Liver specialists, virologists and immunologists from around the world met at the 3rd International Workshop on a Hepatitis B Cure in Toronto last week to share their advances and brainstorm solutions to the challenges they face as they hunt for a cure for the liver infection that affects 240 million worldwide.
Eradicating hepatitis B virus (HBV) infection is no easy task. HBV is a far more complicated and resilient virus than hepatitis C, and scientists predict a cure will require a careful orchestration of drugs and immune-enhancing treatments that could:
Eliminate HBV antigens—especially the hepatitis B surface antigen (HBsAg). This viral protein appears able to “exhaust” or disable the immune system’s T cells so they’re unable to effectively fight the infection.
Find a vulnerability in the HBV replication cycle that can be exploited to keep the virus from entering liver cells and inserting its genetic material (cccDNA) required for viral reproduction.
Enhance or “wake up” the exhausted T cells, after HBsAg is reduced or eliminated, so the immune system can successfully eradicate the HBV-infected liver cells.
As researchers learn more about why HBV is so successful at evading the immune system and hijacking liver cells for viral production, they are also realizing how much they don’t know and what tools they lack to identify if and when they find successful treatment strategies. Here are some of the challenges the researchers addressed during the day-long brainstorming session.
What will a cure look like? Can scientists ever expect to totally eradicate HBV from the liver? Even when healthy adults are able to clear HBV following an acute infection, small reservoirs of the virus remain – similar to chicken pox that causes shingles later in life when the immune system can no longer hold it in check. Should researchers instead set their sights on a cure that duplicates what Mother Nature now achieves following an acute infection, which simply eradicates most of the virus and greatly reduces the risk of liver damage.
Do researchers currently have the right tools to identify when a treatment works? Nearly all hepatitis B lab tests used today evolved from blood bank tests designed to identify HBV-infected donated blood. As a result, lab tests produce a “positive” or “negative” measurements for the presence of antigens and antibodies, but nothing more nuanced. Labs measure the amount of HBV DNA (viral load) in a patient, but rarely measure HBsAg even though patients can have an undetectable viral load and still have lots of HBsAg circulating in their bodies.
But figuring out when a treatment is able to reduce HBsAg or other antigens may be critical to a cure. Several research initiatives are working to reduce HBsAg, which is produced in great quantities and is believed to prevent the immune system from actively attacking the infection. But right now, most lab tests in the U.S. don’t measure how much HBsAg a patient has in their bloodstream.
“We don’t have great assays (lab tests) for measuring treatment responses (to current or new drugs),” said workshop panelist Jordan Feld, a clinical scientists and researcher from the Toronto Western Hospital Liver Center.
“Maybe we don’t have the right endpoints to measure how effective treatment is,” said Marion Peters, chief of hepatology research at the University of California at San Francisco. “A treatment might be having an effect, but we don’t know what to measure so we don’t know it.”
A lost research opportunity with TAF clinical trials? On Nov. 10, the U.S. Food and Drug Administration (FDA) approved TAF, a new, lower-dose formulation of tenofovir that channels the antiviral more effectively to infected liver cells while reducing the drug’s impact on kidney function and bone loss. Because TAF’s clinical trials focused primarily on comparing the reformulated drug’s impact on viral load, ALT (liver health) and side effects, researchers did not conduct liver biopsies on TAF clinical trial participants.
While lower-dose TAF was found to work as well as tenofovir in slowing viral replication, it did something that researchers didn’t expect. During one clinical trial, 50 percent of patients treated with TAF achieved normal ALT levels–indicating no liver damage– compared to only 32 percent of patients treated with tenofovir.
Why was TAF so effective on liver cells? Was it able to remove some of the cccDNA or prevent HBV from replicating in liver cells in a way that tenofovir could not? “There seems to be a correlation, but because they didn’t have that possible endpoint in mind, they didn’t think to perform liver biopsies, which would have answered some of those questions,” Dr. Peters commented.
“We need to go beyond commercially-available tests so we can see with better sensitivity whether TAF or another drug would actually be more efficient and see what the effect is within the liver,” observed Fabien Zoulim, MD, PhD, associate director of the Liver Department at the Hôtel Dieu hospital in Lyon (France) and scientific director of the INSERM Unit 871.
How to eliminate HBV-infected liver cells without damaging the liver: In chronic hepatitis B, a large percentage of liver cells are infected. Some treatments in development, such as those using small interfering RNAs technology, target HBV antigens including HBsAg and quickly reduce their numbers. Using a combination treatment of antivirals to reduce viral load and RNAii technology to eradicate HBsAg, the immune system can swing into action and attack the infected liver cells. But how do you pace this “attack” so the liver is not severely damaged and the patient’s health threatened?
If only a small percentage of infected liver cells are killed during treatment, others will survive and continue to churn out virus. Kill too few infected liver cells and continual re-treatment is required. Kill too many liver cells and a patient could die from liver failure.
Flares are inevitable when the immune system is attacking infected liver cells – such as during an acute hepatitis B infection — but can this clearance be controlled without harming the patient?
The day before the workshop, the FDA ordered Arrowhead Pharmaceuticals to stop its Phase II human trials of its ARC 520 drug that uses RNAii to eradicate HBsAg after reports of deaths in animals that had been given high doses of the drug. The doses were much higher than were administered to humans in the Phase II clinical trial, which was evaluating the reduction of HBsAg after intravenous administration of ARC-520 in combination with entecavir or tenofovir. Panelists noted that this potential cure may still have promise, but the treatment dose must be examined and monitored carefully.
The workshop presentations highlighted the inevitable setbacks and advances that scientists make in the search for a cure. But optimism remained. Never have so many researchers been working from so many directions to find the synergistic solution that will one day reduce HBsAg, stop HBV from reproducing and spur T cells to attack infected liver cells.
One panelist suggested in the next five years, researchers should be able to develop ways to reduce viral load while enhancing the immune system’s T cell response to eradicate a hepatitis B infection. Around the world, 240 million people living with hepatitis B are waiting anxiously.
The Hepatitis B Foundation was a partner of the workshop. For more information about the workshop and researchers’ presentations, please click here.