are we getting closer to healing?

A viral infection that affects the liver and can cause acute and chronic illness, hepatitis B affects an estimated 296 million people worldwide, and, according to the latest statistics from the World Health Organization (WHO), it resulted in around 820,000 deaths in 2019.

The virus is most often passed to children during childbirth, but can also be passed on through contact with blood and other body fluids during sex, unsafe injections or exposure to sharp tools.

While acute hepatitis B infection generally clears up within six months and doesn’t require treatment, chronic infection — meaning infection lasting longer than six months — can be a lifelong problem, causing serious long-term health problems, including liver damage, cirrhosis, and heart cancer. It can even be fatal.

“Chronic hepatitis B greatly affects the quality of life of patients. Physically, the individual may suffer from symptoms including abdominal pain, fatigue, nausea, and vomiting. The psychological toll can be just as important, including fear of disclosure, and contagion. Experiences of discrimination and stigmatization can exacerbate social isolation, lead to depression and anxiety,” commented Sandra Phillips, senior scientist in the Liver Immunology group at the Institute of Hepatology, King’s College London.

Therefore, the cure will significantly change the patient’s life, reducing both the symptoms and psychological consequences caused by chronic hepatitis B infection. But how far are we from healing?

Finding a “functional cure” for hepatitis B

According to Phillips, the ultimate goal is to find a “functional cure” for hepatitis B, which can be defined as the result of undetectable levels of hepatitis B DNA and post-treatment loss of hepatitis B surface antigen (HBsAg).

“This functional cure mimics the natural resolution of infection, further reducing the risk of hepatocellular carcinoma (HCC), making it a highly desirable outcome for patients. Complete cure and sterilization remain elusive due to the persistence of covalently closed circular DNA (cccDNA), a template for hepatitis B replication, a cause of hepatitis B chronicity, and the presence of fragments of hepatitis B DNA integrated in the host chromosome,” explained Phillips.

Currently, the main options for patients with chronic hepatitis B include antiviral treatment with nucleoside/nucleotide analogues (NUCs).

“Direct-acting antivirals that target viral polymerase, which replicates the genome, are the most common treatment option for chronic hepatitis B. They are well tolerated and effective at suppressing genome replication but because the genome survives even without replication, a cure is rarely achieved,” said Bill Schneider, research associate at Rockefeller University’s Laboratory of Virology and Infectious Diseases.

It should be noted that there is also a vaccine available that provides protection against hepatitis B, but that is only a preventative measure and does not offer a cure for active infection.

Recent research to find a cure for hepatitis B

However, there has been a lot of research going into finding a cure for hepatitis B, especially since its cousin the virus, hepatitis C, is now curable in about 95% of cases with antivirals.

In fact, Schneider was recently involved in a study in which researchers developed an approach to studying hepatitis B in the laboratory that allows a much better view of the behavior and characteristics of the virus during key parts of its life cycle.

“Hepatitis B is considered a DNA virus, but its genome passes through RNA intermediaries during replication. We exploited this feature by initiating replication of the hepatitis B genome with RNA. One of the benefits of this approach is that it has excellent signal-to-noise properties, which allow us to identify and quantify rare drug resistance variants in the population,” explained Schneider.

“Monitoring and addressing drug resistance is an important component of the development of antiviral therapy and therefore this approach may be useful for cure efforts. We also envision this method being useful for early steps in drug discovery, such as in high throughput screens.”

And, according to Phillips, the discovery of a hepatitis C drug also appears to have galvanized pharmaceutical and biotech companies, which are now redoubling their search for a hepatitis B drug.

Bepirovirsen is entering phase 3 of development

Bepirovirsen is a very promising therapy currently under development for hepatitis B.

It is an investigative antisense drug designed to inhibit the production of viral proteins associated with hepatitis B. These proteins associated with infection and replication, including hepatitis B surface antigen (HBsAg), are also associated with a poor prognosis in people with chronic disease. hepatitis B

By simultaneously reducing hepatitis B virus replication and suppressing viral antigens, it is hoped that the therapy will stimulate innate immunity and provide functional cure for patients.

Development of bepirovirsen is a collaborative effort between Ionis Pharmaceuticals and GSK, which licensed bepirovirsen from Ionis in August 2019 under a collaborative development and licensing agreement.

It was announced earlier this year that two randomized, double-blind, placebo-controlled phase 3 trials had begun to further evaluate bepirovirsen, which marks a very positive step in terms of approaching 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 phase 1b/2a clinical trials of the drug had positive topline final data.

VTP-300 is a heterologous immunotherapy consisting of main-dose using the company’s ChAdOx vector platform and step-up doses using MVA encoding multiple hepatitis B antigens, including full-length surface, modified polymerase, and core antigens.

The trial itself involved 55 patients with chronic hepatitis B, and VTP-300 was observed to induce a significant and sustained decrease in HBsAg in these patients.

At the time of the announcement of positive final topline data, Bill Enright, chief executive officer (CEO) of Vaccitech stated that the company believes VTP-300 has the potential to become a “critical component of functional cure” for hepatitis B.

Challenges still remain

With ongoing research, it looks like a cure may be possible, but we are still in the early stages, and there are many challenges to be overcome before we get there.

In particular, Phillips said that finding a cure for hepatitis B has proven extremely difficult due to the complicated nature of the replication life cycle and the profound immune dysregulation that exists in chronic hepatitis B.

“It is becoming increasingly clear that combination therapy involving a direct-acting antiviral (DAA) and an immunomodulatory agent, each with a different mode of action, represents the future of hepatitis B therapy. functional healing presents significant challenges. Most importantly, this therapeutic strategy must demonstrate an excellent safety profile,” said Phillips.

But, certainly, given the toll chronic infection takes on a person’s life, as well as the fact that it is clearly a significant global health problem, ultimately developing a cure for hepatitis B would be “a monumental achievement,” as Schneider put it.

Phillips agreed: “Finding a cure would be a game changer for everyone affected by this disease, potentially preventing millions of people from developing liver cancer.”