There Is No Cure for Chronic Hepatitis B. That Could Change.

With the surge in the development of drugs for hepatitis B over the last few years, researchers from the Institute of Hepatology Foundation for Liver Research at King’s College London recently published a comprehensive overview of the therapeutics being evaluated.

Chronic hepatitis B viral infection remains one the biggest threats to global public health, with 296 million chronically infected people worldwide, according to a 2019 report from the World Health Organization. The WHO estimates that 1.5 million people are newly infected each year. Around the world, an estimated 820,000 people die each year from hepatitis B and related complications.

The goal of current hepatitis B therapies is to suppress viral replication to reduce liver damage and improve the patient survival rate, noted Sandra Phillips, Ravi Jagatia and Shilpa Chokshi in their review, which was published in the journal Virulence late last year. But advances in hepatitis research, the success of curative antiviral treatments for chronic hepatitis C and promising compounds undergoing clinical evaluation, offer hope for new and better treatments for patients with chronic hepatitis B.

The hepatitis B drugs in development have introduced many novel therapies aimed at multiple targets that have shown “profound” antiviral properties, moving researchers closer to a functional cure, which Phillips, Jagatia and Chokshi say is characterized by a sustained undetectable viraemia with a durable loss of hepatitis surface antigen (HBsAg) with or without seroconversion to HBsAg antibody. Functional cure is associated with an end to liver injury, they said, and with a decrease in the risk of developing hepatocellular carcinoma. .

Here is a rundown on some of the promising research highlighted by Phillips, Jagatia and Chokshi

• Clinical trials are underway of direct-acting antivirals that could target and disrupt different steps of the HBV life cycle. Those therapeutics could lead to a functional cure, that is, liver injury is resolved, and the risk of cancer decreased to the point of viral clearance.
• Researchers are making headway with new and different classes of core protein allosteric modulators, which change a receptor’s response to a stimulator. These core proteins would be used individually or in combination with other drugs.
• Therapies that target HBV mRNA are in early stages of development. One approach would inhibit all five HBV mRNA transcripts with a single molecule by degrading mRNA or suppressing their translation thus limiting HBV protein production.
• Host targeting therapies would act on the host factors implicated in the HBV replicative cycle rather than acting directly on HBV. The method, however, requires rigorous testing for toxic events.
• A recently identified liver-specific bile acid transporter that acts as a host entry factor for HBV, has opened another possible avenue for blocking and reducing viral spread. But because it does not directly attack or deplete viruses in the cell nucleus, it would most likely be used in tandem with other therapies.
• Host proteins called cyclophilins are implicated in the HBV life cycle. The effect of antiviral blocking of cyclophilins has been confirmed in experiments in-vitro and in mice. A second generation of cyclophilin inhibitors is currently being studied.

The review paper concludes that, given the complexity of HBV’s replication life cycle and other factors, the, the pathway to a cure will likely involve combinational therapies and agents with specific modes of action. The good news is that pharmaceutical companies across the globe are working together to find a cure for HBV.

“It is clear that significant challenges remain,” concluded Phillips, Jagatia and Chokshi, “but for the first time in 20 years, there is renewed hope that a cure for CHB (chronic hepatitis B) is in sight.”