编者按：近年来，免疫疗法已经彻底改变了许多癌症的治疗方法，免疫检查点抑制剂处方不断增加。越来越多的病毒性肝炎患者可能在免疫抑制或免疫调节之前或期间接受抗病毒治疗。接受免疫调节治疗的病毒性肝炎患者的管理成为临床热点问题 。

 

第56届欧洲肝脏研究学会年会（EASL2021）暨国际肝脏会议^TM（ILC2021）特别设置“从检查点阻断到免疫抑制剂：病毒性肝炎患者的免疫调节剂管理”专题，《国际肝病》有幸邀请到论坛主席、加拿大多伦多总医院肝病科主任、加拿大多伦多大学医学教授Harry Janssen博士为我们介绍这部分患者的治疗或预防策略。
 

 

 

《国际肝病》：能否请您介绍目前常见的免疫干预，以及它们如何与肝炎病毒相互作用？

 

Harry Janssen教授：免疫干预药物有两类，刺激免疫系统类和抑制免疫系统类。

 

免疫抑制药物通常是治疗肿瘤和免疫性疾病（类风湿性关节炎、溃疡性结肠炎等）的药物，例如化疗和抑制免疫系统的药物。对于使用这类药物治疗的患者，一定要警惕乙型肝炎病毒（HBV）复制增加、乙肝再激活。通常，如果这些药物的免疫抑制作用非常强，那么我们会使用抗病毒药物治疗乙型肝炎，以保持低病毒载量并预防乙肝再激活。

 

另一组药物是免疫刺激药物，例如检查点抑制剂。这些是重振免疫系统以治疗癌症的药物，它们有一些副作用，例如由于自身免疫引起的包括肝脏在内的特定器官的炎症，例如结肠炎、肝炎、甲状腺炎、肺炎（在特定器官中有各种不同类型的炎症）。如果这种副作用发生在肝脏，那么无论患者是否罹患乙型或丙型肝炎，都会引起肝脏炎症。这些药物不会真正重新激活乙型或丙型肝炎病毒，但会以自身免疫的形式引起其他肝脏问题。

 

因此，免疫抑制药物通常会导致病毒重新激活，进而导致肝炎；而检查点抑制剂，即免疫刺激药物，无论患者是否患有乙型或丙型肝炎，都可能引起肝炎。从这个意义上说，它们是完全不同的，并且以不同的方式与肝脏相互作用。

 

: In recent years, immunotherapy has revolutionized changed the treatment of many cancers, and prescriptions for immune checkpoint inhibitors are increasing. More and more patients with viral hepatitis may receive antiviral therapy before or during immunosuppression or immunomodulation. 

 

Could you please introduce the current common immune interventions and how do they interact with the hepatitis virus?

 

Prof. Harry Janssen: There are two types of interventions I would say. There are drugs that stimulate the immune system; and there are drugs that suppress the immune system. If I start with the latter. The immunosuppressive drugs are typically the drugs that are given in the field of oncology and immunology (rheumatoid arthritis, ulcerative colitis etc.), such as chemotherapy and those types of drugs, which suppress the immune system. There, you have to be afraid that the hepatitis B virus in particular, can increase replication with reactivation of disease. Typically, if those drugs are very strong, then we treat hepatitis B with antiviral drugs to keep the viral load low and to prevent them from reactivating. 

 

The other group of drugs are immune stimulatory drugs such as the checkpoint inhibitors. Those are drugs that revitalize the immune system to treat cancers for instance, and these have other side effects, such as inflammation in specific organs including the liver due to autoimmunity (colitis, hepatitis, thyroiditis, pneumonitis – all different types of inflammation in specific organs). If this happens in the liver, that occurs regardless of having hepatitis B or C or not. These compounds don’t really reactivate the hepatitis B or C virus that much, but can cause other liver problems in the form of autoimmunity. 

 

So the immunosuppressive drugs typically lead to a reactivation of the viruses, and for that reason, inflammation of the liver and hepatitis; whereas the checkpoint inhibitors, the immune stimulatory drugs, cause hepatitis regardless of the presence of hepatitis B or C. In that sense, they are quite different and interact with the liver in a different way.

 

《国际肝病》：对于使用免疫调节剂的慢性HBV感染者，我们应如何监测，以及何时进行干预呢？

 

Harry Janssen教授：很难弄清楚免疫检查点抑制剂是否会重新激活乙型肝炎，或者是否会因为药物本身的毒性而导致 ALT骤升。因此，以乙肝为例，我们通常做的是在免疫调节药物治疗前和治疗期间密切关注HBV病毒载量。如果我们看到病毒升高、肝炎活动，则表明或至少暗示乙型或丙型肝炎因免疫调节药物而重新激活。

 

但这并不总是一种普遍现象，病毒在治疗期间甚至可能会下降。因为检查点抑制剂也可用于治疗乙型肝炎以寻求治愈。因此，大多数接受检查点抑制剂治疗的患者不会出现病毒上升的情况。例如，应用检查点抑制剂治疗伴有乙型肝炎的肝癌患者时，在5%～10%的病例中，由于HBV特异性T细胞的重新激活，检查点抑制剂会导致HBsAg消失。

 

因此，要确定引起肝脏炎症的原因是药物毒性还是病毒再激活，方法之一是在开始治疗前检测病毒或病毒蛋白，并在肝脏出现炎症时再次测量，可能会得到答案。

 

:  As we all know, hepatitis B virus (HBV) can be reactivated in patients undergoing immunosuppression for cancer or non-cancer related diseases, and there is also a risk of reactivation in patients who are treated with immune checkpoint inhibitors (ICI). 

 

For these chronic HBV patients who use immunomodulators, how should we monitor them and when should we intervene?

 

Prof. Harry Janssen: I have already given the answer to a certain extent. It is very difficult to tease out whether an immune checkpoint inhibitor gives a reactivation of hepatitis B, or whether it gives an ALT flare because of the toxicity of the drug itself. So what we typically do is look at the viral load for hepatitis B, for instance, very carefully before treatment and during treatment with immune modulating drugs. If we see that the virus goes up and there is an activation, it is indicative, or at least suggestive, of hepatitis B or C reactivation due to the immune modifying drug. 

 

But that is not always a common phenomenon. The virus may even go down. Checkpoint inhibitors are also used to treat hepatitis B and in trying to get a cure. So it is not the case that the virus will go up in most of the patients treated with checkpoint inhibitors. For instance, checkpoint inhibitors are given to patients with liver cancer who have hepatitis B, and in 5-10% of cases, HBsAg losses occur with the checkpoint inhibitors due to reactivation of HBV-specific T cells. 

 

So a way to tease out whether this is a toxicity of the drug or reactivation of the virus is to measure the virus or viral proteins before starting treatment, and measure again once there is inflammation in the liver. That may likely give an answer whether it is the viral reactivation of the hepatitis B or C, or whether it is a drug-induced liver injury. 

 

《国际肝病》：总体而言，对于使用免疫调节剂的病毒性肝炎患者，我们如何提供治疗或预防策略？

 

Harry Janssen教授：对于免疫抑制剂，它实际上取决于免疫抑制的强度。如果是非常强的免疫抑制药物，特别是作用于B细胞的药物，比如抗CD20药物（例如利妥昔单抗），我们对所有感染HBV的患者都给予抗HBV治疗，即使是既往感染并恢复的患者（抗-HBc阳性但HBsAg阴性）。这些药物的作用非常强，对B细胞的抑制程度可使抗体消失，从而导致疾病复发。 

 

对于接受其他强免疫抑制剂治疗，例如大剂量泼尼松（>40 mg），我们通常也会给予HBsAg阴性、抗-HBc阳性患者抗病毒治疗，以预防病毒性肝炎复发。

 

但是，如果患者只接受低强度的免疫抑制治疗，例如5 mg泼尼松或局部使用皮质类固醇或低剂量硫唑嘌呤，我们通常会等待并观察，因为如果只是曾经罹患乙型肝炎而目前无乙型肝炎，疾病复发的可能性非常低。我们会观察这些患者，并随着时间的推移定期测量HBsAg或HBV DNA，如果这些指标呈阳性，再给予患者治疗。这取决于疾病的活跃程度。

 

对于丙型肝炎，情况有点不同。丙型肝炎不会整合到宿主基因组中。我们尝试在这些患者接受免疫调节剂治疗之前对其进行抗病毒治疗，但我们甚至也可以在免疫抑制期间治疗患者。我认为，丙型肝炎更容易治疗。

 

: Generally speaking, how do we provide treatment or prevention strategies for patients with viral hepatitis using immunomodulators?

 

Prof. Harry Janssen: For the immunosuppressive agents, it depends really on the strength of the immunosuppression. If it is a very strong immunosuppressive drug, which particularly affects the B-cells, like the anti-CD20 drugs such as rituximab, we give antiviral therapy against hepatitis B for all patients, even patients who have had hepatitis B in the past so are anti-HBc positive but HBsAg-negative. These drugs are so strong that they really inhibit B-cells in such a way that antibodies are disappearing and disease comes back. We also typically treat anti-HBc-positive patients who are HBsAg-negative getting other highly immunosuppressive therapy (high doses of prednisone >40mg) to prevent the disease flaring up. 

 

If you get just a tiny bit of immune suppression, like 5mg of prednisone or a topical delivery of corticosteroids or low dose Imuran (azathioprine), we typically wait and observe because the likelihood of disease relapse is very low if you do not have hepatitis B but have had hepatitis B in the past. We then thus watch these patients and regularly measure HBsAg or HBV DNA over time, and if they become positive, we treat them. It depends on how active the disease is. 

 

With hepatitis C, it is a bit different. Hepatitis C does not integrate into the host genome. We try to treat these patients before they receive treatment with these kinds of compounds, but we can even treat patients during immune suppression. It iseasier to treat, I would say.

 

来源：《国际肝病》编辑部