Hi Stephen,
Unfortunately, Dr. Lok’s suggestion is born out of the failure of all new agents (with the exception of NAPs) to achieve functional cure rather than any new clinical data suggesting that a change in the definition is appropriate, especially for the long term benefit of patients. The current definition of functional cure reflects the realities of the substantial clinical data for more than 20 years. Historically, HBsAg loss (and liver enzyme elevations signalling the removal of integrated HBV DNA) are essential during therapy to maintain immunological control off therapy. Continued HBsAg loss off therapy is still the gold standard for remaining disease free with liver healing, the lowest risk for HBV reactivation and the lowest risk for HCC. See here. There has been no new data to provide a clinical justification for altering this definition.
I suggest you see my recent reviews on these subjects here and here.
Without HBsAg loss, there will be the need for lifelong antiviral therapy (but still the risk of HCC). We already have very good drugs for this: ETV, TDF and TAF.
You are correct that siRNA and antisense were designed to degrade HBV mRNA, however there are two fundamental problems in HBV with these approaches:
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Unlike other viruses, HBV replication has no proofreading function so mutations are very common, driving the evolution of thousands of HBV quasispecies in all patients even in the absence of therapy. siRNA and antisense lose all of their activity with a single nucleotide mismatch between the guide sequence and the target mRNA sequence. The presence of these escape mutants in S and X sequences targeted by JNJ-3839 prior to therapy was recently disclosed at AASLD 2022 (abstract 1213) forcing J&J to admit that the HBsAg declines in these patients was not occurring by an RNAi mechanism. Of course this will be the case for all sequence-dependent approaches in HBV: antisense, siRNA, CIRSR-Cas9 and ARCUS endonucleases. In HBV this includes bepirovirsen, JNJ-3839, VIR-2218, AB-729 and RG6346.
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Active cccDNA (the genetic reservoir of viral replication) turns over very rapidly, allowing rapid fixation of escape mutants under selection pressure of antisense or siRNA resulting in rapid rebound on therapy. This was demonstrated in animal systems which model this genetic plasticity many years ago and in the first clinical trial with siRNA (ARB-1467) where viral rebound occurred rapidly, even with three siRNA triggers used in combination.
All of the clinical data presented to date has actually formally excluded the presence of ASO or siRNA mechanisms in the HBsAg responses observed with these agents. These are too numerous to get into this post but some important ones are:
- The presence of ASO / siRNA escape mutants prior to therapy discussed above.
- The formal demonstration that siRNA does not result in declines in SVP (AB-729) by HBsAg isoform analysis.
- With bepirovirsen, antiviral activity is lost when this ASO is more efficiently targeted to hepatocytes (GSK 3389404) which is now abandoned by GSK.
Your confusion is understandable. All of these presentations are made by well known clinicians who have a lot of experience in testing HBV drugs but who are not well versed in oligonucleotide biochemistry, pharmacology or the pharmacological responses to these agents which are well conserved in many other liver diseases.
What is missed by all of these clinicians is the well documented immunostimulatory properties possible with ASOs and inherent in all RNAi (because they mimic the double stranded RNA found in many viruses).
Previous efforts to develop siRNA for influenza in patients demonstrated that the only antiviral activity possible with this approach was from the immunostimulatory properties of RNA and not from the RNAi mechanism.
GSK has formally acknowledged that the HBsAg response to bepirovirsen is occurring via stimulation of innate immunity (which is why it only shows activity in patients with low baseline HBsAg). Arbutus has acknowledged the immunostimulatory properties of AB-729.
In fact all of the clinical data to date very clearly points to these agents acting as simulators of innate immunity (all RNAi) or innate and T-cell mediated immunity (bepirovirsen).
I encourage you and the community to read the recent review I published here on all of these issues which will give you a much better understanding of why functional cure is so difficult to achieve with sequence dependent oligonucleotide approaches.
Best regards,