PHILADELPHIA – The road to absolute cure of hepatitis B virus (HBV) is so well understood that the strategies now being actively pursued may conceivably eliminate this infection from the human population, according to a summary of progress presented at Digestive Diseases: New Advances.
“As in HIV and hepatitis C infections, combination therapies of drugs with different mechanisms of action will be the solution. Which combination will deliver the ultimate cure is yet to be determined, but within 5 years we should have a cure,” reported Vinod K. Rustgi, MD, chief of hepatology at Robert Wood Johnson Medical School, New Brunswick, N.J.
The biggest hurdle to cure may be clearing covalently closed circular DNA (cccDNA) from the hepatocytes of HBV-infected individuals. This structure is derived from cytoplasmic capsid–relaxed circular DNA (rcDNA) and creates a transcriptional template in the nucleus of hepatocytes. This HBV reservoir has been thus far resistant to therapy. According to Dr. Rustgi, eliminating cccDNA along with integrated HBV RNA sequences represents the final two milestones in the road to cure. There are at least theoretical approaches to eliminating both obstacles.
For many patients, available therapies already provide a functional cure of HBV, defined as viral loads below detection. Long-term data show that such patients can anticipate a lifespan equivalent to those without HBV infection, according to Dr. Rustgi, who listed this as one of the three milestones on the road to cure that have already been achieved. The first milestone was identified as a simple reduction in viral load. The second was anti-HBe seroconversion, which can be achieved in most with available treatments. Following functional cure, the fourth milestone, clearance of HBsAg antigen, is not yet reliably achieved, although this has been documented in a proportion of patients on the most effective long-term regimens.
Understanding these milestones is important, because each has prognostic relevance, according to Dr. Rustgi. Noting the direct correlation between increasing levels of serum HBV DNA and risk of hepatocellular carcinoma (HCC) over time, he indicated that reducing HBV DNA replication already reduces risk of complications. It is possible that virologic cure, which he defined as a stable off-drug suppression of HBV viremia and normalization of liver function tests, may be achieved in a larger proportion of patients with more potent versions of existing therapies. However, absolute cure, which includes complete clearance of cccDNA and other integrated HBV DNA, is the ultimate goal. It is expected that complete clearance will eliminate the threat of HCC or other liver complications.
Based on what is understood about HBV infection, increasing the potency of nucleoside analogues, which are the mainstay of current HBV therapy, will only go so far toward absolute cure. These drugs reduce viral replication to prevent liver damage. Although new drugs to prevent cccDNA formation and HBV life cycle events such as capsid assembly and HBeAg expression may further improve outcomes, they still may not be curative without better host defenses.
“One of the ways for trying to get rid of the virus is restoration of antiviral immunity, and there are several strategies to accomplish this,” reported Dr. Rustgi, citing active efforts to mobilize T cells that attack the virus and create toll-like receptor agonists, which play a key role in the innate immune response. He suggested that several strategies now demonstrating benefit in cancer, such as blocking proteins involved in the inhibition of the immune response, are being explored in the treatment of HBV. All of these strategies may be needed.
“No single approach will be sufficient to deliver a cure,” maintained Dr. Rustgi, outlining the many mechanisms HBV employs to defend against eradication. However, he provided a long list of HBV-targeted drugs and immunotherapies, including vaccines, which are now in clinical trials, enabling combinations to attack this infection from multiple fronts.
“A curative regimen might consist of an HBV antigen inhibitor, an immune activator, a cccDNA inhibitor, and a potent nucleoside analogue,” Dr. Rustgi said. Despite the multiple mechanisms that HBV now employs to evade eradication, there are now strategies being pursued to address most of the known vulnerabilities, he said. “I hope I have given you an idea where we are going.”
Digestive Diseases: New Advances was held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education. Global Academy and this news organization are owned by the same company. Dr. Rustgi reported financial relationships with AbbVie, Gilead, Innovimmune, Intercept, and Merck.