又回来了：关于免疫抑制治疗 HBV 再激活的新指南 刘乔治

StephenW

又回来了：关于免疫抑制治疗 HBV 再激活的新指南
刘乔治

George Lau, MBBS (HKU), MD (HKU), FRCP (Edin, London), FAASLD (USA)



乙型肝炎病毒 (HBV) 再激活引起的肝炎越来越被认为是亚太地区肝脏相关发病率和死亡率的一个原因。 HBV 再激活的特征是 HBV DNA 在先前无活动或已治愈的 HBV 感染患者血清中突然重新出现或升高。此外，HBV 再激活通常伴随着肝炎的爆发，这可能导致急性慢性肝衰竭和死亡。

免疫抑制疗法的作用
尽管 HBV 再激活可以是自发的，但其临床相关性主要与在癌症患者、移植受者和受益于免疫调节治疗的患者中使用免疫抑制治疗有关。直到 2020 年，许多临床指南都包含有关如何减少与使用免疫抑制疗法相关的 HBV 再激活发生的建议。 2021 年，亚太肝脏研究协会 (APASL) 制定了一项临床实践指南，专门针对与使用免疫抑制治疗相关的 HBV 再激活。

预防障碍
预防 HBV 再激活的关键步骤是在开始免疫抑制治疗之前筛查患者的 HBV，并在高风险环境中开始优先使用抗 HBV 核苷（酸）类似物。

然而，这些预防措施存在障碍，因此乙肝病毒再激活导致急性-慢性肝功能衰竭导致的肝炎仍然是乙肝病毒感染流行的亚太地区的主要健康威胁。

预防 HBV 再激活的主要障碍似乎是医疗保健专业人员不遵守免疫抑制治疗开始前 HBV 筛查的临床指南建议。最近新的免疫抑制剂如用于肿瘤和风湿病适应症的酪氨酸激酶抑制剂、用于治疗各种癌症的免疫检查点抑制剂和用于许多自身免疫疾病的肿瘤坏死因子抑制剂的快速扩张进一步加剧了这种情况。

丙型肝炎合并感染
在过去几年中，在慢性丙型肝炎和 HBV 合并感染的患者中，也有报道在使用直接抗病毒药物治疗期间和之后发生 HBV 再激活。直接作用的抗病毒药物对共感染患者的丙型肝炎病毒根除非常有效，但比基于干扰素的治疗更有可能诱发 HBV 再激活。即使在 HBV DNA 水平检测不到的患者中也可能发生这种情况。

新指南
2021 年，APASL 发布了临床实践指南，旨在协助所有学科的医疗保健专业人员使用免疫抑制疗法有效预防和管理 HBV 再激活。为了制定该指南，回顾了自 1975 年以来与使用免疫抑制疗法导致 HBV 再激活相关的所有出版物，并收集并同步了 APASL 21 个成员国/行政区域的主要意见领袖的建议。免疫抑制剂根据其各自报告的 HBV 再激活率进行风险分层。

对于应开始优先使用核苷（酸）类似物的 HBsAg 阳性患者，建议保持不变。主要变化影响 HBsAg 阴性但抗 HBc 阳性的患者。随着过去几年不断发展的数据更好地阐明了 HBsAg 阴性但抗 HBc 阳性患者的 HBV 再激活风险，现在建议对这些中危和高危患者优先使用核苷（酸）类似物。 - 风险群体。

此外，该算法还包括肝纤维化评估，因为晚期纤维化和肝硬化患者因 HBV 再激活而死亡和发病的风险更高。还包括使用直接作用抗病毒药物治疗的 HBV 和丙型肝炎病毒合并感染患者中 HBV 再激活的新数据。

针对 HBV 再激活的新指南将为医疗保健专业人员提供指导，强调在开始免疫抑制治疗之前筛查 HBV 的重要性。您可以在专家教员解释关键的 APASL 指南建议以解决 HBV 感染患者管理中的常见误解时了解更多信息。

StephenW

It’s Back Again: New Guidance on HBV Reactivation With Immunosuppressive Therapy
Lau_George
       
George Lau, MBBS (HKU), MD (HKU), FRCP (Edin, Lond), FAASLD (USA)



Hepatitis due to hepatitis B virus (HBV) reactivation is increasingly recognized as a cause of liver-related morbidity and mortality in the Asia-Pacific region. HBV reactivation is characterized by an abrupt reappearance or rise of HBV DNA in the serum of a patient with previously inactive or resolved HBV infection. Furthermore, HBV reactivation is often accompanied by a flare of hepatitis, which might result in acute-on-chronic liver failure and death.

Role of Immunosuppressive Therapy
Although HBV reactivation can be spontaneous, its clinical relevance is mainly related to the use of immunosuppressive therapies in patients with cancer, transplant recipients, and patients who benefit from immunomodulatory therapy. Until 2020, numerous clinical guidelines included recommendations on how to reduce the occurrence of HBV reactivation related to the use of immunosuppressive therapies. In 2021, the Asian Pacific Association for the Study of the Liver (APASL) developed a clinical practice guideline specifically addressing HBV reactivation related to the use of immunosuppressive therapy.

Barriers to Prevention
The key steps to prevent HBV reactivation are to screen patients for HBV prior to starting immunosuppressive therapy and to start preemptive anti-HBV nucleos(t)ide analogs in high-risk settings.

Nevertheless, there are barriers to these preventive steps, so hepatitis due to HBV reactivation leading to acute-on-chronic liver failure remains a major health threat in the Asia-Pacific region, where HBV infection is endemic.

The major barriers to HBV reactivation prevention appear to be the nonadherence of healthcare professionals to clinical guideline recommendations for HBV screening prior to immunosuppressive therapy initiation. This is further compounded by the recent rapid expansion of new immunosuppressive agents such as tyrosine kinase inhibitors used for oncologic and rheumatologic indications, immune checkpoint inhibitors used in the treatment of various cancers, and tumor necrosis factor inhibitors used for many autoimmune diseases.

Hepatitis C Coinfection
In the past few years, in patients coinfected with chronic hepatitis C and HBV, HBV reactivation has also been reported during and after treatment with direct-acting antiviral agents. Direct-acting antivirals are highly effective at hepatitis C virus eradication in coinfected patients but are more likely to induce HBV reactivation than interferon-based therapy. This can occur even in patients with undetectable levels of HBV DNA.

New Guideline
In 2021, the APASL published a clinical practice guideline aiming to assist healthcare professionals in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage HBV reactivation. To develop the guideline, all publications related to HBV reactivation with the use of immunosuppressive therapies since 1975 were reviewed and advice from key opinion leaders in 21 member countries/administrative regions of APASL were collected and synchronized. Immunosuppressive agents were risk-stratified by their individual reported rates of HBV reactivation.

The recommendations remain the same for HBsAg-positive patients in whom preemptive nucleos(t)ide analogs should be started. The main changes affect patients who are HBsAg-negative but anti-HBc–positive. With the evolving data during the past few years better elucidating the risk of HBV reactivation in HBsAg-negative but anti-HBc–positive patients, preemptive use of nucleos(t)ide analogs is now recommended for these patients in the moderate-risk and high-risk groups.

In addition, liver fibrosis assessment was included in the algorithm, as patients with advanced fibrosis and cirrhosis run a higher risk of mortality and morbidity with HBV reactivation. New data on HBV reactivation within patients coinfected with HBV and hepatitis C virus treated with direct-acting antivirals are also included.

New guidelines specific to HBV reactivation will provide guidance to healthcare professionals emphasizing the importance of screening for HBV prior to initiation of immunosuppressive therapy. You can learn more as expert faculty interpret key APASL guideline recommendations to address common misunderstandings in the management of patients with HBV infection.