of long-term nucleoside/nucleotide antiviral treatment for hepatitis B can
allow some people to achieve a cure, according to a pair of presentations last
the 2020 Digital
International Liver Congress. This may happen because the flares of viral
replication and inflammation that can occur when the drugs are stopped induces
durable immune control of the virus.
Nucleoside/nucleotide analogues such as tenofovir disoproxil fumarate
(TDF; Viread), tenofovir alafenamide
(TAF; Vemlidy) and entecavir (Baraclude) can keep hepatitis B virus
(HBV) replication suppressed during treatment, but they seldom lead to a
cure. Very few people experience hepatitis B antigen (HBsAg) loss or hepatitis
B antibody seroconversion using antivirals alone, and guidelines recommend
Prof. Florian van Bömmel of University Hospital Leipzig in Germany
and colleagues evaluated the effect of nucleoside/nucleotide
discontinuation in the Stop-NUC trial.
Partial recovery from an illness, an alternative word for regression.
The study included 158 people with
hepatitis B 'e' antigen (HBeAg) negative chronic HBV infection who had viral
load suppression below 1000 IU/ml for at least four years while taking TDF,
entecavir, lamivudine (Epivir) or
telbivudine (Sebivo). Just over 60%
were men, about 80% were white and the median age was 52 years.
At study entry, they had normal ALT
liver enzyme levels and none had yet progressed to advanced fibrosis or cirrhosis.
People with liver cancer, those with HIV, hepatitis C or hepatitis D
co-infection and those who drank heavily were excluded.
Participants were randomly assigned to
either stop or continue antiviral treatment. Follow-up continued for 96 weeks
follow-up, all patients who stopped antivirals experienced viral load flares,
with HBV DNA exceeding 20 IU/ml. However, in some cases these were transient
and patients went on to re-suppress the virus without the drugs. At 96 weeks,
18% of participants who stopped antivirals had viral suppression.
Resurgence of viral replication was associated with rising ALT levels, an
indicator of inflammation. ALT flares were observed in about a third of people
who stopped antivirals, but in most cases ALT normalised even in the absence of
treatment. At 96 weeks, 77% of people who stopped antivirals had ALT levels
within the normal range. The researchers determined that 41% of those who
stopped treatment were in 'sustained remission', defined as having both HBV DNA
below 2000 IU/ml and normal ALT.
one who stopped treatment experienced serious adverse events related to nucleoside/nucleotide discontinuation, van Bömmel reported.
people (10%) who stopped antivirals – but none of those who remained on
treatment – experienced HBsAg loss by week 96. This happened more often in those
with low HBsAg levels (below 1000 IU/ml) at baseline: 28% of these individuals
experienced HBsAg loss.
loss occurred throughout the follow-up period, with some people having a steep
decline soon after stopping treatment and others having a slow, steady
decrease, van Bömmel said. The study authors mentioned in their abstract (though
not in the presentation) that six people (8%) achieved seroconversion,
considered a higher bar to reach.
people (14%) restarted treatment because of severe or persistent liver enzyme
elevation, high viral load or their physician's decision. But two-thirds (68%) had
no indication for treatment according to current EASL recommendations.
first large-scale randomised study demonstrates the potential of
discontinuation of long-term [nucleoside/nucleotide]
treatment for induction of durable control and functional cure in patients with
HBeAg chronic hepatitis B," the
study by Dr Samuel Hall of St Vincent’s Hospital in Melbourne and colleagues
also looked at changes in HBsAg levels after nucleoside/nucleotide discontinuation
in a mostly Asian but otherwise similar population.
NA-STOP trial included people with viral suppression for at least 18 months. Most were taking TDF
or entecavir. This study will also continue for 96
weeks; Hall presented interim results for 107 people followed through week 48.
too, everyone who discontinued treatment experienced viral reactivation. Further,
42% saw their ALT rise to more than twice the upper limit of normal and 21% had
spikes to more than 10 times the upper limit. Both viral relapse and ALT flares
occurred earlier in people who stopped TDF compared with those who stopped
people (5%) experienced HBsAg loss. Again, this was more likely to occur in
people with lower HBsAg levels at baseline.
described two patterns: "good flares" (seen in five patients), which
involved early steep but brief rises in HBV DNA and ALT and profound reduction
in HBsAg levels, and "bad flares" (seen in 21 patients), which
involved smaller but more persistent viral load increases, persistent or
recurrent ALT elevation and little decline in HBsAg levels.
people (11%) restarted treatment due to elevated viral load and ALT. But a
majority did not meet the traditional start criteria after 48 week off
treatment, with 41% having HBV DNA below 2000 IU/ml and 72% having near-normal
data to date support a place for treatment withdrawal in selected patients on
long-term [nucleoside/nucleotide analogue] therapy," the researchers
Bömmel noted that more than two years of follow-up will
be needed to assess the effects of antiviral discontinuation, as some
people experienced HBsAg only late in the Stop-NUC study. With further
follow-up, more people in the NA-Stop study may achieve HBsAg loss as well.
Bömmel cautioned that ALT flares occurred even during
the second year after stopping antivirals, so long-term monitoring is