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A viral infection that affects the liver and can cause both acute and chronic disease, hepatitis B affects around 296 million people worldwide, and, according to the latest statistics from the World Health Organization (WHO), it resulted in an estimated 820,000 deaths in 2019. The virus is most commonly transmitted to children during childbirth, but it can also be passed on through contact with blood and other bodily fluids during sex, unsafe injections, or exposure to sharp instruments. Although acute hepatitis B infections generally resolve within six months and do not require treatment, chronic infections - meaning the infection lasts for longer that six months - can be a lifelong problem, leading to serious long-term health issues, including liver damage, cirrhosis, and liver cancer. It can even be fatal. “Chronic hepatitis B profoundly impacts patients’ quality of life. Physically, individuals may suffer from symptoms including abdominal pain, fatigue, nausea, and vomiting. The psychological toll can be equally significant, encompassing fear of disclosure, and transmission. Experiences of discrimination and stigmatization can exacerbate social isolation, leading to depression, and anxiety,” commented Sandra Phillips, senior scientist in the Liver Immunology group at the Institute of Hepatology, King’s College London. A cure, therefore, would significantly alter patients’ lives, alleviating both the symptomatic and psychological toll caused by a chronic hepatitis B infection. But just how far away are we from a cure? Finding a “functional cure” for hepatitis B According to Phillips, the ultimate aim is to find a “functional cure” for hepatitis B, which can be defined as resulting in a sustained undetectable hepatitis B DNA level and a loss of hepatitis B surface antigens (HBsAg) post-treatment. “This functional cure mimics natural resolution of infection, further decreasing hepatocellular carcinoma (HCC) risk, making it a highly desirable outcome for patients. A complete cure and a sterilizing cure remain elusive due to the persistence of the covalently closed circular DNA (cccDNA), the template for hepatitis B replication, the cause for hepatitis B chronicity, and the presence of integrated hepatitis B DNA fragments in the chromosomal host,” explained Phillips. Currently, the main option for patients with chronic hepatitis B includes antiviral treatment with nucleoside/nucleotide analogs (NUCs). “Direct acting antivirals that target the viral polymerase, which replicates the genome, are the most common treatment options for chronic hepatitis B. They are well tolerated and effective in suppressing genome replication but because the genome persists even in the absence of replication, cure is rarely achieved,” said Bill Schneider, research associate at Rockefeller University’s Laboratory of Virology and Infectious Disease. It’s worth noting that there is also an established vaccine available that provides protection against hepatitis B, but it is solely a preventative measure and does not offer a cure for active infections. Latest research in search of a cure for hepatitis B There is, however, a lot of research taking place around finding a cure for hepatitis B, especially since its cousin virus, hepatitis C, can now be cured in around 95% of cases with antivirals. In fact, Schneider was very recently involved in a study whereby researchers developed an approach for studying hepatitis B in the lab that allows a much better view of the virus’ behaviors and characteristics during a crucial part of its lifecycle. “Hepatitis B is considered a DNA virus, but its genome passes through an RNA intermediate during replication. We exploited this feature by initiating hepatitis B genome replication with RNA. One benefit of this approach is that it has excellent signal-to-noise properties, which enabled us to identify and quantify rare drug resistant variants in the population,” explained Schneider. “Monitoring and addressing drug resistance is an important component of antiviral therapeutic development and this approach may therefore be useful for the cure effort. We also envision the method being useful for earlier steps in drug discovery, such as in high-throughput screens.” And, according to Phillips, the discovery of a cure for hepatitis C also seems to have galvanized pharmaceutical and biotech companies, which are now redoubling their efforts in search for a cure for hepatitis B. Bepirovirsen enters phase 3 development Bepirovirsen is a particularly promising therapeutic that is currently in development for hepatitis B. It is an investigational antisense medicine designed to inhibit the production of viral proteins associated with hepatitis B. These proteins are associated with infection and replication, including the hepatitis B surface antigen (HBsAg), which is also linked to a poor prognosis in people with chronic hepatitis B. By simultaneously reducing hepatitis B virus replication and suppressing viral antigens, it is hoped that the therapy will stimulate innate immunity and become a functional cure for patients. The development of bepirovirsen is a collaborative effort between Ionis Pharmaceuticals and GSK, who licenced bepirovirsen from Ionis in August 2019 under a collaborative development and license agreement. It was announced earlier this year that two randomized, double-blind, placebo-controlled phase 3 trials had been initiated to further evaluate bepirovirsen, which signals an extremely positive step in terms of edging closer to a cure for hepatitis B. Vaccitech drug for chronic hepatitis B sees positive topline data Another drug that has seen positive results so far in clinical trials for the treatment of chronic hepatitis B infection is Vaccitech’s VTP-300; in March, it was announced that the phase 1b/2a clinical trial of the drug had positive topline final data. VTP-300 is a heterologous immunotherapy consisting of a prime dose using the company’s ChAdOx vector platform and boost doses using MVA encoding multiple hepatitis B antigens, including a full-length surface, modified polymerase and core antigens. The trial itself included 55 patients with chronic hepatitis B, and VTP-300 was observed to induce meaningful, sustained reductions of HBsAg in patients. At the time of the positive topline final data announcement, Bill Enright, the chief executive officer (CEO) of Vaccitech stated that the company believes VTP-300 has the potential to to be a “critical component of functional cure” for hepatitis B. Challenges still remain With the ongoing research, it does seem like a cure may be possible, but we are still in the early stages, and there are numerous challenges to be overcome before we get there. Notably, Phillips said that finding a cure for hepatitis B has proven so difficult due to the intricate nature of its replicative life cycle and the profound immune dysregulation that exists in chronic hepatitis B. “It is increasingly apparent that combinatorial therapies involving direct-acting antivirals (DAAs) and immunomodulatory agents, each with a distinct mode of action, represent the future of hepatitis B therapeutics. However, determining the optimal combinations, appropriate scheduling and treatment duration that induce a functional cure present a significant challenge. Above all, these therapeutic strategies must exhibit excellent safety profiles,” said Phillips. But, what is certain is that, given the toll chronic infection has on a person’s life, as well as the fact it is clearly a significant global health problem, eventually developing a cure for hepatitis B would be a “monumental achievement,” as Schneider put it. Phillips agreed: “Discovering a cure will be a game changer for everyone affected by this disease, potentially preventing millions from liver cancer.”

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