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1、乙型肝炎病毒再激活: 一个能够预防的问题,南昌大学第一附属医院 张伦理,HBV再激活的发生,Hepatitis B: Some Sobering Facts,350 million people chronically infected 2 billion with evidence of past or present infection Country of origin is THE major risk factor,World Health Organization. Hepatitis B Fact Sheet. Centers for Disease Control and Pr
2、evention. CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012.,慢性乙肝病毒感染自然史,Yim HJ, et al. Hepatology. 2006;43:S173-S181.,HBeAg+ HBeAg- HBeAb+,Immune Clearance,Immunotolerance,ALT,HBV DNA,Mos-Yrs,Immune Control (Nonreplicative),HBsAg+ HBsAg- HBsAb+,Infection,
3、Mos-Yrs,5-30 Yrs,Yim HJ, et al. Hepatology. 2006;43:S173-S181.,Immune Clearance,Immunotolerance,ALT,HBV DNA,Mos-Yrs,HBsAg+ HBsAg- HBsAb+,Infection,Mos-Yrs,5-30 Yrs,慢性乙肝病毒感染自然史,Most Oncology PatientsNormal ALTLow/undetectable HBV DNAHBsAg+ and HBeAg-or HBsAg-, anti-HBc+,Immune Control (Nonreplicative
4、),HBV能被清除吗?,Immune controlnot clearance “Resolved HBV” a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.,HBV能被清除吗?,Immune controlnot clearance “Resolved HBV” a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B, et al. Gastroenterology. 20
5、04;126:1750-1758.,HBV能被清除吗?,Immune controlnot clearance “Resolved HBV” a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.,免疫抑制的后果,Immune control can be lost Immune-mediated liver damage with immune reconstitution,HIV Steroids Chemotx,cccDNA,Werle
6、-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.,免疫抑制的后果,Immune control can be lost Immune-mediated liver damage with immune reconstitution,HIV Steroids Chemotx,cccDNA,Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.,HBV 再激活,5-30 Yrs,Mos-Yrs,Infection,Immunotolerance,Immun
7、e Clearance,HBeAg+ HBeAg- HBeAb+,Mos-Yrs,ALT,HBV DNA,HBeAg+,Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.,HBV 再激活,5-30 Yrs,Mos-Yrs,Infection,Immunotolerance,Immune Clearance,HBeAg+ HBeAg- HBeAb+,Mos-Yrs,ALT,HBV DNA,HBeAg+,Immune Suppression,Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S16
8、5.,HBV 再激活,Infection,Immunotolerance,Immune Clearance,HBeAg+ HBeAg- HBeAb+,ALT,HBV DNA,HBeAg+,Immune Suppression,Immune Reconstitution,Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.,5-30 Yrs,Mos-Yrs,Mos-Yrs,HBV 再激活,定义 非活动性或“痊愈”的HBV感染患者失去针对HBV的免疫控制 在免疫重建过程中和/或紧随着免疫重建，病毒复制的突然出现或增加 临床表现 可发生自亚临床到
9、严重致死性肝炎等病变 HBVDNA水平升高，可伴有或不伴有HBeAg的出现 ALT升高（可为轻度或极其严重的升高） 尽管已经采取抗病毒治疗，仍可以进展至肝衰竭或死亡,Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.,已报道的能引起HBV再激活的药物,Yeo W, et al. Hepatology. 2006;43:209-220.,未及时认识HBV再激活的后果,肝炎发作 可以是严重的，甚至是致命的 偶尔HBVDNA检测不到，主要是由于ALT升高时伴HBVDNA下降 可导致误诊，但是最终可出现肝炎复发 一旦ALT升高出现，病情可能就难以
10、控制 化疗中断 肿瘤治疗结局不佳,Yeo W, et al. Hepatology. 2006;43:209-220.,HBV再激活的概率: 实体肿瘤,HBsAg（+）的 乳腺癌患者接受化疗 HBV相关的急性肝炎发生率: 21%1 即使严密监测HBVDNA, 仍有高达41%的HBV 再激活发生2 HBV DNA 在ALT高峰期可检测不到 其他实体瘤的资料有限,Of those who flare2: 35% chemotherapy interruption 35% premature termination of chemotherapy,1. Kim MK, et al. Korean J
11、 Intern Med. 2007;22:237-243. 2. Yeo W, et al. J Med Virol. 2003;70:553-561.,血液系统恶性病变: 更大的风险,HBV Reactivation,Jaundice,Nonfatal Liver Failure,Death,100 patients with NHL undergoing CHOP; 27 HBsAg positive,Lok AS, et al. Gastroenterology. 1991;100:182-188.,HBsAg Patients (%),100,80,60,40,20,0,48,22,4
12、,4,HBV再激活的危险因素,恶性肿瘤 NHL: 40% to 58% of HBsAg positive Breast cancer: up to 41% of HBsAg positive 化疗 Prednisone, 蒽环类抗生素, rituximab increased risk “Potency of immunosuppression”,HBV DNA HBV DNA 3 105 copies/mL Elevated if HBeAg positive 人口统计 Men women,Yeo W, et al. Hepatology. 2006;43:209-220.,单纯抗HBc阳
13、性的意义,表明曾暴露于HBV 通常保持终身，但也可以数年后消失 如果确实没有HBV危险因素，可以是假阳性 目前尚无治疗指南 再激活的风险 对大多数标准的实体肿瘤患者，风险较低 如果存在肝硬化应考虑预先治疗 如果采用下列治疗方案应考虑预先治疗 Rituximab Bone marrow/stem cell transplantation,Manzano-Alonso ML, et al. World J Gastroenterol. 2011;17:1531-1537.,其他因素引起HBV再激活,Roche B, et al. Liver Int. 2011;31(suppl 1):104-11
14、0.,Immunomodulatory Therapy,Anti-TNF (infliximab, adalimumab, etanercept),Antimetabolite (methotrexate),Purine Analogues (azathioprine/6mp),Steroids (prednisone, budesonide),Other (rituximab, cyclosporine),Rituximab: 一特殊的问题,抗CD20单克隆抗体 (B-cell marker) 减少B-cell 的数量和抗体水平 作为 CHOP-R, EPOCH-R方案的一部分，常被使用 增
15、加HBV再激活的风险，包括 HBsAg（-）的病人 逆转学清转换: 由于免疫控制的丧失，原先HBsAg阴性的病人可以再次出现HBsAg阳性,Yeo W, et al. Hepatology. 2006;43:209-220. Papamichalis P, et al. Clin Res Hepatol Gastroenterol. 2012;36:84-93.,采用Rituximab治疗的 HBsAg（-）患者的HBV再激活,Patients with diffuse large B-cell lymphoma HBsAg-negative, anti-HBcpositive individuals treated with CHOP or CHOP-R,HBV Reverse Seroconversion,HBV-Related Death,Yeo W, et al. J Clin Oncol. 2009;27:605-611.,Risk of reactivation with rituximab significant in anti-HBc positive,40,30,20,10,0,24,0,0,5,Proportion of Anti-HBc Positive, HBsAg-Negative Patients (%),
