免疫控制：慢性乙型肝炎治疗的最佳策略概要对慢性乙肝免疫机制的认识乙肝免疫控制的长期益处从免疫机制认识药物的不同制定最佳的治疗策略“在慢性乙肝如此复杂的疾病中，认为HBV DNA 高代表了疾病更重的看法过于简单了”“The concept that high viral load means severe disease is far too simplistic in a disease as complex as chronic hepatitis B”乙肝病毒的复制循环并不直接致病病毒特异性CD4+T 细胞应答病毒特异性CD8+T 细胞应答慢性乙肝通过免疫重建可以取得HBsAg 清除HBeAg 血清转换( HBeAg 阴性, anti-HBe 阳性, HBV DNA < 105 copies/ml, ALT 正常) 是免疫控制的状态，医学上称为非活动状态（inactive HBsAg carrier ）HBsAg 血清转换( HBsAg 阴性, anti-HBs 阳性) HBeAg 和HBsAg 血清转换是更高的治疗目标HBsAg 血清学转换: 是临床终点的冠军免疫调节和抗病毒双重模式单纯抗病毒作用认识免疫价值：免疫控制提供更好的HBeAg 血清转换的持久性“核苷类药物和干扰素治疗后的复发率不同提示诱导免疫的控制是取得长期持久HBeAg 血清转换的关键因素”1 Van Nunen et al. Gut 2003 “核苷类药物使慢性乙肝的治疗有了更多的选择，然而，由于具有免疫的机制，PEG 干扰素为基础的药物可取得更高的持久HBeAg 血清转换率，而且HBsAg 血清转换似乎是一个在近期和远期可能达到的目标”Janssen H, Lau G. H epatology 2006 乙肝病毒变异位点HBV Pol Resistance Mutations 派罗欣治疗HBeAg 阴性慢性乙肝的HBsAg 转阴和血清转换率采用哪种治疗策略? 最适合PEG- 干扰素α治疗的患者肝病程度较轻的患者期望有限疗程治疗的患者年轻并有治疗意愿的患者治疗开始时机的选择可能提高应答发生率采用哪种治疗策略? 最适合核苷类药物治疗的患者IFNα治疗禁忌的患者或肝功能失代偿的患者不耐受注射治疗的患者IFNα治疗无应答的患者HBeAg 阳性乙肝成本效果分析(PEG 干扰素alfa-2a 和拉米夫定比较具有长期的药物经济学价值) 16,280 0.57 9,283 派罗欣vs.4 年拉米夫定15,583 0.68 10,528 派罗欣vs.3 年拉米夫定15,031 0.80 12,094 派罗欣vs.2 年拉米夫定17,207 0.88 15,069 派罗欣vs.1 年拉米夫定ΔC/ΔE ΔE ΔC 4,793 27.51 131,885 拉米夫定4 年4,765 27.41 130,640 拉米夫定3 年4,729 27.29 129,074 拉米夫定2 年4,632 27.22 126,100 拉米夫定1 年5,032 28.06 141,168 派罗欣1 年C/E E C C/E 增量成本效果30 岁时期望寿命（生活质量调整生命年）终生费用（元, 直接和间接费用）Chen Wen. APASL 2007 小结PEG 干扰素alfa-2a 治疗获得HBeAg 或HBsAg 血清转换的疗效更高PEG 干扰素alfa-2a 在慢性乙型肝炎，免疫功能正常和无禁忌症的患者可以作为首选治疗，尤其是年轻、希望短疗程治疗的病人如果无应答或有禁忌，再考虑长期维持治疗，先使用干扰素类药物可能提高后续治疗的应答率THANK YOU ! Figure 2. The Replication Cycle of HBV. HBV virions bind to surface receptors and are internalized. Viral core particles migrate to the hepatocyte nucleus, where their genomes are repaired to form a covalently closed circular DNA (cccDNA) that is the template for viral messenger RNA (mRNA) transcription. The viral mRNA that results is translated in the cytoplasm to produce the viral surface, core, polymerase, and X proteins. There, progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores can either bud into the endoplasmic reticulum to be enveloped and exported from the cell or recycle their genomes into the nucleus for conversion to cccDNA. The small, peach-colored sphere inside the core particle is the viral DNA polymerase. Figure 3. Cellular Immune Responses to HBV. HBV replicates in hepatocytes to produce HBsAg particles and virions. Both types of particle can be taken up by antigen-presenting cells, which degrade the viral proteins to peptides that are then presented on the cell surface bound to MHC class I or II molecules. (Antigen-presenting cells can also process and display viral antigens taken up by phagocytosis of killed infected hepatocytes.) These peptide antigens can be recognized by CD8+ or CD4+ T cells, respectively, which are thereby sensitized. Virus-specific CD8+ cytotoxic T cells (with help from CD4+ T cells, green arrow) can recognize viral antigens presented on MHC class I chains on infected hepatocytes. This recognition reaction can lead to either direct lysis of the infected hepatocyte or the release of interferon-{gamma} and TNF-{alpha}, which can down-regulate viral replication in surrounding hepatocytes without direct cell killing. This slide depicts the different phases of chronic HBV infection Not all patients go through all phases During the Immune tolerant phase patients are HBeAg+, HBV DNA level is high but ALT is normal The Immune clearance phase is characterized by elevated ALT In some patients this is followed by spon HBeAg seroconversion and Patients enter into inactive carrier state with normal ALT and very low HBV DNA In other patients, the immune clearance phase is protracted with recurrent hepatitis flares leading to severe hepatitis and cirrhosis Not all patients who enter the inactive carrier state stay that way Some develop reactivation of HBV replication but remain HBeAg- Many of these patients have precore or core promoter HBV variants that prevent or decrease HBeAg production These patients have e-CHB * * * 廖家杰教授中国香港Maria Peters. AASLD 2006 Ganem, D. et al. N Engl J Med 2004;350:1118-1129 “The HBV replication cycle is not directly cytotoxic to cells.”“It is now thought that host immune responses to viral antigens displayed on infected hepatocytes are the principal determinants of hepatocellular injury.”--- Ganem and Prince. Ganem, D. et al. N Engl J Med 2004;350:1118-1129 乙肝的发病机制：与免疫应答密切相关几乎在所有的急性自限性肝炎患者的外周血中均可监测到对HBV 抗原多个抗原决定簇产生应答的HLA II CD4+T 细胞CD4+T 细胞分泌细胞因子刺激体液免疫(Th2) 和细胞免疫(Th1) 多种细胞因子有助于从血清清除HBV ，有效控制病毒血症在慢性HBV 感染患者中，HLA II CD4+T 细胞的活性要明显低于急性肝炎患者中Jung MC, et al. Lancet Infectious Diseases. 2001;2:43-50. 通过FasL-Fas, Perorin/ 粒酶依赖的细胞凋亡信号诱导肝细胞凋亡释放IFN-γ和TFN-α等抗病毒细胞因子与其他淋巴细胞相互作用清除病毒HBV 持续感染与CTL 对病毒特异抗原的反应弱有关HBV 抗原特异性CD8+ 细胞免疫功能低下是造成慢性乙肝的重要原因Jung MC, et al. Lancet Infectious Diseases. 2001;2:43-50. 通过骨髓移植传递HBV- 特异性免疫8 例HBsAg(+) 血液病患者接受骨髓移植治疗供者：HLA 相匹配的亲属；自发获得HBV 免疫应答者（HBsAg-/ 抗-HBc ＋）6 个月后停用免疫抑制剂骨髓移植后1.7-13.3 个月后肝炎发作（ALT 峰值：145-530IU/mL ）6/8 实现HBsAg 清除Lau et al. Gastroenterology 2002 自然史显示：免疫控制可以实现疾病持续缓解免疫逃避< < > > HBeAg+ve HBeAg–ve ALT HBV-DNA 非活动状态HBeAg 阴性慢性活动性肝炎HBeAg 阳性慢性乙肝免疫耐受期免疫清除期免疫控制期治疗治疗监测监测109-10 cp/ml 107-8 cp/ml < 105 cp/ml > 105 cp/ml 10 －20 ％67 －80 ％Anna Lok, AASLD guideline 2007 免疫控制的临床标志是什么？HBeAg 血清转换/ 免疫控制：慢性乙型肝炎的长期随访HBeAg 血清转换n=85 84 非活动性状态（免疫控制）1 HBeAg 阴性CHB 开始长期随访：6 个月后: 68 非活动性状态4 HBeAg 阴性CHB 13 HBsAg 阴性30 年后: 肝硬化: 		0		0			0 HCC:	 		0		0			0 死亡:	 		0		0			0 Bortolotti, Hepatol 2006 CHB 的自然史Fattovich G et al. Am J Gastroenterol 1998 HBsAg 血清转换: 最接近乙肝“治愈”的强指标309 例肝硬化患者平均随访5.7 年（回顾性研究）生存概率(%) 有HBsAg 血清转换的患者无HBsAg 血清转换的患者患者生存率月100 80 60 40 20 48 72 96 120 144 168 24 P<0.001 时间HBeAg 消失HBV DNA 转阴HBe 血清转换HBsAg 消失HBsAg 血清转换生存率提高组织学改善HBV DNA 抑制HBeAg 血清学转换HBsAg 血清学转换1 3 2 Adapted from A. Lok. Oral communication. Shanghai Int Liver Congress 2006 基于乙肝免疫的重要观点小结乙肝的自然史显示免疫控制可以取得疾病的持续缓解HBeAg 和HBsAg 血清转换是免疫控制的重要标志HBeAg 和HBsAg 血清转换应当作为代偿性乙肝治疗的主要目标乙型肝炎病毒本身并无直接致病原性CHB 属于一种明显的免疫系统疾病基于乙肝免疫的重要观点小结乙肝的自然史显示免疫控制可以取得疾病的持续缓解HBeAg 和HBsAg 血清转换是免疫控制的重要标志HBeAg 和HBsAg 血清转换应当作为代偿性乙肝治疗的主要目标乙型肝炎病毒本身并无直接致病原性CHB 属于一种明显的免疫系统疾病获批准的治疗慢性乙肝的药物抗病毒为主治疗拉米夫定阿德福韦恩替卡韦基于免疫调节的治疗普通IFN α聚乙二醇干扰素alfa-2a (40KD) 0 10 20 30 40 50 % Cooksley n=46 33% Lai n=355 18% Lau n=271 PEG 干扰素& 核苷类似物32% LAM PEG PEG HBeAg 血清转换率HBeAg 阳性CHB 的HBeAg 血清转换PEG 干扰素alfa-2a 核苷类似物Lai n=355 21% ETV Marcellin n=355 18% ADV 1. Dienstag et at. N Engl J Med 1999; 2. Marcellin et al. N Engl J Med 2003; 3. Chang et al. AASLD 2004; 4. Lau et al. N Engl J Med 2005 32 3-4 Pegylated IFNα