people who take nucleoside/nucleotide antivirals for chronic hepatitis B can safely
discontinue treatment, although this usually does not lead to a cure,
researchers reported last week at the AASLD virtual Liver
analogues such as tenofovir disoproxil fumarate (TDF; Viread), tenofovir alafenamide (TAF; Vemlidy) and entecavir (Baraclude)
can keep hepatitis
B virus (HBV) replication suppressed indefinitely during treatment. However, few
people experience hepatitis B antigen (HBsAg) loss or hepatitis B antibody
seroconversion, considered to be a functional cure. People who are hepatitis B 'e' antigen
(HBeAg) positive are less likely to be cured.
guidelines disagree about when it is appropriate to stop treatment. Both AASLD
and EASL guidelines state that HBeAg positive patients can consider
discontinuation if they experience HBeAg seroconversion and have undetectable
HBV DNA for at least six to 12 months, but relapse is common. For HBeAg
negative patients, AASLD recommends stopping only after HBsAg loss, while EASL
guidelines say treatment can be discontinued after three years in those with
viral suppression if close monitoring can be guaranteed.
Prof. Norah Terrault of the University of
Southern California and colleagues compared outcomes among chronic hepatitis B
patients treated with TDF alone or TDF plus pegylated interferon alfa. About
65% of the participants were men, more than 80% were Asian and the median age
was 41 years. About half were HBeAg positive and 7% had liver cirrhosis.
First, 102 participants were randomly assigned to receive TDF monotherapy for 192
weeks, while 99 were assigned to TDF plus pegylated interferon for 24 weeks
followed by TDF alone for 168 weeks. At that point, people who had a low viral
load (HBV DNA below 1000 IU/ml for the previous 24 weeks) and no cirrhosis were
eligible to discontinue TDF; being HBeAg negative was added to the withdrawal
criteria partway through the study.
who experienced severe or prolonged elevation of ALT liver enzyme levels – a
marker of liver inflammation – along with elevated bilirubin, high viral load
or clinical decompensation after stopping treatment were restarted on TDF
monotherapy. Follow-up continued through week 240.
One hundred and five people were eligible to discontinue treatment after 192 weeks, 46 in the TDF group and 55 in the TDF plus pegylated interferon group.
person (1.0%) treated with TDF alone and four people (4.3%) treated with TDF
plus pegylated interferon experienced HBsAg loss by the end of treatment at
week 192. Three more people in the monotherapy group and one more in the
combination therapy group did so during the withdrawal phase, resulting in
similar proportions with HBsAg loss – 4.5% vs 5.7%, respectively – at week 240.
those on TDF monotherapy, three of the patients with HBsAg loss had stopped treatment,
but one was ineligible for discontinuation. Similarly, four people in the
combination therapy arm who experienced HBsAg loss had stopped treatment but
one remained on TDF. Among those who stopped treatment, the rates of HBsAg loss
were 6.5% in the monotherapy group and 7.3% in the combination therapy group. None
of these differences were statistically significant, indicating that adding
pegylated interferon did not improve the likelihood of HBsAg loss.
also reported that 20 people (41%) who used TDF alone and 27 (61%) in the
combination therapy group experienced HBeAg loss. Although the proportion in
the combination group was numerically higher, the difference did not reach
statistical significance. In both groups, about half maintained a viral load
below 20 IU/ml and about 60% had normal ALT at 240 weeks.
end of follow-up, 30% of participants in the monotherapy group and 39% in the
combination therapy group who stopped treatment were considered to have
inactive chronic hepatitis B, with both a low viral load (below 1000 IU/ml) and
normal ALT. This was about twice as likely among those who were ineligible for
treatment discontinuation and stayed on TDF (63% vs 67%, respectively).
to safety, 24% of participants in the TDF monotherapy group and 31% in the
combination therapy group experienced ALT flares. Most flares (70%) in the
monotherapy group occurred during the treatment withdrawal phase after TDF was
stopped. However, in the combination therapy group, a majority of flares (58%)
occurred during the first 24 weeks while participants were still taking
summary, rates of HBsAg loss were similar for people treated with TDF
monotherapy or TDF plus pegylated interferon – showing that adding interferon
did not improve the odds of a functional cure – but the timing of HBsAg loss
a third of those eligible for TDF discontinuation met the criteria for inactive
chronic hepatitis B, leading the researchers to conclude that "withdrawal
of TDF after four years of therapy can be safely achieved in most
patients" who meet the criteria for stopping.
related study, Dr Hassan Azhari of the University of Calgary and colleagues looked at outcomes in a
real-world study of stopping long-term nucleoside/nucleotide
In this retrospective cohort of 1337 chronic hepatitis B patients, a majority
were men and most were Asian. More than 80% were HBeAg negative and had absent
or mild liver fibrosis. About 60% were taking TDF and about 35% were taking
entecavir, with a median treatment duration of more than six years.
Within this cohort, 47 stopped antivirals while the
rest remained on treatment. All who stopped were HBeAg negative and all but one
had undetectable viral load at the time of discontinuation. Only one person in this
group (2.1%) experienced HBsAg loss, but monitoring is continuing and Dr Azhari
suggested more might do so with longer follow-up.
patients restarted antivirals due to viral load rebound (above 2000 IU/ml) or
ALT flares (more than twice the upper limit of normal). In contrast with prior
studies, people who were HBeAg positive prior to initial therapy and those who
had been on antivirals longer were more likely to restart treatment. A majority
of ALT flares occurred within the first six months after stopping treatment,
but some happened later, highlighting the need for ongoing monitoring. None of
the participant experienced liver dysfunction and all responded to retreatment.
"Stopping [nucleoside/nucleotide analogues] is
feasible in HBeAg negative chronic hepatitis B [patients] with minimal fibrosis
and low quantitative HBsAg levels," the researchers concluded.
These findings are in line with those reported at the recent 2020
Digital International Liver Congress. In a German study, 10% of people who stopped antivirals –
but none of those who remained on treatment – experienced HBsAg loss during two
years of follow-up. In an Australian study, 5% achieved HBsAg loss.
HBsAg loss after nucleoside/nucleotide discontinuation may occur because the resulting increase in viral replication and inflammation flares induce
durable immune control of the virus.
people who stop antiviral treatment should be carefully monitored and restarted
on treatment if ALT levels get too high, Dr Azhari suggested that clinicians
may not want to "pull the trigger" and restart antivirals too soon,
as these flares can sometimes lead to a functional cure.