分离抗HBc血清学模式的临床意义

StephenW

Tori Rodriguez, MA, LPC
August 02, 2018
Clinical Significance of the Isolated Anti-HBc Serologic Pattern


Patients with isolated anti-HBc should be counseled for possible risk for reactivation, should they receive any immune-altering medications or direct-acting antivirals.

In recent years, there has been an increasing awareness of the risk for hepatitis B virus (HBV) reactivation associated with the use of direct-acting antivirals (DAAs) and immunosuppressive therapies. A serological pattern called "isolated anti-HBc" (IAHBc), characterized by the presence of hepatitis B core antibody (anti-HBc) and the absence of hepatitis B surface antigen and hepatitis B surface antibody, has been of particular interest in this context.1 Individuals who exhibit this pattern have been found to have higher rates of hepatitis C virus (HCV) coinfection compared with those with positive anti-HBs, and other findings showed a greater prevalence of IAHBc among patients who were HCV RNA-positive vs those who were HCV RNA-negative (22% vs 13%; P <.0001).2,3

This may be a result of "mechanisms of increased HCV replication in patients with IAHBc, including the cross-reactivity of immune response," according to a 2017 review published in the American Journal of Gastroenterology.1 "For instance, the presence of anti-HBs and partial resolution of HBV may have implied a stronger immune response to both viruses, allowing for HCV suppression. Subsequent loss of anti-HBs may then allow for increased viremia and activity of HCV."

Accumulating evidence points to IAHBc as a potential serological marker for occult HBV infection (OBI). "IAHBc has important clinical implications in the setting of co-infection with HCV, HBV reactivation risk with HCV DAA therapy and immunosuppression, as well as the progression of liver disease and HCC development," wrote the authors of the review.

To explore the latest findings on the topic and relevant clinical implications, Infectious Disease Advisor interviewed Mindie H. Nguyen, MD, MAS, hepatologist and professor of medicine in the Division of Gastroenterology and Hepatology at Stanford University Medical Center, Palo Alto, California, and Yee Hui Yeo, MD, a postdoctoral research fellow at Stanford University Medical Center.

Infectious Disease Advisor: What is the clinical significance of IAHBc, and what are the reasons for the growing interest in this topic?

Dr Nguyen and Dr Yeo: In general, the vast majority of these patients are not at higher risk for liver failure or liver cancer. However, there are still some traces of the virus "hidden" in some of the liver cells or blood cells in some latent or "occult" state, which can be reactivated into active infection or even fulminant hepatitis and liver failure if the patient's immune system becomes severely weakened, most commonly in the setting of medications that suppress the immune system.

This has become a topic of increasing importance because of the increasing availability of medications for cancer and noncancer treatments that can cause severe immunosuppression. Another unique situation is reactivation in the setting of DAA treatment for HCV. The high efficacy of DAA leads to rapid suppression of HCV that can allow for OBI to reactivate.

The observation that anti-HBc levels are most elevated during the immune active and immune reactivation phases implicates anti-HBc in the immune response to chronic HBV infection.1

Physicians need to keep in mind that it could be the result of an infection with variant viruses (S-escape mutants) undetectable by HBsAg commercial kits.

The clinical significance of IAHBc includes HBV transmission and HBV reactivation in the context of immunosuppressant therapy. The development of liver fibrosis and hepatocellular carcinoma [are additional concerns].

Infectious Disease Advisor: How are related issues, such as risk for HBV reactivation during DAA therapy for HCV, managed in clinical practice?

Dr Nguyen and Dr Yeo: The risk for reactivation in patients with isolated core antibody is very low, but not zero, so patients need to be monitored for HBsAg and/or HBV DNA PCR, and if either of these becomes positive, the patient should be treated with anti-HBV medications right away to avoid possible severe hepatitis B flare.

Previous research showed that HCV core protein may directly suppress transcription of HBV RNA and also limit HBsAg expression, resulting in lower levels of viremia, as well as enhanced clearance of HBsAg.4,5 Therefore, in patients with HBV and HCV dual infection, the administration of DAA may increase the chance of HBV relapse in patients with IAHBc.

After 29 cases of HBV reactivation occurred in patients with dual HBV and HCV infection who were being treated with DAA therapies, the US Food and Drug Administration issued a drug safety Boxed Warning regarding this risk.1

According to current guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, all patients being treated for HCV with DAA therapy should be tested for HBV coinfection via assessment of HBsAg, anti-HBs, and anti-HBc levels. However, findings from 3 recent reports (total N=168) revealed no HBV reactivation events patients with among IAHBc during DAA treatment.6-8

A report from Hong Kong showed that in 193 patients with HCV/IAHBc, DAA treatment did not result in HBV reactivation.9 Another report that included 765 patients with IAHBc with HCV co-infection showed that HBV reactivation occurred in 1 (0.1%) patient after initial resolution.10 However, the HBV DNA level spontaneously decreased after DAA therapy. Therefore, the overall risk for HBV reactivation among patients with IAHBc is low.

Infectious Disease Advisor: In addition to the points noted here, what would be the additional clinical implications if IAHBc is confirmed as a serological marker for OBI?

Dr Nguyen and Dr Yeo: A cohort study showed that in cirrhotic patients with negative hepatitis B surface antigen and negative anti-hepatitis C virus, OBI increased hepatocellular carcinogenesis by 8 times.11

Before initiating immunosuppressive medications, physicians need to consider the types of immunosuppression and the risk for HBV reactivation. Previous studies suggested that B-cell-depleting agents such as rituximab and tumor necrosis factor-α inhibitors are associated with HBV reactivation in patients with IAHBc.12,13

In 1 meta-analysis, HBV reactivation (ALT >3× normal and either an increase in HBV DNA from baseline or HBsAg seroreversion) was estimated at 6.3% in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma.14 Wang et al reported that in 124 patients who were diagnosed with HCV and OBI, DAA treatment did not result in HBV reactivation.9

In addition, OBI can be transmitted, for example, through blood transfusion and liver transplantation, causing classic forms of hepatitis B in newly infected individuals. Therefore, the implementation of progressively more sensitive and specific diagnostic tests is important to lower the risk for posttransfusion hepatitis B infection.

StephenW

Tori Rodriguez，MA，LPC
2018年8月2日
分离抗HBc血清学模式的临床意义


如果他们接受任何免疫改变药物或直接作用抗病毒药物，应该告知患有孤立性抗-HBc的患者可能存在再激活的风险。如果他们接受任何免疫改变药物或直接作用抗病毒药物，应该告知患有孤立性抗-HBc的患者可能存在再激活的风险。

近年来，人们越来越意识到与使用直接作用抗病毒药物（DAAs）和免疫抑制疗法相关的乙型肝炎病毒（HBV）再激活的风险。称为“分离的抗-HBc”（IAHBc）的血清学模式，其特征在于存在乙型肝炎核心抗体（抗-HBc）并且不存在乙型肝炎表面抗原和乙型肝炎表面抗体，在此背景下特别令人感兴趣。 .1与抗HBs阳性的患者相比，表现出这种模式的个体丙型肝炎病毒（HCV）合并感染率更高，其他研究结果显示，HCV RNA阳性患者的IAHBc患病率更高。谁是HCV RNA阴性（22％vs 13％; P <.0001）.2,3

这可能是“IAHBc患者HCV复制增加的机制，包括免疫反应的交叉反应性”的结果，根据美国胃肠病学杂志发表的2017年评论。“例如，抗 - 的存在HBs和HBV的部分消退可能意味着对两种病毒都有更强的免疫反应，从而可以抑制HCV。随后，抗-HBs的丢失可能会增加病毒血症和HCV的活性。

越来越多的证据表明IAHBc是隐匿性HBV感染（OBI）的潜在血清学标志物。 “IAHBc在HCV共感染，HCV DAA治疗和免疫抑制的HBV再激活风险以及肝病和HCC发展的进展中具有重要的临床意义，”该评价的作者写道。

为了探索有关该主题和相关临床意义的最新发现，传染病顾问采访了加利福尼亚州帕洛阿尔托市斯坦福大学医学中心胃肠病学和肝病学部的医学博士，医学博士，医学博士Mindie H. Nguyen， Yee Hui Yeo，医学博士，斯坦福大学医学中心博士后研究员。

传染病顾问：IAHBc的临床意义是什么，以及对这一主题越来越感兴趣的原因是什么？

Nguyen博士和杨博士：总的来说，绝大多数这些患者的肝衰竭或肝癌风险并不高。然而，在一些潜伏或“隐匿”状态的某些肝细胞或血细胞中仍然存在一些病毒“隐藏”的痕迹，如果患者的免疫系统可以重新激活为活动性感染甚至暴发性肝炎和肝功能衰竭。变得严重虚弱，最常见的是抑制免疫系统的药物。

由于可以引起严重免疫抑制的癌症和非癌症治疗的药物越来越多，这已成为一个日益重要的话题。另一个独特的情况是在DAA治疗HCV的环境中重新激活。 DAA的高效率导致HCV的快速抑制，其可以允许OBI重新激活。

免疫活性和免疫再激活阶段抗HBc水平升高的观察结果表明抗HBc在慢性HBV感染的免疫反应中。

医生需要记住，这可能是HBsAg商业试剂盒无法检测到的变异病毒（S-escape突变体）感染的结果。

IAHBc的临床意义包括免疫抑制剂治疗中的HBV传播和HBV再激活。肝纤维化和肝细胞癌的发展[另外的担忧]。

传染病顾问：在临床实践中如何管理相关问题，例如在DAA治疗期间HBV再激活的风险？

Nguyen博士和Yeo博士：分离核心抗体患者再激活的风险非常低，但不是零，因此需要对患者进行HBsAg和/或HBV DNA PCR监测，如果其中任何一种变为阳性，患者应该立即接受抗HBV药物治疗，以避免可能的严重乙型肝炎发作。

以往的研究表明，HCV核心蛋白可能直接抑制HBV RNA的转录并限制HBsAg的表达，导致病毒血症水平降低，以及HBsAg清除率增加.4,5因此，在HBV和HCV双重感染患者中，给予DAA可能会增加IAHBc患者HBV复发的机会。
在接受DAA治疗的双重HBV和HCV感染患者中发生29例HBV再激活后，美国食品和药物管理局就此风险发布了药物安全盒装警告。

根据美国肝病研究协会和美国传染病学会的现行指南，所有接受DAA治疗的HCV患者均应通过评估HBsAg，抗HBs和抗HBc进行HBV合并感染检测水平。然而，最近3篇报告（总N = 168）的结果显示，在DAA治疗期间，IAHBc患者中没有HBV再激活事件.6-8

来自香港的一份报告显示，在193例HCV / IAHBc患者中，DAA治疗未导致HBV再激活。另一项报告包括765例伴有HCV共感染的IAHBc患者，其中1例（0.1％）患者发生HBV再激活最初的解决方案。但是，DAA治疗后HBV DNA水平自发降低。因此，IAHBc患者HBV再激活的总体风险较低。

传染病顾问：除了这里提到的要点之外，如果IAHBc被确认为OBI的血清学标志，那么其他临床意义是什么呢？

Nguyen博士和Yeo博士：一项队列研究显示，肝硬化患者乙型肝炎表面抗原阴性，抗丙型肝炎病毒阴性，OBI使肝细胞癌发生率增加8倍.11

在开始使用免疫抑制药物之前，医生需要考虑免疫抑制的类型和HBV再激活的风险。先前的研究表明，B-cell-depleting agent（如利妥昔单抗和肿瘤坏死因子-α抑制剂）与IAHBc患者的HBV再激活有关[12,13]。

在1项荟萃分析中，接受利妥昔单抗治疗淋巴瘤的HBsAg阴性/ HBcAb阳性患者HBV再激活（ALT> 3倍正常，HBV DNA从基线增加或HBsAg血清反转增加）估计为6.3％.14 Wang et al据报道，在124例被诊断为HCV和OBI的患者中，DAA治疗未导致HBV再激活

此外，OBI可以通过例如输血和肝移植传播，在新感染的个体中引起经典形式的乙型肝炎。因此，逐步更敏感和特异性的诊断测试的实施对于降低输血后乙型肝炎感染的风险是重要的。