Currently, there are about 257 million people living with chronic hepatitis B (CHB) worldwide, and about 887,000 people die each year from hepatitis B virus (HBV) infection-related diseases. A very small number of CHB patients can be functionally cured by antiviral therapy, and the majority of CHB patients require long-term or even lifelong treatment. Can a variety of new antiviral drugs under development make more patients with HBV clinically cured? This is a hot topic in current research. "Can We Cure Hepatitis B Virus Infection with Novel Direct Acting Antivirals?" was presented by Professor Fabien Zoulim, University of Lyon, France, during the annual conference of the Asia Pacific Society for the Study of Liver Diseases (APASL). ". In this issue of Hepatology Digest, Professor Fabien Zoulim is invited to share further on this topic.
Hepatology Digest: So, the first question: How to define HBV cure? What percentage of the patients could achieve the ideal endpoints with currently available antiviral therapies?
Dr. Zoulim: So, the functional cure is defined, today, as a clear answer for HBs antigen in serum. And this is associated with undetectable HBV DNA and normal transaminase. Anti-s antibody seroconversion is not mandatory for the definition. So, a confirmed HBs antigen negativity at several time points, several weeks apart, is sufficient to define a functional cure.
Now, today, with the currently available drugs—which are mainly nucleoside analogues for long term treatment, or short term interferon therapy—the rate of functional cure is around 10 percent in selected populations of patients treated with interferon or in patients undergoing at least 5 years of nucleoside analogue therapy. So, this is the best step we can achieve today with the currently available drugs. So, the majority of patients have to continue the treatment because only 10 percent, maximum, can be cured.
Hepatology Digest: OK, the second one: What’s your opinion about the combination of pegylated interferon and nucleos(t)ide analogues in the treatment of chronic hepatitis B?
Dr. Zoulim: Sure. So this is an important question, because nucleos(t)ide analogues and pegylated interferon have two different modes of action. So, scientists and doctors have investigated whether a combination of two drugs with two different modes of action would increase the rate of functional cure in patients. So, several studies have been performed worldwide—in Asia, in Western countries—with different schedules of administration. So, either leading with nucleos(t)ide analogues or with an add-on of interferon, or a de novo combination therapy. So, in all of these three scenarios—so, the three types of combinations—there was no study that could show that the combination could increase the rate of functional cure.
So, today, there is no recommendation to treat, in clinical practice, patients with a combination of nucleos(t)ide analogues and interferon. So, the combination therapy has to be done in clinical trials, in clinical studies, so that we can learn more about how to combine, and whether there are some predictive factors that could help to identify the best population that could receive a combination of the two drugs. Outside of clinical studies, there is no recommendation to combine the two treatments.
Hepatology Digest: OK, third question: Are there any novel direct acting antivirals under clinical trials showing promise to achieve HBV cure? Is it monotherapy or combination therapy with other antivirals?
Dr. Zoulim: OK. So, again, a very exciting and important question. Because, today, we have many drugs, many new antivirals, or immune modulators that are under clinical development for hepatitis B. Some of them are in phase 1B or in phase 2A or, even, phase 2B clinical trials. So, this is very exciting. Now, today's drugs are used in combination, not in monotherapy. I don't think there is any drug that is developed for the treatment of Hep B in monotherapy. The most encouraging results, today, are really the combination of nucleoside analogues, capsid assembly modulators, and siRNA. That's one point.
Another point is the combination of nucleoside analogues and antisense oligonucleotides. Another very interesting combination is a combination of entry inhibitors—the Myrcludex, which is developed for hepatitis D—in combination with interferon and with tenofovir. In that situation, we may see functional cure of hepatitis B. And another very interesting combination is a combination of nucleic acid polymers with tenofovir and pegylated interferon, and it was published that almost 40 percent of patients can achieve functional cure. So, we have several combination strategies that show very promising results. So, we would need to wait for results of phase III clinical trials. The phase III clinical trials have not started yet, but they will start very soon. So, this is really promising.
Hepatology Digest: OK. The last one: If new antivirals with high cure rates become available in the future, should all patients with HBV infection be treated?
Dr. Zoulim: Yeah, I think the question is really where we should aim to go for the treatment of hepatitis B. So, if we are able to achieve functional cure in a very significant proportion of patients—it's difficult to say what number, but let's say at least 20 or 30 percent of patients, which would already be a great achievement—I think the overall aim would be not only to treat chronic hepatitis patients, but also patients with chronic infections. So, the overall objective would be to treat all HBs antigen carriers. Obviously, this would need a step by step evaluation. First, we are treating chronic hepatitis B patients. And then, if it works well and it is confirmed in phase III clinical trials and outside of clinical trials, then we'll have to treat the chronic infections so that we can, in the end, treat all of the HBs carriers. So, this is the real aim that we want to achieve to have a major impact on the public health burden of hepatitis B.
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