Somewhere between 240 million and 350 million people worldwide are chronically infected with hepatitis B virus (HBV), making the liver-based infection about twice as common as hepatitis C virus (HCV) and more than six times as common as HIV. According to the World Health Organization, worldwide each year more than 686,000 people die from HBV-related disease, including cirrhosis and liver cancer. An estimated 850,0000 to 2.2 million U.S. residents are living with chronic hep B.

Like HIV, hep B is treatable—with drugs used for HIV, in fact, which can suppress HBV’s replication and reduce the risk of liver disease. Also like HIV, but unlike HCV, HBV is generally not curable. (Hep B is the only virus among the three for which there is a vaccine.)

Of those receiving ongoing hep B treatment with a drug in the nucleos(t)ide analogue class, such as Viread (tenofovir disoproxil fumarate), only about 0.5 to 1 percent achieve hepatitis B surface antigen (HBsAg) clearance each year, one of the hallmarks of a cure, or at least a functional cure (more on that later). Most will need lifelong treatment to keep the virus at bay.

Then there’s interferon treatment, which spurs the immune system’s attack on hep B. But while this treatment has a HBsAg clearance rate similar to Viread’s, it comes with miserable, flulike side effects. By comparison, Viread is a highly tolerable drug. The key to the recent revolution in hep C treatment was the development of highly effective and highly tolerable treatments that directly assault viral reproduction without requiring the addition of interferon as was the case with older antiviral medications.

Compared with hep C, hep B takes up a much more stubborn residence inside the liver cells it infects, making HBV much more difficult to cure.

HBV stores its genetic code, or genome, in the nucleus of liver cells in a form known as covalently closed circular DNA, or cccDNA. This genetic safe house is “a pretty darn stable molecule to the best that we can tell,” says John Tavis, PhD, a professor of molecular microbiology and immunology at Saint Louis University. Tavis has long been researching an enzyme key to HBV’s reproduction called ribonuclease H in hopes of developing a drug to attack RNAseH, as the enzyme is known.

Part of the reason hep B is harder to cure is that its genome turns over much more slowly than HCV’s. The latter virus requires only eight to 24 weeks of suppressive treatment before every bit of HCV has been flushed out. Meanwhile, even when currently available treatment greatly suppresses HBV’s replication, the cccDNA remains in the cell’s nucleus, yielding an effective viral reservoir. Stop the treatment, and the infected cells’ machinery will likely jump back into action, churning out new virus and sending its levels skyrocketing.

Researchers such as Tavis are currently investigating ways to combat HBV’s life cycle at points other than the one targeted by currently approved drugs like Viread. Even with such highly suppressive treatment, people may have to take HBV treatment for much longer than HCV therapy to achieve a cure. And they may require an additional kick to the immune system to succeed in beating hep B.

However, if there is a treatment that can eliminate the HBV cccDNA, a treatment for hep B may not take very long.

Of course, treatment must be safe, a necessity that potentially poses a catch-22. If people with hep B have quite damaged livers, they may be at risk of complications if cures for the virus are themselves are primarily processed in the same organ.

A cure for HBV is defined in various ways. As a baseline, someone would need to: have no hep B viral load; have no evidence of the hep B s-antigens (HBsAg negative) that the virus produces; and develop anti-hepatitis B s-antigen antibodies (anti-HBs Ab positive). Such a scenario is associated with a reduced risk of health complications, at least among those who do not already have cirrhosis. A cure would be considered “complete” if the cccDNA were eliminated entirely or “functional” if any remaining genetic code was either kept at bay by the immune system or effectively crippled by a cure treatment.

Research into hep B cures is divided into two major avenues: 1) seeking ways to attack various points in the viral life cycle; and 2) trying to prompt the human immune system to wage its own battle, perhaps similar to the one that in most people clears the virus soon after infection. In 95 percent of babies and about 5 percent of adults who contract hep B, the immune system will mount a response that clears the virus early without the need for treatment. In the remaining cases, individuals wind up chronically infected, with the virus persisting in part because it hobbles the immune system’s defense mechanisms.

Researchers are also trying to develop treatments that target cccDNA in particular—for example, blocking its formation, inhibiting its synthesis and maintenance, or promoting its loss.

On the immune modulation front, Gilead Sciences is conducting early clinical trials of a drug called GS-9620. The medication targets the toll-like receptor-7 (TLR-7), a signaling device on the surface of dendritic immune cells that when stimulated leads to virus-fighting interferon (which is both a manufactured drug and a natural part of the immune system) and cytokines.

Then there are agents seeking to hinder the virus’s reproduction.

“I think the current antiviral drug development looks very promising,” says James Ou, PhD, a professor of molecular microbiology and immunology at the Keck School of Medicine at the University of Southern California, who studies the molecular and cellular biology of HBV and HCV. “I anticipate that in about five years’ time, the new therapeutic approaches will be developed. But of course, it will take another five years for them to undergo clinical trials. So in about 10 years’ time, maybe [new curative] drugs will come out.”

Ou cautions, however, that such clinical trials may take twice that long, if the pace set by hep C cure development is any guide.

Tavis is more optimistic, saying that perhaps within three to five years, the first wave of new hep B drugs should undergo review for approval.

One such drug, Myrcludex B, blocks hep B’s entry into liver cells. The treatment recently showed promise in its first round of Phase II trials and has entered a second phase in which it is being used in combination with interferon to treat those coinfected with hepatitis B and D. (There are three main phases in the clinical trials process, each one larger and more complex than the last. Success in Phase III opens the door for potential approval of a treatment.)

Another hep B treatment in development is Arrowhead Pharmaceuticals’ ARC-520, which uses what are called small interfering RNAs (siRNAs) to target a phase in the HBV life cycle at a step prior to the reverse transcription process that Viread targets. Arrowhead just entered a partnership with Spring Bank Pharmaceuticals to test that company’s SB 9200, a treatment geared to modulate the immune system, in combination with ARC-520 in a Phase IIb trial. Researchers are hoping the combo treatment will yield a functional cure.

Assembly Biosciences is one of the many biotech companies developing hep B core protein assembly modifiers. The biotech seeks to push one of its experimental CpAMs, as they’re known, into human trials later this year. CpAMs are compounds that prevent new HBV cccDNA from forming and inhibit the function of key viral proteins.

Referring to the multiple therapeutic approaches advancing through the research pathways, Tavis says, “Which ones, which companies are going to win, if you can read those tea leaves, you are going to be a very wealthy person.”

Indeed, Gilead, the undisputed king of hep C treatments, has reaped tens of billions of dollars in sales since the approval of the extraordinarily high-priced Sovaldi (sofosbuvir) in 2013, Harvoni (ledipasvir/sofosbuvir) in 2014 and Epclusa (sofosbuvir/velpatasvir) this past June.

Considering such a pot of gold at the end of the clinical trials process, people with hep B who hope for a cure can indeed take solace in the powerful influence of multibillion-dollar carrots luring scientific progress.