Authors: Geoffrey Dusheiko (University College London, UK)
Take a look behind the scenes of a recent Future Virology review entitled ‘Current and future directions of management of hepatitis B: steps toward a cure’ as we ask author Geoffrey Dusheiko (University College London, UK) about the challenges facing hepatitis B and what the future may hold in terms of functional cure and new research directions.
What inspired you to write this review?
The pressing but often neglected public health impact of chronic hepatitis B. Fortunately the direction of travel is changing with the advent of new, finite and even curative therapies. The field is on fire. The article was meant to provide a staging post of progress. Presently we are shooting for the moon, but like the moon landings, the research will spawn a great deal of new technologies and insights.
What are the main challenges in the management of hepatitis B?
We have managed to hold the line with maintenance suppressive therapy; however, young, HBeAg-positive patients with high levels of replication are not usually offered treatment with interferon alpha or nucleoside analogs. The disease is underway in these patients, and finite therapies could turn this on its head; such patients would be the first to be offered treatment if treatments prove safe and effective treatments to durably clear HBsAg.
Several demanding intellectual and technological challenges remain including resolving definitions of cure, the application of the correct sequencing of combination treatments and finding the right synergies at different stages of the disease. It may not be necessary to eradicate the last molecule of cccDNA in order to modify the natural history of the disease with finite treatments. Another question that remains is how will we get curative treatments to lower-income countries in a reasonable space of time?
What recent treatment developments are most promising?
Several lines of treatment are promising including siRNA, capsid assembly modulators, entry inhibitors and nucleic acid polymers that apparently block release of HBsAg. In addition, immune modulatory therapies may acquire a new potency and efficacy after HBsAg concentrations and viral replication are reduced to a greater extent, which is now possible with nucleoside analogs. Who knows – even short (and more tolerable courses) of interferon may play a role in the correct sequence of some treatments. RIG I sensing and agonists are of interest; inhibitors of X gene are somewhat further back but X gene could prove a pivotal target; the scientific endeavors and efforts are encouraging. However, new treatments will quickly be required to surpass the 20–30% rate of loss of HBsAg achieved in HBeAg-negative patients after stopping nucleoside analogs.
Realistically how far away are we from developing a functional cure?
A remarkable assemblage of brain power from the pharmaceutical industry, (both large and smaller) biotechnology groups and academia makes me think that we are further ahead in the search for HBV cure than for HIV cure; we are likely to see quite steady increments in HBsAg loss in the not too distant future – say 2 years – as many compounds enter Phase II clinical trials. We are somewhat further (perhaps more than 5 or 7 years) from achieving HBsAg loss in the majority of patients. Some combinations may work better in HBeAg-positive patients and others in HBeAg-negative patients. The work required will demand painstaking empirical research.
What work are you hoping to do/ what do you think needs to be done in this area?
I would like to see a big bang of combination treatments; at present most groups seem intent on developing their own in house assets. That strategy may work but if not it would be useful, sooner rather than later, to see greater cooperation across development groups to best synergize available assets. We require better standardization of cccDNA, pgRNA, HBcrAg and HBsAg assays.
Immunologists will require at least limited amounts of liver tissue with fine needle biopsies to advance our understanding. Finally, along the way it would be helpful to gain a better understanding of HBV oncogenesis, so that we can determine the residual risk of hepatocellular carcinoma after loss of HBsAg has been achieved.
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