Hepatitis B research presented at the 2016 International Liver Congress
focused on optimising antiviral treatment for hepatitis B and new approaches
to treatment of hepatitis B.
Nucleoside/nucleotide analogues like tenofovir can
effectively suppress hepatitis B virus (HBV) replication during treatment, but they usually do not
lead to a cure – as indicated by hepatitis B surface antigen (HBsAg) loss and
development of anti-HBs antibodies – so long-term therapy is generally needed.
Gilead Science’s tenofovir disoproxil fumarate (Viread)
is one of the most effective antiviral drugs for hepatitis B and one of the
most widely used antiretrovirals for HIV. It is generally considered safe and
well tolerated, but it can cause a small amount of bone loss soon after
starting therapy and can lead to kidney problems in susceptible people.
Tenofovir alafenamide (TAF) is a new pro-drug formulation
that produces high levels of the active drug (tenofovir diphosphate) in
hepatocytes and CD4 T-cells with smaller doses than tenofovir disoproxil fumarate (TDF), which means lower
concentrations in the blood and less drug exposure for the kidneys, bones, and
other organs and tissues.
Results
of two phase III studies presented at last month’s International Liver Congress
showed that TAF is as potent against HBV as the current TDF
formulation, but with fewer detrimental effects on bone and kidney biomarkers.
A
retrospective study conducted in South Korean hepatitis B 'e' antigen (HBeAg)
positive people with early hepatitis B infection, no cirrhosis, moderate
liver enzyme elevations but high viral load, found that early treatment in this
patient population was associated with a two-thirds reduction in the risk of
cirrhosis, an 80% reduction in the risk of developing hepatocellular carcinoma
and an 86% reduction in the risk of death during a six-year follow-up period.
The investigators concluded that treating hepatitis B in
people with high viral load but little evidence of liver inflammation –
so-called immune-tolerant patients – resulted in improved survival and cancer
prevention, and may be cost-effective in some countries.
Researchers also discussed the prospects for curing
hepatitis B infection. Hepatitis B presents significant challenges to
researchers who hope to develop a cure, because the virus inserts itself into
the nucleus of cells, where a form called cccDNA maintains persistent
infection.
Curative approaches are likely to combine antiviral
treatment to suppress virus production and immunological treatment to improve the
ability of the immune system to identify and kill HBV-infected cells. It is
unknown whether total clearance might be possible, or whether a 'functional'
cure, in which HBV replication can be controlled without elimination, is a more
realistic prospect.
An experimental drug, NVR 3-778,
being developed by Novira Therapeutics, is a first-in-class small molecule that
directly targets the HBV core protein, which plays key roles in viral
replication and persistence. The protein is responsible for assembly of the
viral nucleocapsid and enables replenishment of HBV cccDNA. Depletion of HBV cccDNA
is likely to prove critical in attempts either to cure hepatitis B completely
or to achieve a functional cure, whereby hepatitis B virus replication is
permanently controlled without treatment.
NVR 3-778 appears to inhibit HBV
by multiple mechanisms, offering a new approach to hepatitis B treatment.
Current therapy using nucleoside/nucleotide analogue antivirals or interferon
can suppress HBV replication long-term, but seldom leads to a cure as indicated
by hepatitis B surface antigen (HBsAg) loss and development of anti-HBs
antibodies.
An
early phase 2 trial testing various doses of NVR 3-778 in combination with
pegylated interferon found that the experimental drug produced substantial
reductions in HBV DNA after one month of treatment. Further studies will
investigate the effect of longer treatment courses and use in combination with
first-line HBV treatments such as tenofovir and entecavir.
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