While hepatitis B virus (HBV) infection is treatable (and preventable with a vaccine), it is not yet curable, despite the best efforts of researchers.
HBV can be controlled with antiviral therapy, which helps reduce long-term complications of the disease, but similar to HIV, the search for any kind of cure remains elusive.
Jennifer Price, MD, of the University of California San Francisco, told 鶹ý that HBV is so difficult to treat because "the virus integrates into the host hepatocytes and it's challenging to eradicate the virus from the liver cells."
Currently, there are different mechanisms researchers are exploring as avenues for a cure, she said. These include "impacting the virus," which would prevent the virus from entering the hepatocytes and block covalently closed circular DNA replication, and "working on the host," where specific compounds would trigger a host's immune response to fight off the virus.
Similar to the work in HIV research, a combination approach is likely to win out for a functional cure in HBV, Price said, adding that some early-stage studies have examined both approaches in combination.
Price cited previous research into toll-like receptor 7 agonists, which had shown in animal models. The right therapeutic vaccine could have potential, but a found that current therapeutic vaccines did not appear to be effective in treating chronic HBV. However, the authors noted that there were few randomized trials, as well as "suboptimal vaccines and patient selection."
At the American Association for the Study of Liver Diseases annual meeting in November 2019, Price noted two abstracts that took different approaches to a functional cure for HBV. The first targeted the host, with the goal of making the host mount an immune response. A small open-label study examined a novel nasal administrative therapeutic vaccine. The vaccine contained both the surface antigen of the hepatitis B virus (HBsAg) and the core antigen, indicating the person is infectious (HBcAg). The study found that the vaccine reduced HBsAg in patients under nucleoside/nucleotide analogue treatment and those without that treatment. Moreover, four patients achieved a "functional cure."
A second abstract, Price noted, examined an agent that targeted the virus. JNJ-64530440 is a novel capsid assembly modulator, which "targets the virus' ability to assemble capsids," or the protein shell of a virus, she explained. A phase I trial found the therapy was well tolerated in patients with chronic HBV, and longer-term treatment is planned.
"Some [agents] are looking quite good. It's several years away, and we're not there yet, but a lot are looking promising," Price said.
Late-breaking research on another agent targeting the virus was presented at the European Association for the Study of the Liver (EASL) annual meeting in April 2019. Patients treated with entecavir (Baraclude) plus a novel core protein inhibitor, ABI-H0731, were linked to declines in both hepatitis B DNA and RNA.
And for virally suppressed patients, this combination treatment was associated with additional declines in HBV DNA. At EASL, press conference moderator Francesco Negro, MD, of the University Hospital of Geneva, told 鶹ý that "under the threshold viremia is very interesting -- I've never seen that data before."
But which patients would receive these therapies? Price said that a variety of factors could impact how a patient with HBV responds to treatment, such as different genotypes that could respond differently to different compounds, different modes of transmission (patients infected as infants vs adults, for example), as well as if patients are coinfected with HIV and HBV.
She added that there has also been discussion about what types of patients with HBV to target with drug trials, with the consensus that those with chronic active hepatitis should be treated, and that those are the patients in most of the studies. But there is no consensus about patients in the "immune tolerant phase," when patients have extremely high HBV viral loads, no inflammation, and typically do not meet treatment criteria, Price said.
"The question is whether that would be a good group to study, and we still don't have equipoise about whether treatment is indicated," she noted.
Still, Price said the focus is trying to get patients to a functional cure, "where they would be off drugs," and she is happy to see research moving the field in this direction.
"It's very exciting in the field right now, there's a lot of attention and energy, but we need to be realistic about how long it's going to take. Hopefully the attention and energy [in cure research] can be sustained," she said.