Scientists are reporting a significant leap forward in treating chronic Hepatitis B infections. A new class of drugs, known as RNA interference (RNAi) therapeutics, shows promise in targeting viral antigens and silencing the virus, potentially leading to a functional cure.
These RNAi drugs, likely to be used in combination with other medications, aim to invigorate the body’s immune response. This advancement could move us closer to a functional cure for Hepatitis B (HBV), a virus that chronically infects approximately 256 million people globally. Despite existing vaccines and treatments, a complete cure has remained elusive.
While most adults clear HBV infection, those infected as infants often develop a persistent, chronic condition. This chronic infection can lead to severe liver damage, cirrhosis, and liver cancer. HBV is primarily transmitted through blood, sexual contact, or from mother to child. Without treatment, researchers estimate that 20 to 40 percent of individuals with chronic HBV will succumb to the infection, typically from liver failure or cancer. Hepatitis B, a decades-long progressive disease, is responsible for half of all liver cancer cases and significantly diminishes quality of life.
Defining a Functional Cure
“A functional cure means eliminating the viral DNA and a viral protein called the surface antigen, which accumulates in high levels in the bloodstream, for at least six months post-therapy,” explained John Tavis, Ph.D., a professor of molecular microbiology and immunology at Saint Louis University School of Medicine and an author of the study published in Science Translational Medicine. “If you achieve that, it’s very unlikely to come back. It’s the equivalent of a natural clearance of the virus.”
Tavis noted that even those who recover from acute HBV can sometimes harbor replication-competent virus, which can re-emerge if their immune system weakens. Furthermore, a portion of HBV viral DNA can permanently integrate into a person’s own DNA. While this integrated DNA cannot replicate, it can still produce viral antigens and potentially contribute to cancer. These factors explain why scientists don’t yet classify the new treatments as a “true” cure, though a functional cure would be a monumental achievement.
Achieving a functional cure would not only save millions of lives but also curb the virus’s spread. Researchers are optimistic that strategies to reach this goal are within reach.
A Three-Pronged Approach to Clearing HBV
The study’s authors suggest that combination therapies are key to a functional cure. Beyond replication inhibitors that halt viral reproduction, they are particularly enthusiastic about drugs that disrupt viral antigen production. A third component involves using drugs that stimulate the immune system to aid in fighting the virus.
Viral antigens, which are viral proteins, not only facilitate viral formation and replication but also actively suppress the immune system. “If you suppress the immune system, your body has a hard time controlling the infection,” Tavis said. “It’s like your body is fighting the virus with one hand behind its back.”
“We’re really excited about some of these RNAi’s because they seem to have two modes of action, both suppressing the viral antigens and turning on the immune system,” Tavis stated. He highlighted Bepirovirsen, a drug developed by GlaxoSmithKline, which he says not only suppresses HBV for extended periods, even after treatment cessation, but also triggers the immune system to participate in clearing the virus.
The strategy involves reducing the “smokescreen” of viral proteins in the blood by eliminating antigens, simultaneously activating the immune system, and blocking viral replication. “If we do those three things together, we’re eventually going to clear the virus,” Tavis added.
Current clinical trial data suggests that combination therapies incorporating RNAi drugs are achieving functional cures in about 30 percent of patients after one to one-and-a-half years of treatment. This marks a significant improvement over the 5 percent success rate of standard care alone. “So, we’re making steady progress. Though we’re not there yet, it’s very promising given the complexity of what we’re facing,” Tavis concluded.
Reference: Iannacone M, Beccaria CG, Allweiss L, et al. Targeting HBV with RNA interference: Paths to cure. Sci Transl Med. 17(805):eadv3678.
