Dr Kennedy: A lot of our work to-date has shown that when we look at patients who are labeled or considered immune tolerant, they are actually not immunologically tolerant. This confirms what we have been proposing for some time, that this is a clinical categorization based on clinical parameters (HBV DNA, serum ALT), but when we look at these patients immunologically, we don’t see any difference between patients who are labeled immune tolerant from those labeled immune active. This is an argument against the fact that these patients have immune tolerant disease, and part of the driver for the change in terminology. We are now calling these patients formerly labeled as immune tolerant as patients with HBeAg chronic infection. As a consequence of that, we are considering other strategies in terms of their treatment and management.
Dr Kennedy: This is a good question, and a question that comes back time and again. If you take our data for what it shows, it makes an argument for treating these patients. Of course, there are some more real world issues to consider when faced with this scenario. There is the cost of the drug, whether the patients will take the drug, whether patients will be adherent to the drug, and the fact that the treatments we are using at present are not ideal, and probably even suboptimal. If we are using NUCs, for example, we are looking at long-term viral suppression and the patient having to maintain that drug in order to achieve this. For pegylated interferon, in truly immune tolerant patients from seminal work from Buster et al, pegylated interferon works poorly in these patients. So while we are making the case that we should be treating patients who are labeled immune tolerant, we also recognize that this is not something we can necessarily do straight away in the clinic and that we need better biomarkers and identifiers so we can specifically target patients who will probably do better with early treatment, but in the longer run, that this early treatment strategy will become the main strategy to avoid the long-term sequelae of chronic infections. It is a very important subject.
Dr Kennedy: I have mentioned the limitations of both pegylated interferon and NUCs already. For pegylated interferon, the response rates are not ideal. There are systemic effects associated with the drug. And we know it only works in a proportion of patients. NUCs, on the other hand, are well tolerated. They can achieve viral suppression, but the patient must be adherent to them and must take them for a long time. Given the fact that we have a gap in the therapies that we can give to achieve the more robust endpoints that want, such as HBsAg loss, there is certainly an argument for looking at combinations of some of these drugs and using some of these drugs in sequence. There have been some good recent publications showing the use of pegylated interferon followed by lamivudine in sequence has much greater levels of HBeAg seroconversion and greater levels of HBsAg loss. These data are consistent with previously published data suggesting the same thing, that treating patients younger can lead to better treatment outcomes, and also probably resonate with some of our early data about using pegylated interferon and NUCs in sequence to achieve better treatment outcomes.
Dr Kennedy: There are multiple new agents in development and in the development pipeline as potential new treatment strategies. Personally, I think patients labeled as immune tolerant should be considered for those new therapies and considered for those clinical trials, because we see them as treatment candidates as much as other patients with hepatitis B. The difficulty is that we are not clear at this stage what the best therapy will be and what the most advantageous therapy will be in order for them to achieve the treatment outcomes we want. The treatment goal that we really want is HBsAg loss or functional cure. Any therapy that can deliver that in a relatively timely manner will be the ideal therapy for these patients. We think that if we treat patients and achieve HBsAg loss then that is the ideal scenario to reduce the risk of disease progression and reduce the risk of the development of HCC. That is clear.
