A new breakthrough offers hope for a ‘functional cure’ of hepatitis B

Scientists have been chasing a cure for chronic hepatitis B for decades. The disease is notoriously difficult to eliminate: As the leading cause of liver cancer, more than 240 million people worldwide are living with chronic hepatitis B—yet only 13 percent are aware of it, earning the disease the moniker of “silent killer.”

Now, researchers are closer than ever to stopping it. On May 28, researchers published results in the New England Journal of Medicine from their phase III clinical trial testing a new drug called bepirovirsen in a group of 1,838 adults with chronic hepatitis B across 29 countries.

With the new drug added on to standard treatment, approximately one in five participants experienced what researchers call a “functional cure,” meaning their immune systems appeared to keep the virus under control without medication for more than six months. That’s far better than the current standard of care alone, which achieves a functional cure rate in approximately 3 percent of patients after eight to 10 years of therapy.

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The new data will provide a “boost to many infected patients who do not even believe a cure is achievable and have to live with long term oral antiviral therapy as well as the continued stigma of being a hepatitis B carrier,” says Seng Gee Lim, study co-author and director of hepatology at the National University Health System, Singapore. “We’ve not had a treatment come close to this level of cure. I think my patients will be extremely delighted to have this treatment available.”

Independent experts agree.

“After many failed trials in the last 10 years, the B-Well Trials’ results provide hope that functional cure for hepatitis B is feasible,” says Anna Suk-Fong Lok, the director of clinical hepatology and assistant dean for clinical research at the University of Michigan Medical School. Lok, a leading expert on chronic hepatitis B, was not involved in the study and published an editorial commentary responding to the trial.

However, the results cannot be generalized to patient groups that were excluded from the trials—those with cirrhosis, coinfection with human immunodeficiency virus (HIV), or whose disease was severe. The drug worked best for those whose condition was already better controlled.

As it stands, there’s still a long way to go in tackling chronic hepatitis B. But these are “promising initial results” and an important step forward, says Jane Davies, an infectious disease specialist at the Royal Darwin Hospital in Australia and director of Hepatitis Australia.  And it’s particularly welcome news among those who have seen the damage that hep B can do.

Why hepatitis B is so dangerous

Hepatitis is a general term for inflammation of the liver. It’s caused by five main viruses—A, B, C, D, and E—as well as heavy drinking, exposure to toxins, and certain autoimmune conditions.

Hepatitis B is the most common of these viruses—and also the most contagious. Transmitted through blood and bodily fluids like semen, vaginal, and amniotic fluids, this tough virus is capable of living outside the human body and on surfaces up to a week. You cannot get hepatitis B through casual contact like kissing, coughing, or sharing a meal. But you can pick it up by sharing toothbrushes, nail clippers, or razors; through exposure to infected needles; in health care settings through blood transfusions; or through sexual contact.

Once infected, patients run the risk of developing chronic hep B—a potentially lifelong condition that can spend years “quietly damaging the liver,” explains Davies.

When the liver malfunctions, the consequences can be dire. The vital organ performs dozens of jobs throughout the body: processing nutrients from food, filtering toxins, producing essential substances like bile and clotting factors, and storing vitamins, minerals, and sugar. These functions influence overall metabolism, immune function, digestion, and detoxification.

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Over time, it can cause liver scarring, liver failure, liver cancer, and early death—making it the second most potent carcinogen after tobacco. More than one million people die annually due to hepatitis B complications—and many don’t know they have it.

“Hepatitis B is a silent killer,” says Lok. The virus moves stealthily, frequently with no symptoms or only mild ones such as stomach pain, fatigue, fever, joint pain, and loss of appetite. More than half of people with hepatitis B are unaware of it, and approximately 50 to 70 percent of people with acute hepatitis B show zero symptoms.

These people may pass it to others unwittingly.

It’s especially harmful for babies, says Davies, as it can be passed from mother to baby during childbirth. And those infections have a “disturbing propensity” to become chronic, adds Geoff Dusheiko, a hepatologist and professor at the Royal Free Hospital and University College London School of Medicine. Catching hepatitis B close to birth leads to chronic infection in about 90 percent of babies, while older children, teens, and adults have a 5 percent chance.

“The tragedy,” Davies notes, “is that this disease is largely preventable and manageable.”

Containing a ‘silent epidemic’

Experts agree that we already have tools to control hepatitis B: safe vaccines, simple blood tests to diagnose it, and effective anti-viral medications. Yet they aren’t widely available in many of the places they’re needed—making the race for a cure all that more urgent.

Much of the focus for controlling hepatitis B has been on the vaccine, which was first introduced in 1981. It provides nearly 100 percent protection against the virus for multiple decades and has cut new cases of hepatitis B by more than 90 percent in many countries—prompting some to deem it the world’s first “anti-cancer” vaccine for its ability to reduce the risk of liver cancer.

People can receive this vaccine at any time of life, but the earlier the better: birth dosing has averted more than 90,100 potential childhood deaths in the United States since 1994.

“The newborn hepatitis B vaccine is one of the most effective public health tools we have,” says Davies. Without the vaccine, some babies will get infected, develop chronic disease, transmit the infection to other unvaccinated people, or die young, adds Lok.

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The challenge is reaching people who need the vaccine, especially in communities with the highest infection rates such as sub-Saharan African and western Pacific regions, which have lower rates of vaccination, primarily due to limited resources and infrastructure.

Then there’s the problem with treating the virus once infected. Hepatitis B is considered a “stealth virus,” known for its ability to evade detection and confuse the immune system—requiring a lifetime of medication to suppress it. Doctors typically prescribe generic nucleos(t)ide analogues, antivirals that Lok says are “cheap, safe, and effective”—but rarely clear the virus completely or induce a functional cure.

Patients may also receive interferon—specifically pegylated interferon-alpha, which is an expensive 48-week treatment for chronic hepatitis B. It works by suppressing viral replication and modulating the immune system. It has a higher functional cure rate than antiviral meds, but comes with some nasty side effects, so is often hard to tolerate.

Like with vaccines, the costs of hepatitis B treatments can be low, but cheap generics aren’t available everywhere, says Alice Lee, a gastroenterologist, hepatologist, and professor at Macquarie University. This gap in affordability and access is why some experts consider hepatitis B as the greatest public health failing of the 20th century, says Dusheiko, calling it an example of “appalling inequity.”

The search for a cure

To eliminate hepatitis B, scientists have been looking for a cure—likely a combination of drugs that block viral replication, curb the production of viral proteins, and stimulate the immune system to clear the virus. With bepirovirsen, they think they can do all three—at least in some patients.

The drug binds with the virus’ messenger RNA to curb protein and RNA production. It also fires up the immune system to attack hepatitis B in a unique way: After injection, it appears to be taken up by macrophages—specialized white blood cells and the immune system’s first line of defense against pathogens. This means it functions more as an immunomodulator than a direct-acting antiviral, explains Lok, and allows a person’s immune system to regain control.

In the clinical trial, participants were given a weekly dose of either the bepirovirsen or a placebo for six months in addition to their regular nucleotide analogue therapy, leading to functional cure rates in 19 percent of participants. Those who entered the study with the lowest levels of the viral surface antigen achieved an even higher functional cure rate at 26 percent.

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Although they did see positive results among those on the drug, one of the important signals from these results is that bepirovirsen appears to work better in people whose hepatitis B is already more controlled.

“That reinforces a critical point: New treatments will only change lives if people are diagnosed early, regularly monitored and connected to care,” says Davies.

As it stands, drugs like bepirovirsen could be a backbone of future therapies for chronic hepatitis B, Dusheiko says. These latest findings are “encouraging,” he adds, however, substantial numbers of patients live in resource-poor regions, and it is not clear how affordable or accessible bepirovirsen would be for them.

It may also come with side effects on platelet counts and renal function, or injection site reactions, which require close monitoring. The drugmaker GSK has submitted their data to drug regulatory agencies in the United States, Canada, Europe, Japan, and China, and expects approval decisions to come through later this year.

“These are exciting new developments but the immediate priority remains the same: Find people living with hepatitis B, connect them with culturally safe care, and support them before liver disease or liver cancer develops,” Davies says.

 “This does not have to remain a silent epidemic.”