Are We Close to Curing HBV?

I recently “attended” the virtual International Liver Congress, the annual meeting of the European Association for the Study of the Liver. One of the most exciting areas in which there were many interesting reports was that of strategies to cure hepatitis B virus (HBV). Before we discuss any of these strategies, we should first discuss what we mean by “cure.” Functional cure is defined as hepatitis B surface antigen (HBsAg) loss in patients who are HBV DNA negative. Sterilizing cure is removal of all covalently closed circular DNA from the liver cell and complete cure is removal of all HBV integrated virus.

Testing and Linkage to Care
One of the most integral steps to cure is testing and linkage to care. A report from Uzbekistan talked about a simplified test-and-treat protocol that would include a population-level screening and found that linkage to care for large numbers of people with hepatitis C virus (HCV) or HBV using nurses and their primary care physicians was rapid and efficient.

More than 60,000 people were screened over 6 months. In this period, 70% of people with HBV were linked to care and 86% of those were prescribed treatment. Correspondingly, 57% of patients with HCV were linked to care and 84% received treatment.

It should be noted that patients with cirrhosis were referred to specialists, but that persons with less severe disease were treated by general practitioners trained by specialists. This success was achieved in the milieu of COVID-19 and was done in tandem with COVID-19 and other testing, but this was truly a remarkable outcome.

There were many other reports in both the HBV and HCV arenas about testing and linkage to care.

New Molecules for HBV Cure
Other interesting reports were on compounds being tested either alone or in combination with current HBV treatments for HBV cure. These molecules were in many different classes, including short or small interfering RNAs (siRNAs), monoclonal antibodies, antisense oligonucleotides, polymerase inhibitors, nucleoside prodrugs, among others. Some of the interesting molecules included:

• AB-729: an siRNA that sustained HBsAg loss and/or suppression of HBV DNA in a small trial of hepatitis B e antigen (HBeAg)–negative patients with chronic HBV infection.
• GSK3228836: an antisense oligonucleotide that had previously shown reductions in both HBsAg and HBV DNA in a phase IIa clinical trial. In the EASL report, GSK3228836 was associated with both HBsAg reduction and dose-dependent induction of immune response in both treatment-naive patients and those previously treated with nucleos(t)ide analogues (NAs).
• VIR-3434: a single low-dose administration of this neutralizing monoclonal antibody resulted in rapid lowering of HBsAg in a phase I study in HBeAg-negative patients.

An important future cornerstone of therapy will be core protein allosteric modulators or capsid inhibitors. There was a report on the pharmacodynamics of the second-generation core inhibitors ABI-H2158 and ABI-H3733 demonstrating enhanced potency and better target coverage for both antiviral inhibition and action against covalently closed circular DNA.  

There were also preclinical data on AB-836, a highly selective HBV capsid inhibitor, that demonstrated inhibition of HBV in vitro and in mouse models, a unique binding mode to core protein, and a favorable preclinical profile. This compound is in phase I trials.

There were interesting data from phase IIb trial that combined JNJ-3989, an siRNA, with NAs in patients with HBeAg-positive or HBeAg-negative HBV infection. The investigators showed inhibition of viral markers including HBsAg, HBeAg, hepatitis B core-related antigen, and HBV RNA. These data were interesting to me because I think that true cure efforts will only be achieved with a combination approach, using 3-4 drugs with different modes of action—“pillars” if you will—including an immunotherapy.

So, which of these cure strategies, if any, might be fruitful in the end? Initially, I believe most patients will be on a combination with one of the currently available NAs or perhaps one of the newer NAs, such as ATI-2173, a clevudine prodrug that has been developed to deliver potent anti-HBV activity at a much lower dose than clevudine, thereby sparing toxicity and adverse events. Beyond that, many combinations are being tested—too many to list here. The combination of siRNA, NA, and capsid inhibitor is currently in phase III trial and will probably be the first drug combination to be approved.

Viral Hepatitis Elimination
Finally, importation information was disseminated at EASL on the new WHO guidance on viral hepatitis elimination. A progress report by region and by country highlighted the major steps forward to our 2030 targets. Progress is being made, but it is still quite heterogeneous. The advent of support of the birth-dose vaccine globally through nonprofit organizations such as Global Alliance for Vaccines and Immunizations will also help with the elimination efforts.

Your Thoughts?
What questions do you have on these strategies for HBV cure? Please share your thoughts and elaborate in the comments section—I’ll be happy to provide any insight that I have.