Evaluating Hepatitis B Virus Reactivation During Solid Tumor Chemotherapy: Evidence to Guide Pretreatment Hepatitis B Screening and Prophylaxis
Evaluating Hepatitis B Virus Reactivation During Solid Tumor Chemotherapy: Evidence to Guide Pretreatment Hepatitis B Screening and Prophylaxis
复制标题
DOI：
10.7326/m15-2722
复制
发表时间：
2016-01
影响因子：
39.2
通讯作者：
V. Lo Re;M. Schuster
中科院分区：
文献类型：
--
作者：
V. Lo Re;M. Schuster
乙型肝炎病毒（HBV）感染的再激活越来越被认为是免疫抑制治疗，特别是化疗的并发症。其特征是乙型肝炎表面抗原（HBsAg）阳性患者的HBV DNA水平突然升高，或血清学证据表明已解决感染（HBsAg阴性和核心抗体[HBcAb]阳性，伴或不伴HBV表面抗体）的患者血清HBV DNA再次出现。通常伴有肝转氨酶水平升高。再激活可导致严重的肝损伤、化疗中断、肝功能衰竭和死亡(1)。HBV的再激活发生是因为在感染后，病毒在复制过程中在感染肝细胞的细胞核内建立了共价闭合的环状DNA作为持久的微型染色体。由于HBV闭合环状DNA持续存在，即使在血清学解决感染后，获得性免疫抑制可以破坏宿主免疫系统控制HBV复制的能力并导致再激活。全世界有超过2.48亿人患有慢性HBV感染，并可能因癌症、自身免疫性疾病或器官移植而接受免疫抑制治疗，这使他们面临HBV再激活的风险。预防性治疗可以大大降低接受化疗的高危患者的这种风险(2)。最近的荟萃分析(3)显示，在血液学肿瘤中使用b细胞消耗剂（利妥昔单抗或ofatumumab）与HBV再激活的风险特别高相关。因此，美国食品和药物管理局发布了一份药物安全通讯(4)，敦促卫生保健提供者在开始使用这些药物治疗之前对所有患者进行HBV感染筛查。在实体瘤的化疗中观察到再激活，但在这些情况下再激活的风险尚不清楚。关于各种肿瘤（特别是实体肿瘤）化疗后HBV再激活风险的有限流行病学数据导致了关于HBV筛查和抗病毒预防的相互矛盾的建议。疾病控制和预防中心、美国肝病研究协会、美国胃肠病学协会、亚太肝脏研究协会和欧洲肝脏研究协会(5)建议在所有接受免疫抑制治疗的患者中筛查HBsAg和HBcAb的HBV感染。他们的理由是，这些检测是敏感的，特异性的，廉价的，基于风险的筛查方法可以遗漏没有明显危险因素的HBV感染患者。相比之下，美国临床肿瘤学会（American Society of clinical Oncology） 2010年的一项临时临床意见(6)指出，没有足够的证据来确定化疗患者常规筛查HBV感染的净收益和危害，并建议在HBV感染风险增加或将接受高度免疫抑制方案的患者中考虑筛查。建议的差异引起了肿瘤学家的混淆，在开始化疗前进行HBV感染筛查的不到20%(7)。在本期中，Paul和他的同事(8)提供了一项元分析的结果，填补了一个重要的知识空白。在慢性HBV感染的情况下，没有抗病毒预防的HBV再激活风险从4%到68%不等（中位数为25%）。在没有抗病毒预防的情况下，慢性HBV感染患者接受胃肠道、乳腺癌、肺癌或头颈部癌症化疗的HBV再激活风险超过10%。抗病毒预防显著降低HBV再激活、HBV相关肝炎和化疗中断的风险超过80%。在解决HBV感染的情况下，无预防的HBV再激活风险较低（范围为0.3%至9%），尽管这些结果仅基于3项已发表的研究。该荟萃分析提供了关于实体瘤化疗后HBV再激活风险的宝贵数据，但仍存在重要问题。许多纳入的研究来自HBV感染普遍的亚洲，该地区以外的研究结果的普遍性尚不清楚。此外，许多研究集中于乳腺癌，这限制了确定HBV再激活率和结果严重程度是否因性别而不同的能力。此外，皮质类固醇的使用在所有研究中没有一致的报道，可能是HBV再激活的一个重要因素。鉴于HBV暴露的流行程度、慢性或缓解型HBV感染患者再激活的风险以及再激活后潜在的不良后果，目前的数据支持在化疗前对所有癌症患者进行HBsAg和HBcAb的HBV感染筛查，并应促使美国临床肿瘤学会重新检查HBV筛查。由于肿瘤学家对HBV筛查的接受程度较低(7)，初级保健提供者可以帮助确保在化疗开始前进行这项重要的检测。现有研究还表明，在接受实体或液体肿瘤免疫抑制治疗的慢性HBV感染患者中，抗病毒预防可降低HBV再激活的风险。对于需要化疗的HBV消退患者，预防的益处尚不清楚。对于这些患者，美国胃肠病学协会建议，在接受癌症化疗的患者中，HBV再激活风险适中（即酪氨酸激酶抑制剂[伊马替尼或尼罗替尼]或蒽环类衍生物[阿霉素或表柔比星]）或高（即b细胞消耗剂）的患者应采取抗病毒预防措施，这是明智和适当的（9,10）。需要对HBV再激活进行更多的评估。需要进一步的研究来确定血清学证据表明感染消退的患者化疗再激活的风险。抗病毒预防的最佳持续时间也尚不清楚，应在未来的临床试验中进行检查。
Reactivation of hepatitis B virus (HBV) infection is increasingly recognized as a complication of immunosuppressive therapy, particularly chemotherapy. It is characterized by an abrupt increase in HBV DNA level among patients with positive hepatitis B surface antigen (HBsAg) or the reappearance of serum HBV DNA in those with serologic evidence of resolved infection (negative HBsAg and positive core antibody [HBcAb] with or without HBV surface antibody). It is usually accompanied by elevations in liver aminotransferase levels. Reactivation can lead to serious hepatic injury, chemotherapy interruption, liver failure, and death (1). Reactivation of HBV occurs because after infection, the virus establishes covalently closed circular DNA as a durable miniature chromosome within the nuclei of infected hepatocytes during replication. Because HBV closed circular DNA persists, even after serologic resolution of infection, acquired immunosuppression can disrupt the ability of the host immune system to control HBV replication and result in reactivation. More than 248 million persons worldwide have chronic HBV infection and may receive immunosuppressive therapy for cancer, autoimmune disease, or organ transplantation, which puts them at risk for HBV reactivation. Prophylactic treatment can substantially reduce this risk in at-risk patients receiving chemotherapy (2). Recent meta-analyses (3) show that use of B-celldepleting agents (rituximab or ofatumumab) in hematologic tumors is associated with a particularly high risk for HBV reactivation. Therefore, the U.S. Food and Drug Administration issued a drug safety communication (4) urging health care providers to screen all patients for HBV infection before starting treatment with these agents. Reactivation has been observed with chemotherapy for solid tumors, but the risk for reactivation in these settings has been unclear. The limited epidemiologic data on the risk for HBV reactivation with chemotherapy for various tumors, particularly solid tumors, have led to conflicting recommendations on HBV screening and antiviral prophylaxis. The Centers for Disease Control and Prevention, American Association for the Study of Liver Diseases, American Gastroenterological Association, Asian Pacific Association for the Study of the Liver, and European Association for the Study of the Liver (5) recommend screening for HBV infection with HBsAg and HBcAb in all patients receiving immunosuppressive therapy. Their rationale is that these assays are sensitive, specific, and inexpensive and that risk-based screening methods can miss patients with HBV infection who do not have apparent risk factors. In contrast, a 2010 provisional clinical opinion by the American Society of Clinical Oncology (6) stated that there was insufficient evidence to determine the net benefits and harms of routine screening for HBV infection in patients having chemotherapy and recommended that screening be considered in those at increased risk for HBV infection or who will receive highly immunosuppressive regimens. The variability in recommendations has engendered confusion among oncologists, and fewer than 20% screen for HBV infection before initiating chemotherapy (7). In this issue, Paul and colleagues (8) provide results from a meta-analysis that fills an important knowledge gap. In the setting of chronic HBV infection, the risk for HBV reactivation without antiviral prophylaxis ranged from 4% to 68% (median, 25%). In the absence of antiviral prophylaxis, the HBV reactivation risk exceeded 10% among patients with chronic HBV infection receiving chemotherapy for cancer of the gastrointestinal tract, breast, lung, or head and neck. Antiviral prophylaxis significantly reduced the risk for HBV reactivation, HBV-related hepatitis, and chemotherapy interruption by more than 80%. In the setting of resolved HBV infection, HBV reactivation risk without prophylaxis was low (range, 0.3% to 9%), although these results were based on only 3 published studies. The meta-analysis provides valuable data on the risk for HBV reactivation with chemotherapy for solid tumors, but important questions remain. Many of the included studies were from Asia, where HBV infection is prevalent, and the generalizability of the findings outside of this region remains unclear. Further, many studies focused on breast cancer, which limits the ability to determine whether rates of HBV reactivation and severity of outcomes differ by sex. Moreover, corticosteroid use was not consistently reported across the studies and could be an important factor in HBV reactivation. Given the prevalence of exposure to HBV, risk for reactivation in patients with chronic or resolved HBV infection, and potential for adverse outcomes after reactivation, current data support screening for HBV infection with HBsAg and HBcAb in all patients with cancer before chemotherapy and should prompt a reexamination of HBV screening by the American Society of Clinical Oncology. With the low uptake of HBV screening by oncologists (7), primary care providers could help ensure that this important testing occurs before chemotherapy initiation. Existing studies also show that antiviral prophylaxis reduces the risk for HBV reactivation among patients with chronic HBV infection receiving immunosuppressive therapy for solid or liquid tumors. The benefits of prophylaxis in patients with resolved HBV who require chemotherapy remain less clear. For these patients, recommendations by the American Gastroenterological Association, which suggest antiviral prophylaxis in those having cancer chemotherapy where the risk for HBV reactivation seems moderate (that is, tyrosine kinase inhibitors [imatinib or nilotinib] or anthracycline derivatives [doxorubicin or epirubicin]) or high (that is, B-celldepleting agents), are sensible and appropriate (9, 10). More evaluation of HBV reactivation is needed. Additional studies are necessary to determine the risk for reactivation with chemotherapy among patients with serologic evidence of resolved infection. The optimal duration of antiviral prophylaxis also remains unclear and should be examined in future clinical trials.