Oral HBV cccDNA inhibitor a promising cure against chronic HBV infection
A recent study has found a small-molecule covalently closed circular DNA (cccDNA) inhibitor that reduces levels of hepatitis B virus (HBV) cccDNA. This discovery offers a new way to cure patients with chronic HBV infection.
The investigators used a phenotypic assay with HBV-infected primary human hepatocytes (PHHs) to screen for novel cccDNA inhibitors. They also utilized an HBVcircle mouse model and a urokinase-type plasminogen activator-severe combined immunodeficiency humanized liver mouse model to assess the anti-HBV efficacy of the discovered cccDNA inhibitors.
Initiation of ccc_R08 treatment 2 days after the HBV infection of PHHs resulted in potent and dose-dependent decreases in extracellular HBV DNA, HBsAg, and HBeAg levels. Notably, ccc_R08 reduced the level of cccDNA, without affecting the mitochondrial DNA, and did not exhibit significant cytotoxicity in PHHs or in multiple proliferating cell lines.
Oral administration of ccc_R08 twice daily to HBVcircle model mice containing surrogate cccDNA molecules led to significant reductions in serum levels of HBV DNA and antigens. These effects persisted during the off-treatment follow-up period.
At the end of follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice decreased to below the lower limit of quantification.
The root cause of chronic HBV infection is cccDNA persistence in HBV-infected hepatocytes, a major barrier that prevents viral eradication with existing therapies in patients.
“Therapeutic agents that can eliminate cccDNA are urgently needed to achieve viral eradication and thus HBV cure,” the investigators said.