Interview with Professor Carla S. Coffin, University of Calgary, Canada
"At present, long-term nucleoside analog (NA) treatment cannot achieve the functional cure of chronic hepatitis B patients. It is estimated that it may take up to 40 years to achieve this goal. In most of the registered clinical studies and long-term follow-up studies on NA, we have observed that the probability of functional cure is about 1%, but it is absolutely less than 5%. In the future, we still have a long way to go..."
At the just concluded annual meeting of the American Association for the Study of Liver Diseases (AASLD) in 2022, Professor Carla S. Coffin from the Department of Gastroenterology and Hepatology, University of Calgary, Canada, participated in several clinical conferences on chronic hepatitis B (CHB) and made wonderful academic reports. During the meeting, we invited Professor Coffin to conduct in-depth interviews on the current hot spots of CHB clinical research and the future development direction.
iHepatology: Clinically, some patients with chronic hepatitis B can be cured by NA combined with interferon. Can NA therapy alone achieve this goal? Why?
Dr Coffin: No. Unfortunately, long-term nucleoside analog therapy is not able to achieve a functional cure. There are some estimates that it could take up to 40 years for this to happen. In most of the registry studies and long-term follow-up studies of people on nucleoside analogs, there is a chance of functional cure of maybe 1%, and definitely less than 5%. So unfortunately, no.
iHepatology: What traditional and new serological markers have been identified that can reflect the activity of cccDNA in the liver tissue of hepatitis B patients?
Dr Coffin: That’s a good question. There are a lot of interesting studies being done looking at new viral, as well as host or immune markers. What has been shown recently is that quantitative HBsAg (which is not a perfect biomarker, because it is also a reflection of integrated hepatitis B virus as well as cccDNA) may be a useful marker for seeing treatment response to nucleoside analogs. But at a certain point, quantitative HBsAg levels can plateau in patients on long-term therapy, and that could be related to the presence of integrated virus. Serum HBV RNA is another interesting biomarker that has been looked at. There are some studies showing that that combined with HBV DNA, especially using very sensitive assays, can help predict response and risk of flares with stopping antiviral therapy. Then there is another marker called hepatitis B core-related antigen (HBcrAg), which is interesting because it looks at different parts of the virus in terms of HBeAg and the capsid and the core protein. That may be useful as a serum marker. There are a whole host of biomarkers in terms of immune biomarkers and testing the host response, and those would probably take a lot of time to go into in any great detail, but that is also an interesting area to look at.
iHepatology: Compared with other antiviral drugs that can only achieve clinical cure, can the drugs targeting cccDNA achieve complete cure?
Dr Coffin: The drugs that are targeting cccDNA are unfortunately still very early in development. Most of them are preclinical, meaning they are being tested in cell culture or tested in animal models, but not yet in human patients. So I won’t be able to answer that question, but that is our hope. The goal is to directly target cccDNA, like with gene editing therapies.
iHepatology: Are there any drugs targeting cccDNA in clinical trials? Is it monotherapy or combined therapy with other antiviral drugs?
Dr Coffin: None of the drugs that are directly targeting cccDNA itself. But there is a better understanding of how the different drugs in clinical trials are working. For some of these drugs, it is hypothesized that they could be affecting cccDNA activity, they could be affecting regulation of cccDNA and its transcriptional activity, and controlling different viral proteins, such as the core protein, for example, that traffics to the nucleus and affects cccDNA activity. So not directly, but indirectly, some of these drugs may have a benefit. I think it will definitely be combined therapy. I should have mentioned as well that there are also studies looking at interferon. Interferon is known to have an antiviral effect, which has been shown to impact cccDNA as well as a broader immunomodulatory effect. That may be one of the reasons why patients who receive interferon therapy are more likely to achieve HBsAg loss or a functional cure. Maybe having that as part of the different combination regimens would be beneficial.
iHepatology: Looking forward to the treatment of chronic hepatitis B, how many years is it expected that there will be new therapeutic drugs for hepatitis B on the market? Can this new drug cure most patients in a limited course of treatment within 3-6 months?
Dr Coffin: There are a lot of exciting new drugs. Some of them are going to phase III studies starting next year in 2023. Once a drug gets to phase III, that is the final step before regulatory approval, but it can still take some time before it actually gets to market, because you have to apply to all the different regulatory agencies for approval and going through all the reviews. Whether it would be three versus six months of therapy, I don’t think so, because most of the treatments they have been looking at have been expecting maybe a year or two of treatment, but still better than the NUC drugs we have, which can take up to 40 years. Then maybe some selected populations of patients with hepatitis B with low level HBsAg or with what we call better immune control of their infection, with some of these direct-acting antiviral agents and some of these combination regimens, they could get away with three months or six months of therapy. But the vast majority of patients, I think, will need to have a longer duration of treatment, at least with these new drugs that are coming out.
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