与新型免疫抑制剂和免疫调节剂相关的乙型肝炎病毒再激活

StephenW

与新型免疫抑制剂和免疫调节剂相关的乙型肝炎病毒再激活：系统评价、荟萃分析和专家意见
2022 年 7 月 15 日 - George V. Papatheodoridis1,†, Vasileios Lekakis1,†, Thodoris Voulgaris1,†, Pietro Lampertico2,3, Thomas Berg4, Henry L.Y. Chan5, Jia-Horng Kao6, Norah Terrault7, Anna S. Lok8,*,#, K. Rajender Reddy9,*,#
概括
核苷（酸）类似物（NAs）可以预防HBV再激活（HBVr）。我们对与新型免疫抑制和免疫调节疗法相关的 HBVr 风险进行了系统回顾和荟萃分析，并制定了 NA 预防指南。一个专家小组审查了数据并将与每类药物相关的 HBVr 风险分为低 (<1%)、中 (1-10%) 和高 (>10%)。我们的搜索发现了 59 项研究，包括 3,424 名 HBsAg+ 和 5,799 名 HBsAg-/anti-HBc+ 患者，符合我们的资格标准。基于中等质量证据，免疫检查点抑制剂、酪氨酸激酶抑制剂、细胞因子抑制剂、嵌合抗原受体 T 细胞免疫疗法和皮质类固醇与 HBsAg+ 患者的高 HBVr 风险相关；细胞因子抑制剂、嵌合抗原受体 T 细胞免疫疗法和对 HBsAg-/anti-HBc+ 患者具有中等风险的皮质类固醇；以及在 HBsAg-/anti-HBc+ 患者中风险较低的抗肿瘤坏死因子药物和免疫检查点抑制剂。对证据质量低的药物提供了临时建议。当使用与高 HBVr 风险相关的药物时，建议使用 NA 预防，而对于低风险药物，建议使用按需 NAs 进行监测——这两种方法都可能适用于中度风险药物。就报告 HBVr 的定义和方法达成共识，以及将 HBsAg+ 和 HBsAg-/anti-HBc+ 患者纳入临床试验，将是收集与免疫抑制或免疫调节治疗相关的 HBVr 风险的可靠数据的关键。

介绍
HBV 再激活 (HBVr) 是一种严重的事件，可导致肝功能衰竭和死亡，但它是可以预防的。 [1]
当 HBV 感染患者的免疫反应受到抑制时，就会发生 HBVr。多见于慢性 HBV 感染者（乙型肝炎表面抗原阳性 [HBsAg+]），但也可发生于既往 HBV 感染者，无论是否存在乙型肝炎表面抗体（HBsAg 阴性，IgG 乙型肝炎核心抗体阳性 [HBsAg-/anti-HBc+]），因为即使在血清学恢复后，肝脏中仍持续存在 HBV DNA。[2][3]

HBVr 最初是在接受化疗的恶性肿瘤患者中描述的。此后据报道，它与其他免疫抑制疗法有关，包括用于各种非恶性疾病的生物制剂，以及针对恶性肿瘤的靶向疗法。由于缺乏对定义的共识，以及研究设计和患者选择的差异，与每一类免疫抑制剂或免疫调节剂相关的 HBVr 的发生率差异很大。目前的文献表明，B 细胞消耗剂，如利妥昔单抗，与 HBVr 的最高风险相关。 [3]

已经发表了许多关于与每类免疫抑制治疗相关的 HBVr 风险的综合评论，但很少有对已发表研究的荟萃分析。自 2015 年美国胃肠病学协会组织的荟萃分析发表以来，[4] 新类别的免疫抑制剂和免疫调节剂已获准用于临床。这些新疗法导致 HBVr 风险的数据很少。一些专业协会指南就预防与新型免疫抑制剂和免疫调节剂相关的 HBVr 提供了建议，但这些指南侧重于针对该专业内的疾病通常开具的选择疗法，并且大多数都没有对已发表的文献进行系统评价。 5， 6、7、8、9、10、11、12
我们对与用于广谱疾病的新型免疫抑制剂和免疫调节剂相关的 HBVr 风险进行了系统回顾和荟萃分析；我们还分析了预防性 HBV 抗病毒治疗在降低风险方面的影响，并为各专业的医生提供指导。此外，我们回顾了 2 种常用免疫抑制剂、皮质类固醇和抗肿瘤坏死因子 (anti-TNF) 药物的数据，以提供与这些疗法相关的 HBVr 风险和预防性抗病毒治疗指征的最新指南。

StephenW

Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: A systematic review, meta-analysis, and expert opinion
July 15, 2022 - George V. Papatheodoridis1,†, Vasileios Lekakis1,†, Thodoris Voulgaris1,†, Pietro Lampertico2,3, Thomas Berg4, Henry L.Y. Chan5, Jia-Horng Kao6, Norah Terrault7, Anna S. Lok8,*,#, K. Rajender Reddy9,*,#
Summary
HBV reactivation (HBVr) can be prevented by nucleos(t)ide analogues (NAs). We conducted a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressive and immunomodulatory therapies and developed guidance on NA prophylaxis. An expert panel reviewed the data and categorised the risk of HBVr associated with each class of drugs into low (<1%), intermediate (1-10%), and high (>10%). Our search uncovered 59 studies, including 3,424 HBsAg+ and 5,799 HBsAg-/anti-HBc+ patients, which met our eligibility criteria. Based on medium-high quality evidence, immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids were associated with high HBVr risk in HBsAg+ patients; cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids with intermediate risk in HBsAg-/anti-HBc+ patients; and anti-tumour necrosis factor agents and immune checkpoint inhibitors with low risk in HBsAg-/anti-HBc+ patients. Provisional recommendations are provided for drugs with low quality evidence. NA prophylaxis is recommended when using drugs associated with a high HBVr risk, while monitoring with on-demand NAs is recommended for low-risk drugs – either approach may be appropriate for intermediate-risk drugs. Consensus on definitions and methods of reporting HBVr, along with inclusion of HBsAg+, and HBsAg-/anti-HBc+ patients in clinical trials, will be key to gathering reliable data on the risk of HBVr associated with immunosuppressive or immunomodulatory therapies.

Introduction
HBV reactivation (HBVr) is a serious event which can result in liver failure and death, but it is preventable.[1]
HBVr occurs when the immune response of patients with HBV infection is suppressed. It is more common in patients with chronic HBV infection (hepatitis B surface antigen positive [HBsAg+]), but it can also occur in those with past HBV infection regardless of the presence or absence of hepatitis B surface antibody (HBsAg negative, IgG hepatitis B core antibody positive [HBsAg-/anti-HBc+]) because of the persistent presence of HBV DNA in the liver even after serologic recovery.[2][3]

HBVr was first described in patients receiving chemotherapy for malignancies. It has since been reported to be associated with other immunosuppressive therapies including biologics used in a variety of non-malignant diseases, as well as targeted therapies for malignancies. The incidence of HBVr associated with each class of immunosuppressant or immunomodulator is highly varied due to a lack of consensus regarding definitions, and variations in study design and patient selection. Current literature show that B-cell-depleting agents, such as rituximab, are associated with the highest risk of HBVr.[3]

Many comprehensive reviews have been published on the risk of HBVr associated with each class of immunosuppressive therapy, but few have included a meta-analysis of the published studies. Since the publication of the meta-analysis organised by the American Gastroenterological Association in 2015,[4] new classes of immunosuppressants and immunomodulators have been approved for clinical use. Data on the risk of HBVr with these new therapies are sparse. Several professional society guidelines provided recommendations on the prevention of HBVr associated with new classes of immunosuppressants and immunomodulators, but these guidelines focused on select therapies commonly prescribed for diseases within that specialty and most were not accompanied by a systematic review of the published literature.5, 6, 7, 8, 9, 10, 11, 12
We performed a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressants and immunomodulators used for a broad spectrum of diseases; we also analysed the impact of prophylactic HBV antiviral therapy in reducing that risk and provide guidance to physicians across a wide range of specialties. In addition, we reviewed data on 2 commonly prescribed immunosuppressants, corticosteroids and anti-tumour necrosis factor (anti-TNF) agents, to provide updated guidance on risk of HBVr associated with these therapies and indications for prophylactic antiviral therapy.