Similarly, telbivudine and lamivudine combined did not achieve additional antiviral activity over that of telbivudine alone.47 Combination therapy with agents of differing resistance profiles should limit the emergence of resistance; however, resistance is so negligible during the early years of treatment with entecavir or tenofovir that demonstrating the superiority of preemptive combination therapy over initial monotherapy will be challenging. Indeed, adding a second, complementary drug after the emergence of resistance has been a very successful strategy.54,55,100 Because of the lack of data to provide support for the efficacy of combination therapy over monotherapy in patients who have not received treatment, current treatment guidelines5 do not recommend combination therapy except for patients in whom drug resistance can precipitate or aggravate hepatic failure, as in decompensated cirrhosis or after liver transplantation. Among patients with drug-resistant HBV who have received treatment, available data provide support for adding, rather than switching to, a second drug with a different resistance profile.5,6,100
HIV and HBV Coinfection
Antiviral therapy for patients with human immunodeficiency virus (HIV) and HBV coinfection has been reviewed recently in the Journal.89 In such patients, durable responses are rare, and indefinite but continuing therapy is usually required. Many of the drugs for HBV infection are effective against HIV, and HIV and HBV resistance to monotherapy with these drugs emerges rapidly. Thus, monotherapy with most of the approved drugs for HBV infection should not be used in HIV and HBV coinfection. In patients with coinfection requiring treatment for HIV or for both HIV and HBV infection, the use of two HBV drugs is recommended. For patients with coinfection who require therapy for HBV but not HIV infection, the antiviral agent should have little or no activity against HIV; however, except for interferon, the available agents are effective against HIV (i.e., lamivudine, entecavir,101 tenofovir, and emtricitabine) or, theoretically, can promote HIV mutations with cross-resistance to the drugs (i.e., adefovir and telbivudine).102 Therefore, simultaneous combination antiretroviral therapy is advisable.
Indications for Antiviral Therapy
Recommendations for antiviral therapy in patients with chronic HBV infection have been issued by several professional societies5,103,104 and by a group of U.S. hepatologists supported by an unrestricted grant from a pharmaceutical company.105 The most updated, authoritative, and influential of these recommendations is the practice guideline of the American Association for the Study of Liver Diseases (Table 3).5
Table 3. Treatment Guidelines for HBV Infection.
For HBeAg-reactive chronic HBV infection, antiviral therapy is indicated for patients with an ALT level that is more than two times the upper limit of the normal range and HBV DNA that is greater than 20,000 IU per milliliter; patients with an elevated level of ALT are more likely to have potentially durable HBeAg, biochemical, and histologic responses. Without antiviral therapy, fibrosis progresses in approximately one quarter of such patients followed for 1 year.33,37,38 The indication for therapy is so clear-cut that a pretreatment liver biopsy is optional, and therapy should be instituted urgently in patients with jaundice or other evidence of hepatic decompensation. For HBeAg-positive patients with an HBV DNA level that is greater than 20,000 IU per milliliter but an ALT level that is two times the upper limit of the normal range or less (a pattern common among young Asian patients with perinatally acquired infection), progression is limited during the early decades when high HBV DNA levels are accompanied by biochemical quiescence, the baseline histologic grade and stage tend to be low, and ALT levels are already normal or near normal. Although controversy surrounds the treatment of such patients,106 the opportunity for biochemical and HBeAg serologic responses in these patients is so low that committing them to antiviral therapy rarely achieves any near-term clinical benefit; clinical monitoring should suffice to identify the emergence of active liver disease in time to intervene therapeutically.107 Therefore, antiviral therapy is not recommended routinely in these patients unless they have risk factors for progression (i.e., they are older than 40 years of age, they have a family history of hepatocellular carcinoma, or they have an ALT level in the high-normal range [up to two times the upper limit of the normal range]). In these circumstances, liver biopsy should be considered and treatment should be initiated for moderate-to-severe necroinflammatory activity or fibrosis.
Patients with HBeAg-negative chronic HBV infection, an ALT level that is more than two times the upper limit of the normal range, and an HBV DNA level that is more than 20,000 IU per milliliter are candidates for antiviral therapy; liver biopsy is optional. If the ALT level is persistently one to two times the upper limit of the normal range or less and the HBV DNA level is greater than 2000 IU per milliliter, antiviral therapy is not recommended routinely; a liver biopsy should be considered and treatment should be advised for moderate-to-severe necroinflammatory activity or fibrosis. Antiviral therapy is not indicated for inactive HBV carriers (i.e., persons with a persistently normal ALT level and an HBV DNA level that is 2000 IU per milliliter). Conversion to this status is the clinical end point reached in most successfully treated patients. However, inactive carriers, like other patients with chronic HBV infection, can have severe HBV reactivation during withdrawal of immunosuppressive therapy; thus, preemptive treatment with a nucleoside or nucleotide analogue is recommended before the initiation of immunosuppressive or cytotoxic chemotherapy.108,109
During oral-agent therapy of HBeAg-positive chronic HBV infection, HBeAg loss - preferably seroconversion - can serve as a milestone, after which treatment can be discontinued. Therapy should be continued for at least 6 months. In patients with perinatally acquired HBV infection, therapy should be continued for 1 year or longer. After such consolidation therapy, the durability of sustained responses can exceed 80%. In HBeAg-negative chronic HBV infection, the opportunity for HBeAg responses is absent; although sustained virologic responses occur in a small proportion of patients,60,70,110,111 in the vast majority of patients, indefinite therapy is required to maintain clinical benefit.
Patients with compensated cirrhosis and a detectable level of HBV DNA, independent of HBeAg status, are candidates for antiviral therapy to prevent progression; if the level of HBV DNA is greater than 2000 IU per milliliter, therapy is recommended, but if the level of HBV DNA is less than 2000 IU per milliliter, treatment is reserved for patients with an elevated level of ALT. Patients with decompensated cirrhosis and a detectable level of HBV DNA should be treated in coordination with a liver transplantation center. For patients with cirrhosis who have an undetectable level of HBV DNA, observation without therapy is recommended; patients with decompensated cirrhosis should be referred to a transplantation center.
The therapy for patients with a reduction in the HBV DNA level of less than 2 log10 within 6 months after the initiation of treatment (a "primary nonresponse") should be switched to an alternative drug. For patients with lamivudine resistance, the potential choices are switching to or adding adefovir or switching to entecavir. Because switching from lamivudine to adefovir may result in biochemical flares55 and can be accompanied subsequently by adefovir resistance,100 switching is no longer recommended; the nucleotide should be added to the nucleoside. Although a double dose (1 mg) of entecavir is approved for the treatment of lamivudine resistance, entecavir resistance in patients who have received lamivudine is substantial87; therefore, entecavir has not been widely used as treatment for lamivudine resistance. Now that tenofovir is approved, it is likely to replace adefovir as a treatment for nucleoside resistance. In patients who do not meet the criteria for antiviral therapy and in patients who have completed successful antiviral therapy, close clinical and laboratory monitoring is indicated to identify potential reactivation.
As noted above, combination therapy is not recommended as the initial antiviral therapy for patients who have not received treatment. However, it is the approach of choice for patients with drug-resistant HBV infection who have received treatment.
Because the 6-month virologic response to some oral agents is predictive of beneficial outcomes and reduced resistance at 1 year, a group of experts supported by an unrestricted grant from Idenix Pharmaceuticals and Novartis recommended a "road-map" approach to managing oral antiviral therapy for chronic HBV infection based on the level of residual HBV DNA at week 24.99 In patients with a complete virologic response (i.e., no detectable residual HBV DNA) at 24 weeks, the likelihood of the anticipated treatment outcome (i.e., HBeAg seroconversion and maintenance of an undetectable level of HBV DNA) is high and resistance is unlikely; therefore, continued monotherapy with the same drug is recommended. At 24 weeks, in patients with a partial virologic response (i.e., residual HBV DNA of <2000 IU per milliliter) to a drug such as lamivudine, which has a low genetic barrier to resistance, a second drug that is not cross-resistant such as a nucleotide should be added to prevent resistance. For inadequate virologic responses (i.e., a residual level of HBV DNA of 2000 IU per milliliter) at 24 weeks, switching to a more effective drug, if available (as recommended in the current guidelines of the American Association for the Study of Liver Diseases), or adding a second drug that is not cross-resistant is suggested.
Because adefovir reduces HBV DNA more slowly than the other drugs, and because the 24-week milestone is not predictive of 48-week outcomes, the recommended timing of the adefovir decision node is week 48 instead of week 24. For entecavir, which has a very high genetic barrier to resistance and a very rapid decrease in the HBV DNA level in almost all patients, interim modifications of the treatment are not recommended.
The most compelling data providing support for this road-map approach, however, were derived from clinical trials of lamivudine and telbivudine48; because of their high resistance profiles, these drugs are not preferred as first-line therapy. With the anticipated replacement of lamivudine, telbivudine, and adefovir by the more highly potent, rapidly suppressive, and less resistance-prone entecavir and tenofovir, a 24-week (or a later time point) interim decision may be irrelevant. However, monitoring serum HBV DNA levels during treatment and modifying treatment in patients with an inadequate response is recommended.5
Choice of Agents
The availability of so many potential drugs to treat HBV infection presents clinicians with a confusing wealth of choices. Among the oral agents, the high rate of viral resistance to lamivudine and telbivudine limits their appeal (Table 1 and Table 2), and, now that it is approved, tenofovir is likely to supplant adefovir. Therefore, among the oral agents, entecavir or tenofovir would be preferable for first-line therapy.
Oral agents are the only option for treating decompensated chronic HBV infection and for preventing hepatic decompensation in patients with advanced fibrosis and cirrhosis.72,75,112,113 However, for patients with compensated disease who have not received previous treatment, pegylated interferon and oral agents are recommended, and current guidelines do not favor one approach over the other. Whether to treat with a finite course of side-effect–intense pegylated interferon injections or, in most cases, a longer, sometimes indefinite course of a well-tolerated oral agent remains the subject of debate (Table 4).114,115
Table 4. Advantages and Disadvantages of Pegylated Interferon and Oral Nucleoside and Nucleotide Analogues as Treatment for Chronic HBV Infection.
Favoring pegylated interferon as first-line treatment is the value of a 48-week period of therapy, freedom from drug resistance, and the high likelihood of durable HBeAg and HBsAg responses after a course of therapy. In most studies, however, interferon-based therapy is less effective in patients with high-level hepatitis B viremia93 and, as compared with most oral agents, it suppresses HBV DNA less profoundly. Clinicians who favor oral agents emphasize the direct correlation between the profundity of viral suppression and beneficial serologic, biochemical, and histologic outcomes and the inverse correlation between HBV DNA suppression and the emergence of resistance.48,99,116 As compared with treatment with lamivudine for 1 year, treatment with pegylated interferon for 1 year is more likely to achieve durable HBeAg, HBsAg, and HBV DNA responses.30,31 However, longer treatment with oral agents can achieve the same responses39,40,45,49,61,63,87 and the newer, more potent oral agents51 can achieve similar HBsAg responses at 1 year without the side effects associated with interferon, injections, or the need for more costly laboratory monitoring and medical supervision. In addition, the newer oral agents are associated with no or negligible resistance over several years of therapy.87 Moreover, in HBeAg-negative patients, HBV DNA suppression is sustained after interferon therapy in a minority of patients and degrades gradually over time.60,111
Because pegylated interferon tends to be more effective in patients with a low level of HBV DNA, a high ALT level, and genotype A, some authorities favor first-line pegylated interferon for such patients114,115; however, oral agents are also more effective in patients with a low HBV DNA level and a high ALT level.94 In addition, in definitive clinical trials, genotype A favored HBeAg responses to pegylated interferon alfa-2b20 but not pegylated interferon alfa-2a,30 and the trial of pegylated interferon alfa-2b did not include a nucleoside-only group.20 In all likelihood, genotype A would favor HBeAg seroconversion independent of the type of therapy.117 Finally, because of a modest advantage in achieving clinical end points during a finite treatment period, some authorities advocate pegylated interferon as first-line therapy for younger patients to avoid committing them to many years of treatment.114 However, only a small proportion of patients will be spared the need for long-duration oral therapy by an initial course of pegylated interferon, and tolerability issues are just as important, if not more so, in younger persons. Ultimately, cogent arguments provide support for both injectable and oral agents, and the choice is often dictated by physician and patient preference.
Conclusions
Recently, more effective and less resistance-prone antiviral agents have become available to treat HBV infection. Substantial data provide support for the link between high-level HBV replication and the late consequences of chronic HBV infection, and there is increasing evidence of the importance of profound, durable therapeutic HBV DNA suppression in slowing and reversing the progression of chronic HBV infection. In the future, we can expect antiviral drug regimens to improve in efficacy without engendering resistance, and combination drug therapy may contribute to this evolution. The challenge will be to develop shorter treatment regimens with more durable clinical outcomes and treatments targeted more accurately to the time during HBV infection when the most substantial, injurious disease activity occurs, especially in patients with perinatal infection.
Dr. Dienstag reports serving as a member of scientific advisory boards for Vertex Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Metabasis, SciClone, and Nucleonics and as an ad hoc consultant for Achillion Pharmaceuticals, Amgen, Biogen, Cubist Pharmaceuticals, Oxxon Therapeutics, CombinatoRx, Pharmasset, Wyeth, ViroPharma, AstraZeneca, and Avant Immunotherapeutics; receiving research support from Vertex; holding stock options from Achillion Pharmaceuticals, Metabasis, and Nucleonics; and serving on clinical trial data monitoring and adjudication committees for Schering-Plough Research Institute, Genzyme, Human Genome Sciences, and Gilead Sciences. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Gastrointestinal Unit (Medical Services), Massachusetts General Hospital; and the Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School - both in Boston.
Address reprint requests to Dr. Dienstag at the Gastrointestinal Unit, Jackson 7, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, or at [email protected].
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