For decades, people living with chronic hepatitis B were told they would be “cured” only after they lost the hepatitis B surface antigen (HBsAg) and developed surface antibodies. It represented the holy grail of recovery that everyone hoped for, but very few achieved.
Today, experts are redefining what constitutes a “functional cure” from chronic hepatitis B and taking the surface antibody out of the primary equation.
Researchers, including expert Dr. Robert Gish, suggest if people have an undetectable viral load (HBV DNA), undetectable HBsAg, and no signs of liver damage, they may be “functionally cured,” even if they haven’t developed surface antibodies. The cure is called “functional” because the only cure for hepatitis B is when the immune system is able to control or suppress the virus.
People with chronic hepatitis usually experience several infection stages, starting with a high viral load (called immune-tolerant or immune-trained) during childhood and early adulthood, followed by years and even decades of “active” hepatitis B where the immune system tries to clear the infection, indicated by elevated liver enzyme tests.
In some lucky people, the “active” phase successfully eradicates HBsAg and infected liver cells. They test negative for HBsAg, their viral load (HBV DNA) drops to undetectable levels and their liver enzyme tests (for ALT or SGPT) show no signs of liver damage. Despite their “inactive” infection, studies show two-thirds of these people will never develop surface antibodies, said Dr. Gish, medical consultant to the Hepatitis B Foundation and professor consultant of gastroenterology and hepatology at Stanford University.
But isn’t developing surface antibodies the gold standard for recovery from hepatitis B? Not any more, explained Dr. Gish. Historically, medical guidelines dictated that chronically-infected patients must generate at least 10 mIU/mL of surface antibodies to be “functionally cured”. That level was used because most adults who had a short-term or acute case of hepatitis B were able to generate lots of surface antibodies once they’ve cleared the infection, and people who were vaccinated also tended to generate high surface antibody levels.
“But we’ve learned that standard is no longer useful for patients who’ve been chronically infected,” Dr. Gish explained. “Hepatitis B surface antibodies are very specific in their mission, and we’re learning that the body may be making other types of surface antibodies that we cannot measure. Today, we’re only measuring one type of surface antibody, and for some reason we don’t know yet, it may never become positive in people who have been chronically infected and cleared HBsAg.
Dr. Gish speculates that the surface antibodies that labs measure may all bind to any HBsAg that remain following infection, so there may not be any excess of this one type of surface antibodies to measure.
It may be similar to what happens in vaccinated people who over time no longer test positive for surface antibodies. “In the old literature, people thought having lots of surface antibodies meant better protection, but now we know people who’ve been vaccinated remain protected by their immune system’s T-cell response and also ‘memory B cells’ even if their surface antibodies decline or become undetectable,” he said. Bottom line, “immune memory” and antibodies that labs may not be able to identify remain ready to fight infection following vaccination and even after a chronic infection.
As a result of these findings, people who have gone two or more years with undetectable viral load and HBsAg, and no signs of liver damage just might be “functionally cured”, Dr. Gish suggests, even if their surface antibodies remain undetectable. “It’s clearly a new gold standard,” he added, referring to recent studies that found no hepatitis B reactivations in these “inactive” patients who were followed for up to eight years.
However, Dr. Gish cautions, it’s important to remember that once infected with hepatitis B (indicated by presence of the hepatitis B core antibody - anti-HBc), people will always retain low levels of the hepatitis B virus in their bodies – even if they develop surface antibodies. Like the chicken pox virus, the hepatitis B virus remains suppressed only as long as the immune system remains healthy enough to keep it in check. Old age, other illnesses, chemotherapy or drugs that suppress the immune system can allow a reactivation of hepatitis B in the same way that chicken pox returns as “shingles” in older adults. Unfortunately, there is no cure available that totally eradicates all hepatitis B virus from the body.
Today, chronically-infected people can look forward to a new, more accurate benchmark that represents a functional cure: clearing both HBV DNA and HBsAg, and experiencing no liver damage for two or three years. All three goals must be achieved–especially undetectable surface HBsAg–otherwise they remain at risk of reactivation, according to recent studies.
According to Dr. Gish, once patients achieve two or three years of consistently undetectable viral load (HBV DNA below 8-12 IU/mL) and HBsAg levels (below 0.05 IU/mL), they do not require frequent monitoring unless they have a history of cirrhosis or signs of liver damage.
Why has it taken so long for researchers to figure this out? Historically, researchers have focused on patients with active infections that damaged their livers and led to cancer in their search for effective treatments. For the first time, researchers are also monitoring “inactive” patients who clear both HBV DNA and HBsAg and are publishing studies about their long-term outcomes.