乙型肝炎病毒再激活及其预防性治疗

doi:10.3877/cma.j.issn.1674-1358.2017.01.002

全球约20亿人曾感染乙型肝炎病毒（HBV），而任何损害免疫应答的因素均可能明显改变HBV感染的状态，引发HBV感染再激活。再激活可表现为无症状，也可为暴发性肝炎、肝功能衰竭甚至死亡。在不同危险因素下，HBV再激活率为24%～88%，病死率高于10%。HBV再激活的危险因素包括使用生物制剂、糖皮质激素，基线高病毒载量以及HBV表面抗原阳性等。准备接受化疗和免疫抑制剂治疗的患者均需进行HBV标志物筛查，并进行危险度分级，继而确定预防性治疗方案，这对预防HBV再激活所致的危害具有重要意义。

关键词: 肝炎病毒, 乙型, 再激活, 预防

It is estimated that two billion people have had hepatitis B virus (HBV) infection worldwide. Any immunocompromised status will change the state of HBV infection and lead to HBV reactivation. The consequences of reactivation could be asymptomatic, fulminant hepatitis, hepatic failure and even death. The reactivation rate of HBV ranges from 24% to 88% with different risk factors, and the mortality rate is higher than 10%. The risk factors include the use of biological agents and glucocorticoids, high level of viral load at baseline, and positive HBV surface antigen, etc. All candidates for chemotherapy and immunosuppressive therapy should be screened for HBV infection, and receive risk classification and then prevention and treatment, which is significant for preventing the hazard that caused by HBV reactivation.

Key words: Hepatitis B virus, Reactivation, Prophylaxis

表1 HBV再激活危险度分层

影响因素	预测HBV再激活率	HBsAg	HBcAb	糖皮质激素	其他药物
高危因素	> 10%	+	+	/	B细胞单克隆抗^a
		-	+	/	B细胞单克隆抗体
		+	+	/	蒽环类衍生物^b
		+	+	每日中等剂量^c或大剂量^d疗程≥ 4周	/
中危因素	1%～10%	+	+	/	抗TNFα^e，细胞因子单克隆抗体^f，酪氨酸激酶抑制剂^g
		-	+	/	抗TNFα，细胞因子单克隆抗体，酪氨酸激酶抑制剂，蒽环类衍生物
		+	+	每日小剂量^h疗程≥ 4周	/
		-	+	每日中等剂量或大剂量疗程≥ 4周	/
低危因素	< 1%	+	+	/	硫唑嘌呤，甲氨蝶呤，关节内糖皮质激素治疗
		-	+	/	硫唑嘌呤，甲氨蝶呤
		+	+	任意剂量疗程≤ 1周	/
		-	+	任意剂量疗程≤ 1周	/
		+	+	小剂量疗程≥ 4周	/

表1 HBV再激活危险度分层

影响因素	预测HBV再激活率	HBsAg	HBcAb	糖皮质激素	其他药物
高危因素	> 10%	+	+	/	B细胞单克隆抗^a
		-	+	/	B细胞单克隆抗体
		+	+	/	蒽环类衍生物^b
		+	+	每日中等剂量^c或大剂量^d疗程≥ 4周	/
中危因素	1%～10%	+	+	/	抗TNFα^e，细胞因子单克隆抗体^f，酪氨酸激酶抑制剂^g
		-	+	/	抗TNFα，细胞因子单克隆抗体，酪氨酸激酶抑制剂，蒽环类衍生物
		+	+	每日小剂量^h疗程≥ 4周	/
		-	+	每日中等剂量或大剂量疗程≥ 4周	/
低危因素	< 1%	+	+	/	硫唑嘌呤，甲氨蝶呤，关节内糖皮质激素治疗
		-	+	/	硫唑嘌呤，甲氨蝶呤
		+	+	任意剂量疗程≤ 1周	/
		-	+	任意剂量疗程≤ 1周	/
		+	+	小剂量疗程≥ 4周	/

表2 各国指南对乙型肝炎病毒再激活的预防策略

指南	筛查人群	筛查项目	预防用药疗程	药物选择	疫苗
中国慢乙型肝炎指南2015版^[41]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb、HBV DNA	治疗前1周至停止治疗后6个月	恩替卡韦或替诺福韦酯	/
AASLD2009版^[42]	高危人群	HBsAg、HBcAb	HBV DNA<2 000 U/ml，停止治疗后6个月；HBV DNA >2 000 U/ml，同慢性乙型肝炎患者的治疗终点	预期治疗持续时间较短（≤ 12个月）且，血清HBV DNA低于检测下限，拉米夫定或替比夫定；预期治疗持续时间较长，则优选恩替卡韦或替诺福韦酯	/
EASL2012版^[40]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后12个月	预期治疗持续时间较短，HBV DNA< 2 000 U/ml，拉米夫定；预期治疗持续时间较长，HBV DNA> 2 000 U/ml，选择恩替卡韦和替诺福韦酯	血清学阴性时
AGA2015版^[9]	中高危人群	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后6个月；B细胞单克隆抗体最少12个月	建议采用更不易产生耐药性的药物	/
APASL2015版^[43]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后12个月	/	HBsAb阴性时

表2 各国指南对乙型肝炎病毒再激活的预防策略

指南	筛查人群	筛查项目	预防用药疗程	药物选择	疫苗
中国慢乙型肝炎指南2015版^[41]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb、HBV DNA	治疗前1周至停止治疗后6个月	恩替卡韦或替诺福韦酯	/
AASLD2009版^[42]	高危人群	HBsAg、HBcAb	HBV DNA<2 000 U/ml，停止治疗后6个月；HBV DNA >2 000 U/ml，同慢性乙型肝炎患者的治疗终点	预期治疗持续时间较短（≤ 12个月）且，血清HBV DNA低于检测下限，拉米夫定或替比夫定；预期治疗持续时间较长，则优选恩替卡韦或替诺福韦酯	/
EASL2012版^[40]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后12个月	预期治疗持续时间较短，HBV DNA< 2 000 U/ml，拉米夫定；预期治疗持续时间较长，HBV DNA> 2 000 U/ml，选择恩替卡韦和替诺福韦酯	血清学阴性时
AGA2015版^[9]	中高危人群	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后6个月；B细胞单克隆抗体最少12个月	建议采用更不易产生耐药性的药物	/
APASL2015版^[43]	所有准备接受化疗及免疫治疗的患者	HBsAg、HBcAb；必要时检测HBV DNA	停止治疗后12个月	/	HBsAb阴性时

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