Scientists Block Viral RNA in Hope of Curing Hepatitis B

The hepatitis B virus, which kills more than a million people each year, is a notoriously 'sneaky' virus, often lingering in the body and reappearing even after treatment. But thanks to a new class of drugs, its luck may be running out.

In a recently published paper in the journal Science Translational Medicine, scientists report that a class of drugs called RNA interference (RNAi) therapies represent a significant advance in the treatment of chronic HBV infections. These drugs expand treatment strategies by targeting viral antigens, suppressing the virus, and helping restore the body’s immune response.

These drugs will likely be given to patients in combination with other medications, and researchers hope that their inclusion in combination therapy regimens will bring us closer to a functional cure.

Although there are effective vaccines and drugs for the virus, which causes chronic infection in about 256 million people worldwide, there is still no cure. Most people who become infected with HBV as adults clear the infection immediately. But some, especially those infected as infants, remain infected. Chronic infection can lead to liver damage, cirrhosis, and liver cancer. HBV is most often transmitted through blood, sexual contact, or from mother to child.

Scientists estimate that 20% to 40% of people with chronic HBV infection will die from it if left untreated, usually from liver failure or liver cancer. A progressive disease that lasts for decades, hepatitis B causes half of all liver cancers and reduces quality of life by causing fibrosis and cirrhosis.

“Functional cure means the elimination of viral DNA and a viral protein called surface antigen, which accumulates in high concentrations in the blood, for at least six months after the end of therapy,” said John Tavis, PhD, professor of molecular microbiology and immunology at Saint Louis University School of Medicine and one of the paper’s authors.

"If you achieve that, it's very unlikely that the virus will come back. It's equivalent to the virus clearing itself naturally. And the risk of future health problems for that person is not going to be much different than someone who had an acute infection and recovered."

Doctors and scientists would be thrilled to be able to offer patients a functional cure. However, even then they do not call it a cure, for two reasons.

“Ninety-five percent of people who get HBV as adults have mild hepatitis and then clear the virus,” Tavis explained. “But even they sometimes have replicating virus in their system. And if they become immunosuppressed, it can come back with a vengeance. That’s one aspect that makes it hard to think of it as a true cure. Another is that when you get HBV, part of the viral DNA is permanently incorporated into your DNA. Even though that piece can’t replicate, it can still produce viral antigens — and those can cause cancer.”

Still, a functional cure would save millions of lives and ultimately limit the spread of the virus. And researchers believe we may already be close to a strategy that will do just that.

Three-pronged attack

The authors of the paper argue that a functional cure could likely be achieved with multiple drugs used in combination therapy. In addition to replication inhibitors, which stop the virus from replicating, they are particularly excited about drugs that interfere with the production of viral antigens. A third prong of this strategy is drugs that stimulate the immune system to recruit the body’s defenses to fight the virus.

By analyzing the mechanisms of action of the virus and existing classes of drugs, they say it becomes obvious that viral antigens, being viral proteins, not only participate in the formation and replication of the virus, but also suppress the immune system.

“When you suppress the immune system, it becomes difficult for the body to control the infection,” Tavis said. “It’s like the body is fighting the virus with one hand while the other is held behind the back.”

“We’re really excited about some of these RNAi drugs because they seem to work in two ways – both by suppressing viral antigens and by activating the immune system. There’s one particular drug we’ve been studying – Bepirovirsen from GlaxoSmithKline – that not only suppresses HBV for many months even after you stop taking it, but it also triggers a mechanism that causes the immune system to step in and help fight the infection.”

“We want to turn off the smokescreen that the virus creates — all those extra viral proteins floating around in the blood — by eliminating the antigens. Then we want to activate the immune system while simultaneously blocking viral replication,” Tavis added. “If we do all three of those things at once, we’ll eventually clear the virus from the body.”

After analyzing data on drugs in clinical trials, scientists believe that functional healing is no longer a myth.

“So how close are we? In clinical trials, the best combinations of drugs, including RNAi, are curative in about 30% of patients after a year to a year and a half of therapy,” Tavis said. “That’s much better than standard therapy, which works in about 5% of cases. We’re making progress. While we’re not there yet, it’s very encouraging given the complexity we face.”