Hep B More Complex Than C, But Here's a Plan to Cure It Too

Ingrid Hein

April 11, 2019

VIENNA — A global scientific strategy to cure hepatitis B — developed by the International Coalition to Eliminate HBV after consultation with more than 50 scientists — was released here at the International Liver Congress 2019.

Despite effective therapy for hepatitis B and a preventive vaccine, 887,000 people around the world died from the virus in 2017, according to a report from the World Health Organization. And for the 257 million people chronically infected with the virus, there is no cure.

In Africa, prevalence is at 3%, and "deaths among infected adults born before the era of vaccination will continue to increase if they are not diagnosed and treated," according to the WHO report.

"This is unacceptable," said Peter Revill, MD, from the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, who is a member of the coalition.

Yet hepatitis B research is largely underfunded, "to the point of being compared to a neglected tropical disease," he told Medscape Medical News.

And a "one size fits all" solution does not apply. The lifecycle of the virus depends on the genotype, and transmission differs from region to region, so "different countries might need different approaches," he explained. "In China, it's mother to baby; in other regions, adult transmission is a problem."

In addition, some people's immune systems can resolve the virus; others, who have an exhausted immune system or just plain bad luck, cannot.

Hepatitis B does not have borders.

Now, the coalition has come up with a scientific consensus on how to go about developing a cure, Revill said. "The strategy has to be global," he added. "Hepatitis B does not have borders."

Su Wang, MD, found out she had hepatitis B after donating blood when she was in college. Because she was in China, she was allowed to continue her medical education, but that is not true everywhere.

In many parts of the world, the disease is still highly stigmatized, said Wang, who is from Saint Barnabas Medical Center in Livingston, New Jersey.

For many patients, the virus has serious consequences. Wang said she hears about people losing their families, jobs, and even the right to study to become a healthcare worker. The stigma itself can be life-altering, she said, relaying the story of a woman who was 5 months pregnant being asked to move out of her boyfriend's family's home when she was diagnosed.

In poor countries, even when patients get medication, they often have trouble getting blood work done to check their viral load, so they have no idea if the treatment is having an effect.

"It is a complex disease," Wang explained. "My patients hear there is research happening" and are confused by the slow progress and frustrated by the lack of a cure.

Consensus for Two-Tiered Approach

"Hep B is a complicated beast," Revill explained. Members of the coalition "conceded that we need a two-tiered approach. We need to both target the virus and stimulate the host response."

The viral lifecycle of hepatitis B is even more complicated than that of hepatitis C. "Current drugs do not target the covalently closed circular [ccc]DNA, the viral persistence reservoir that hides in the nucleus."

According to the strategy, the first thing that scientists need to tackle is how to confront the cccDNA in the hepatocyte nucleus, which forms the stable minichromosome of the hepatitis B virus genome.

"We suggest that research directed toward the elimination of cccDNA" or the permanent silencing of cccDNA transcription should be prioritized, the coalition writes in its report published online in the Lancet Gastroenterology and Hepatology.

An understanding of ccDNA mechanisms and the development of serum markers for cccDNA and methods to degrade it would help point to the cure, as would methods to prevent transcription and the development of functional in vitro cccDNA systems.

"A true cure for HBV requires clearance of intranuclear cccDNA from infected hepatocytes, so understanding the mechanisms involved in cccDNA biogenesis, regulation, and stability is mandatory to achieve HBV eradication," said Fabien Zoulim, MD, PhD, from Hospices Civils de Lyon in France, who is also a member of the coalition.

A second research priority is the immune system.

We need to boost the exhausted immune response if we are going to clear the infection.

"We need to boost the exhausted immune response if we are going to clear the infection," Zoulim told Medscape Medical News.

Many different components of the immune system need to be looked at to achieve viral clearance, so innate immunity and adaptive immunity against the virus are key.

This would involve determining whether the mechanism of T-cell exhaustion is reversible, durable, and needed, and identifying biomarkers in the blood that best reflect the intrahepatic immune response. The degree of immune-mediated destruction required and the category of patients also need to be established.

"Combination strategies will be an important first step to finding a cure," Zoulim said.

Improving Prospects

This strategy to cure hepatitis B is really good because it outlines the complexities and offers hope, Wang told Medscape Medical News.

There is a lack of understanding about the virus that she has witnessed with her infected patients. "I tell them you can lead a normal life, that I'm infected," she said.

"I started to see that the patient voice is important, so I try to activate patients to be more vocal and more demanding and to share their experiences," she added.

"This strategy is so much more than a guideline," she said. "For patients, this is a realistic view. Even for me."

Revill, Zoulim, and Wang have disclosed no relevant financial relationships.

International Liver Congress (ILC) 2019. Presented April 10, 2019.

Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Ingrid Hein @ingridhein

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