In recent years, immunotherapy has revolutionized the treatment of many cancers with an increasing number of prescriptions for immune checkpoint inhibitors. An increasing number of patients with viral hepatitis may receive antiviral therapy before or during immunosuppression or immunomodulation. The management of patients with viral hepatitis receiving immunomodulatory therapy has become a hot clinical issue.
The 56th Annual Meeting of the European Society for the Study of Liver (EASL2021) and the International Conference on Liver (ILC2021) specially set the theme "From checkpoint blockade to immunosuppressive agents: immunomodulator management for patients with viral hepatitis". Dr. Harry Janssen, chairman of the forum, director of the Department of Liver Diseases, General Hospital of Toronto, Canada, and medical professor at the University of Toronto, Canada, was invited by Hepatology International to introduce to us the treatment or prevention strategies for these patients.
<Hepatology Digest>: 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.
<Hepatology Digest>: 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.
<Hepatology Digest>: 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.
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