Now that the HBV world has gathered extensive clinical experience with interferons and polymerase inhibitors (NUCs) and with the resolve to finally find a cure for a serious disease afflicting hundreds of millions worldwide, the hepatitis B surface antigen (HBsAg) has become recognized as the key determinant for treatment outcome. This is being confirmed by trial after trial investigating combining the actions of both NUCs and interferons, either one after the other or together at once.
Some of these studies were presented at the International Liver Congress last week in Vienna (ILC2015). Emerging from them are actionable HBsAg rules which can predict fairly well whether a patient will eventually seroconvert to (or at least lose) HBsAg. No matter the excitement around CRISPR technologies, HBsAg seroconversion remains the gold standard outcome in HBV treatment in the foreseeable future.
These rules can be divided into pre- and post-IFN treatment onset.
In the pre-IFN setting, it is those patients that have below ~500 IU/ml serum HBsAg as a result of NUC treatment that will most likely respond to interferon treatment/immune stimulation with s-antigen seroconversion (see earlier blog entry). Since NUCs alone hardly do anything to promote s-antigen seroconversion despite its dramatic lowering of viral HBV titers, it appears to be their slow impact on HBsAg levels ( 0.1 log per year HBsAg reduction) that has the synergistic effect with interferon: with HBsAg lowering you take off the foot on the immune brake, with interferon you step on the immmune gas pedal.
As such, HBsAg knockdown by RNA(i) Therapeutics would seem to do the same for interferons as NUCs do, only in a more rapid and potent manner. Of course, both could be used concurrently as a run-in to IFN treatment.
However, once on IFNs (post-IFN onset), it is the relative HBsAg decline that has high positive predictive value in prognosticating who will seroconvert. Of note, the HBsAg decline comes before any adaptive immunity can be detected. This supports that HBsAg decline in itself contributes to seroconversion rather than it being a mere correlation. In that setting, it is a 1 log decline in HBsAg the first few weeks after IFN treatment onset that separates the winners from the losers.
It is uncertain to me, however, whether 1 log is a precondition to s-antigen seroconversion as the non-responders do not even come close to that (maybe 0.3log). It is therefore possible that anything that pushes HBsAg below say -0.3-0.5log could have a dramatic effect on s-antigen seroconversion rates.
An RNAi Therapeutic for HBV used simultaneously with IFNs may therefore aim at helping IFNs to get to the 0.5-1log reduction threshold, and rapidly at that.
Ergo, there are now a number of obvious strategies that one can apply regarding the use of RNAi Therapeutics in HBV with various knockdown goals, both absolute and relative. The exact strategy would depend on how the RNA agent is combined with polymerase inhibition/NUCs or immune stimulation.
While a number of other HBV targets were reported at the conference such as core assembly and entry inhibitors, HBsAg (and HBV mRNA knockdown in general) lowering remains the most distinguished and the mechanism predicted to be most synergistic to existing treatment approaches. As combination treatment is strongly predicted to be the future of HBV, HBsAg lowering should become a pillar of those treatment regimes.