Among them, Prof.Henry Chan from The Chinese University of Hong Kong was invited to give a special report on the latest progress of clinical trials of new antiviral drugs.
For this reason, we specially invited Prof.Henry Chan to have an in-depth interview on the challenges and prospects of the cure of CHRONIC hepatitis B.
IH：How about the long-term durability after patients with chronic hepatitis B achieved hepatitis B surface antigen (HBsAg) loss? Nowadays，is it different between nucleos(t)ide analogue and interferon-based therapy?
Prof. Chan: HBsAg loss is very durable. We have learned this from data on spontaneous loss, interferon-induced loss and NA–induced loss. About 95% of patients will remain sAg-negative after long-term follow-up. But among those patients who have reverted back to HBsAg positivity, most of them have very low HBV DNA levels, and most of them have inactive disease not requiring treatment. So that is the reason why we usually use surface antigen loss as the marker of a functional cure, because most patients will exhibit very mild disease afterwards.
IH：Is there any difference in hepatitis B surface antigen (HBsAg) kinetics during treatment with nucleoside and nucleotide analogues, in other words, is HBsAg decline and HBsAg loss rate different in patients treated with entecavir and tenofovir?
Prof. Chan: With nucleos(t)ide analogue (NA) treatment, HBV DNA will drop very fast. However, over time on nucleoside analogues, the HBsAg is not directly affected. Most patients have a flare of HBsAg kinetics on NA treatment, and it is only a few of them that may see a very fast decline in the first year. It is those patients with a very fast, early HBsAg decline who may see surface antigen loss on subsequent treatment. This accounts for <5% per year of treated cases. There are no hard data suggesting that entecavir or tenofovir can result in a faster or higher proportion of sAg loss during NA treatment, so in my opinion, these two drugs are similar in terms of their ability to induce sAg loss.
IH：What are the main challenges in design of clinical trials for hepatitis B cure?
Prof.Chan: For a hepatitis B cure, we usually aim for HBsAg loss. But we know that HBsAg loss will not happen in one to two years. Most early clinical trials need to be designed over 1- 3 months (phase 1 to phase 2, and phase 2 to phase 3). The biggest challenge in designing HBV trials nowadays is having a reliable short-term biomarker that can indicate positive or negative progress. Today, most investigators rely on markers of target engagement, such as HBV DNA reduction, HBV RNA reduction, or even a decline in HBsAg. However, if only focused on target engagement, it may not reliably predict the chance of HBsAg loss in the future. This is one of the biggest challenges we have when we design a clinical trial for new HBV drugs.
IH：Among novel antiviral therapies for HBV in development currently under clinical trials, which is the most promising to achieve functional cure?
Prof. Chan: There are a lot of new HBV treatments in the pipeline. We can divide them into directing-acting antiviral agents and immune modulators. It is still too early to say which group will be the ultimate winner, but I believe we will need combination therapy in order to cure HBV. My personal opinion is that we may need a very strong direct-acting antiviral agent to block the transcription of cccDNA, such as through RNA interference. And we may also need to have an immune modulator to complete the clearance of virus from inside the hepatocytes. Whether this immune clearance can be induced through the drop of viral product or by enhancing host interference is uncertain. I am sure that this will be required, and we need combination therapy trials starting at phase 2 to address these questions.
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