An experimental immune-based therapy for chronic
hepatitis B combined with tenofovir was safe and well tolerated but did not
lead to greater reductions in hepatitis B surface antigen (HBsAg) than the
antiviral alone, according to a study reported at the 2016 AASLD Liver Meeting last
month in Boston.
Antiviral therapy using nucleoside/nucleotide analogues
such as tenofovir disoproxil fumarate (Viread)
or entecavir (Baraclude) is the
mainstay of treatment for chronic hepatitis B. While
these drugs can suppress hepatitis B virus
(HBV) replication during therapy, they seldom lead to a cure as
indicated by HBsAg loss and anti-HBs antibody seroconversion.
Chronic hepatitis B is associated with dysfunctional
T-cell responses characterised by T-cell exhaustion, and immune-based therapies
may help the immune system fight the virus. Improved T-cell responses could
potentially reduce HBV DNA and HBsAg levels.
enzyme that can be measured in a blood sample that indicates the health of the
Harry Janssen of the Toronto Centre for Liver Diseases
and colleagues evaluated GS-4774, a yeast-based therapeutic T-cell vaccine
containing a recombinant antigen with HBV core, surface and X proteins,
designed to elicit HBV-specific T-cell responses. The vaccine was previously
shown to be immunogenic in mice and healthy human volunteers without hepatitis
B, and it had a modest effect on HBsAg levels in chronic hepatitis B patients
with suppressed HBV viral load.
This multicentre phase 2 study evaluated GS-4774 in
195 people with chronic hepatitis B who were not currently on antiviral treatment.
About 60% were men, most were Asian and the median age was approximately 44
years. About a third had previously been treated for hepatitis B using either
nucleoside/nucleotide antivirals or interferon.
About 40% of people were hepatitis B 'e' antigen
(HBeAg)-positive, most had HBV genotypes B or C and they did not have liver
cirrhosis. At baseline they had HBV viral load above 2000 IU/ml, the mean HBV
DNA level was approximately 5.8 log10 IU/ml and the mean HBsAg level
was 3.7 log10 IU/ml. About 70% had elevated alanine transaminase
Participants were randomly allocated to receive
tenofovir DF alone or tenofovir plus 2, 10 or 40 'yeast units' of GS-4774
administered as 6 subcutaneous injections every 4 weeks to week 20. The
primary study endpoint was the change in HBsAg at week 24.
There was no significant difference in mean changes in
HBsAg levels between people in the tenofovir monotherapy arm and those
treated with GS-4774 at week 24 or 48. There was also no significant difference
in the proportions reaching undetectable HBV DNA at week 48 (69-76%).
More people in the GS-4774 arms saw a > 0.5 log10
reduction in HBsAg at week 24, but by week 48 this was just as common in the
tenofovir monotherapy arm as in the higher-dose GS-4774 groups (about 10%). Having
a > 0.5 log10 HBsAg reduction was associated with higher baseline
ALT, being HBeAg-positive and having a specific genetic variation (HLA
DRB*15:02). No participants achieved HBsAg loss.
Among HBeAg-positive people, only those treated with
GS-4774 experienced HBeAg loss (5 people) or seroconversion (3 people).
Treatment with GS-4774 was generally safe and well tolerated,
with no serious adverse events or discontinuations due to adverse events. The
most frequently reported adverse event was injection site reactions, ranging
from 37% in the lowest-dose GS-4774 arm to 86% in the highest-dose arm.
"GS-4774 in combination with tenofovir DF was
safe and well-tolerated in patients with chronic HBV infection," the
researchers concluded, but "GS-4774 administration did not result in
greater reductions in HBsAg."
Janssen said that while the results
were disappointing, negative studies are also informative. He suggested
therapeutic vaccines are "still an interesting option" – likely as
part of combination therapy, or used after other agents bring down HBV viral
load – but it will be "a long and winding road to get a functional cure
for hepatitis B."