A majority of
people with chronic hepatitis B treated with a nucleic acid polymer (REP
2139 or REP 2165) plus tenofovir and pegylated interferon were able to achieve
'functional control' of hepatitis B virus (HBV) for at least six months after stopping treatment, according to a late-breaking poster presentation at the 2017
AASLD Liver Meeting last month in Washington, DC.
A majority of study participants achieved HBV DNA
suppression, hepatitis B surface antigen (HBsAg) loss and normalisation of
liver enzymes, which were maintained for up to 24 weeks after the end of
therapy, suggesting a potential functional cure.
Over years or decades
chronic HBV infection can lead to advanced liver disease including cirrhosis
and liver cancer. Nucleoside/nucleotide antivirals such as tenofovir
disoproxil fumarate (DF) (Viread), tenofovir
alafenamide (Vemlidy) and entecavir (Baraclude) can
suppress HBV replication during therapy. But they usually do not lead to
a cure – as indicated by HBsAg loss and anti-HBs antibody seroconversion – and
long-term treatment may be required.
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
A shortage of neutrophils, a type of white blood
cell that fights bacterial infections.
A low level of platelets in the blood. In people with hepatitis, this may be due to cirrhosis or interferon treatment.
enzyme that can be measured in a blood sample that indicates the health of the
is developing nucleic acid polymers (NAPs) that interfere with assembly
and release of HBV subviral particles from infected liver cells, which make up
most of the HBsAg in the blood. Lower HBsAg levels lead to stronger immune responses and enhance the activity of
immune-based therapy such as interferon. This can trigger liver enzyme 'flares' – sharp increases in alanine and aspartate transaminase (ALT and AST) levels – and
lead to HBV control in some individuals.
Andrew Vaillant, Replicor's chief scientific officer, and
colleagues presented the latest interim findings from the REP 401 trial (NCT02565719), evaluating
the safety and efficacy of two NAPs, REP 2139 and REP 2165, used in combination
with tenofovir disoproxil fumarate and pegylated interferon for the treatment
of chronic hepatitis B.
This study included 40 previously untreated hepatitis
B 'e' antigen (HBeAg)-negative chronic hepatitis B patients in Moldova. Most
were men, all were Caucasian and the average age was about 38 years. Most had
mild to moderate liver fibrosis (stage F0-F2) and they did not have hepatitis
delta, hepatitis C or HIV co-infection.
All participants in this open-label study started
taking once-daily tenofovir DF (300mg). After 24 weeks they were randomly
assigned to add either weekly 250mg intravenous infusions of REP 2139 or REP
2165 plus weekly injections of pegylated interferon alfa-2a (180 mcg/week), or
only pegylated interferon, for 48 weeks. People who did not achieve at least
a 3 log10 decline in HBsAg after 24 weeks on dual therapy – which
turned out to be all of them – then crossed over and added REP 2139 or REP
All participants showed a reduction in HBV DNA after
starting tenofovir DF. HBsAg levels did not decline with tenofovir alone or
during dual therapy with tenofovir plus pegylated interferon, but did so during
In the REP 2139 triple therapy arm, 8 of 10 people saw
their HBsAg fall below 1 IU/ml by the end of treatment, including 7
people with undetectable HBsAg (< 0.01 IU/ml). These responders saw large
increases in anti-HBs antibody titres and strong ALT and AST flares.
All 8 responders maintained functional control
(defined as HBsAg < 1 IU/ml and HBV DNA < 10 IU/ml) for 4 to 24 weeks after
stopping all treatment. ALT and AST normalised during follow-up. Among
people with the longest follow-up, 4 so far have met the new AASLD/EASL
endpoints for a functional cure of hepatitis B: HBsAg loss and HBV DNA < 1000
copies/ml for 6 months after the end of treatment. Vaillant suggested that this
number would likely rise as further data become available.
In the REP 2165 triple therapy arm, 6 of 10
participants had HBsAg below 1 IU/ml (all also < 0.01 IU/ml) by the end
of treatment. Five of these responders maintained functional control for 4 to
24 weeks post-treatment. Another 3 people saw their HBsAg drop by at least 1
log10 from baseline during treatment, but it did not fall below 1 IU/ml and
rebounded after stopping therapy.
People who crossed over from dual therapy to REP 2139
or REP 2165 triple therapy did not see such consistent HBsAG declines, anti-HBs
increases or ALT and AST flares, suggesting that starting all three types of
therapy at the same time is a more effective strategy.
Treatment was generally safe and well tolerated. ALT and AST
flares were asymptomatic and other liver function biomarkers (bilirubin,
albumin, blood clotting time) remained stable. Only one participant
discontinued treatment early due to an adverse event (depression attributed to
As expected, pegylated interferon was associated with
side-effects including weakness, neutropenia (low white blood cells) and
thrombocytopenia (low platelets), but these did not differ according to whether
or not REP 2139 or REP 2165 were also used. Kidney function (a potential
concern with tenofovir DF) remained normal throughout treatment.
"Clearance of HBsAg uniquely occurs with NAP
exposure. In the presence of [pegylated interferon], HBsAg clearance is
accompanied by dramatic increases in circulating anti-HBs and the increased
prevalence and magnitude of otherwise asymptomatic transaminase flares,"
the researchers concluded.
"Recent clinical studies have shown that [tenofovir DF] and [pegylated interferon] combined achieve HBsAg
clearance in less than 10% of patients," Vaillant said in a Replicor press
release. "The addition of REP 2139’s unique ability to clear circulating
HBsAg improves this outcome in a striking fashion, achieving functional control
in 80% of patients not only during treatment but persisting after treatment is
withdrawn. Equally important is the normalization of liver function during
follow-up in all these patients, even those with significantly elevated liver
enzymes at the start of therapy."