Towards a cure for hepatitis B

A new treatment that successfully eliminates the hepatitis B virus (HBV) in preclinical mouse models holds promise as a potential cure for the infection in humans.

The treatment, a combination of an antiviral drug and an anticancer drug, is being developed by researchers Dr Marc Pellegrini, Dr Greg Ebert and colleagues at the Walter and Eliza Hall Institute in Melbourne.

More than two billion people worldwide are infected with HBV and about 400 million have a chronic HBV infection. The virus infects liver cells and can lead to complications including cirrhosis and liver cancer, resulting in more than 780,000 deaths annually.

Treatment of people infected with the virus is limited and the virus can persist within the body for many months or years.

A large proportion of infected people control the infection by staying on antiviral therapies indefinitely, but HBV DNA persists in the liver and flare-ups of hepatitis can occur. A proportion of people are unable to control HBV infection and risk developing liver failure and liver cancer.

In previous studies the researchers showed that HBV overrides apoptosis in liver cells via cellular inhibition of apoptosis proteins (cIAPs) that prevent TNF-mediated death of infected cells.

“Normally, liver cells would respond to infection by switching on a signal that tells the cell to destroy itself ‘for the greater good’, preventing further infection,” Pellegrini said. “However, our research showed that the virus commandeers the liver cells’ internal communications, telling the cells to ignore the infection and stay alive.”

The knowledge that HBV overrides apoptosis in liver cells led the researchers to birinapant, a drug developed by US biotech company TetraLogic Pharmaceuticals for treating cancer.

“Birinapant flips the cell survival ‘switch’ used by the virus, causing the infected cell to die,” said Pellegrini, adding that the treatment destroyed HBV-infected liver cells yet normal cells were unharmed.

Drugs that inhibit cIAPs have been developed as anticancer agents to promote TNF-mediated death of tumor cells. Using birinapant to antagonise cIAPs, the researchers found they could promote clearance of HBV infection (serum HBV DNA, serum HBV surface antigen and hepatocytes containing HBV core antigen) from an immunocompetent mouse model of chronic HBV infection.

The researchers also found that a combination treatment of birinapant and entecavir, an antiviral drug currently used to treat people with chronic HBV, resulted in an infection clearance rate twice as fast compared with using birinapant alone.

A clinical trial in humans began in December 2014 in Melbourne, Perth and Adelaide. It is currently in phase 1/2a.

The research has been published in two papers (paper one and paper two) in Proceedings of the National Academy of Sciences.

Image caption: Drs Marc Pellegrini (left) and Greg Ebert in the Lab. Photo: Walter and Eliza Hall Insitute.