How low must HBsAg levels go?

by Robert Kruse


I wanted to write some commentary on HBsAg levels and the therapeutic goal for knockdown that must be achieved in order to have clinical responses. This is in response to some speculation from the current ILC 2015 meeting. I wanted to say as a disclaimer that I believe that siRNA and antisense drugs (Tekmira, Isis, Arrowhead, Analym) could very well work against HBV and mediate clinical response; I am just more apprehensive about the certainty of its clinical success. I also do not own any stock in the companies referenced here, and this is not meant to be investment advice, but a scientific discussion.

My fellow HBV commentator at the RNAi Therapeutics Blog suggests that if levels of HBsAg under 500 IU/mL are achieved, that a synergy between interferon and siRNA could be achieved and cure could happen. He suggested that a month treatment of siRNA could get this low level, and then interferon could finish the job.

Let's assume that theory is right. It makes me nervous that even in patients under this magical threshold, they only had 9% cure rate after an entire year of interferon treatment, which most patients can't even tolerate. Does that mean the siRNA combo plus interferon will only have a 9% cure rate? I would hope not, otherwise the therapy would not be very efficacious. Since siRNA knocks down all viral genes, there is the hope that other mechanisms could be at play that would increase this cure rate.  (edit: @RNAianalyst clarified reported data was for all patients with different HBsAg levels, so 9% cure rate was for combined group. In the link below though, HBeAg negative patients with HBsAg levels of ~200 IU/mL and pegasys and adefovir treatment had 17% cure rate (defined as HBsAg loss) at 2 years after 48 weeks of treatment. Definite improvement over non-responders with higher levels of HBsAg, but not still not a home run like HCV blockbuster medications)

I also want to comment on applying a retrospective clinical cohort analysis to prognostications about the potential of this therapy. The study by Dr. Joerg Petersen is likely true and is similar to other clinical reports I've read on pubmed before, that patients with baseline HBsAg that is lower will respond to treatment better. The problem is that if you compare a patient with 5000 IU/mL vs 500 IU/mL, there are likely a host of differences in their baseline status, namely different levels of ongoing immune responses and/or viral genotype.

The lower HBsAg patient possibly has a more vigorous ongoing polyclonal T cell response against HBV that is keeping the levels of HBsAg low - there must be a reason for the difference in the first place after all. It is likely then that adding interferon to this patient can help push that person's immune system over the top. In the example above, the HBeAg negative patients are negative for that antigen because of a more active immune response against HBV, which lent themselves for a 17% cure rate with IFN added versus HBeAg+ patients who had an 11% cure rate (differing levels of HBsAg modified this as well). Indeed, the type of immune response a person has greatly influences the effect of IFN on the course of HBV.

This situation is analogous to how checkpoint inhibitors for certain tumors are very efficacious, likely because the tumors are more immunogenic, so there is a better immune system at the site ready to fight the tumor. The checkpoint inhibitors can easily push the anti-tumor T cells over the top. On the other hand, the patient with the 5000 IU/mL baseline, even if artificially induced to have lower HBsAg levels to 500 IU/mL, still has a poor ongoing immune response that might not be boosted well by interferon. It's certainly possible that the HBsAg drop could help DC presentation and augment T cell polyclonality, but I don't know how long that might take and I'm not sure if anyone in the field does either. It's possible that their viral antigen specific T cells are already exhausted against the given epitopes and are beyond recovery. The siRNA is analogous to holding the target still, interferon could be bullets, but if the patient doesn't have a gun, ie effective adaptive immunity, it all might be a waste.

There is also the black box of how different viral genotypes secrete HBsAg at different levels, and different viral genotypes respond to interferon differently. This has been reported in several papers on pubmed, and I wonder how this might influence the goal biomarker levels of any siRNA treatment. I would guess in Dr. Peterson's previous study that the patients were all controlled for the same genotype (typically these studies are at centers in a certain area, so the geography dictates similar genotypes), but this is one confounder to look at in any future clinical reports.

In summary, I believe siRNA and ASO drugs are definitely exciting therapeutic modalities and potential game changers for HBV treatment, since they offer a new mechanism to fight the virus. I just want to add caution, though, to benchmarking certain data points and prognosticating success. HBV is one virus, but with a heterogeneous course across patients, the natural history of which is still being learned. The key immunological studies being discussed above have been limited since we can only really gain relevant data from chimpanzees and humans. It will be fascinating as an HBV researcher to see if knockdown could truly reactivate the immune system in all patients. Even if it doesn't in all, there could be a treatment cohort where a 100% cure rate is achieved, like the patients with better baseline status (<500IU/mL) discussed above. However this goes, it will at least be interesting from a basic science perspective.