The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

A Modern Therapy for an Ancient Disease

Jay H. Hoofnagle, M.D.

Chronic infection with the hepatitis B virus (HBV)
affects 4% of the population worldwide and ac-
counts for more than a half million deaths yearly.1
An ancient disease, perhaps dating before ana-
tomically modern humans left Africa,2 chronic
hepatitis B is present in virtually all populations
on Earth. The highest prevalences are found in
Asia and Africa, whereas the prevalence in the
United States (0.3%) is among the lowest.3 The
control and ultimate elimination of HBV will
depend on wide-scale use of the HBV vaccine. In
the United States, universal childhood HBV vac-
cination was initiated in 1991 and has now made
hepatitis B rare in U.S.-born persons younger
than 30 years of age. New recommendations sug-
gest that the HBV vaccine be given, or at least
offered, to all adults.4
The benefits of HBV vaccination, however, came
too late for persons who were born and acquired
chronic infection before its availability. Fewer
than half of such persons are aware of their in-
fection,2 and thus they do not know that it can
be treated.
Treatment for chronic HBV infection now rests
on the use of entecavir or tenofovir disoproxil
fumarate, two orally available nucleoside or nucle-
otide analogues (NAs) with potent activity against
HBV, a high barrier to antiviral resistance, and
an acceptable side-effect profile.5 These medica-
tions allow for long-term therapy with sustained
viral suppression, improvements in serum alanine
aminotransferase (ALT) levels, and ultimately de-
creases in rates of cirrhosis and liver cancer. With
a once-a-day, safe, and highly effective therapy,
why should more be needed?
New approaches to therapy are needed because
of the unique complexity of HBV replication and
its ability to persist despite profound viral suppres-
sion. Thus, even with clearance of serum HBV
DNA and of hepatitis B e antigen (HBeAg), the
replicative backbone of HBV (covalently closed
circular DNA [cccDNA]) can persist in hepato-
cytes, protected in a micro-chromosome. Most
patients who receive NA therapy remain positive
for hepatitis B surface antigen (HBsAg) and are
at risk for relapse if therapy is stopped — relapse
that can be severe and even fatal.
What is needed is a regimen that would lead
to clearance of both HBV DNA and HBsAg and
allow for withdrawal of therapy without a risk of
relapse, an end point colloquially known as a
“functional” cure. Results of a new approach to
therapy that may clear both HBV DNA and HBsAg
are now described in the Journal by Yuen et al.6
Bepirovirsen, an antisense RNA–based therapy
(“-virsen”), targets RNA sequences present in all
HBV messenger RNAs (mRNAs), including those
responsible for synthesis of HBV antigens as well
as the pregenomic RNA that is the necessary in-
termediate through which the HBV cccDNA rep-
licates. The antisense RNA uses modified ribo-
nucleotide bases that improve its absorption,
resistance to enzymic degradation, and binding
affinity to HBV mRNAs, which leads to their
degradation.
In this phase 2b trial, participants were ran-
domly assigned to receive bepirovirsen given in
300-mg doses subcutaneously once weekly for
either 12 or 24 weeks, with or without a lead-in
phase, and with or without dose reduction at 12
weeks. Patients were stratified according to re-
ceipt or nonreceipt of NA therapy. The primary
outcome was the absence of detectable HBsAg
and HBV DNA for 24 weeks after the end of

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 The n e w e ng l a n d j o u r na l
bepirovirsen treatment. The incidence of response
was also analyzed according to HBeAg status and
category of HBsAg level.
The complexity of the trial design makes it
difficult to summarize, but overall, only 26 pa-
tients (6%) had a primary-outcome event. The
incidence of response was higher with 24 weeks
of bepirovirsen treatment than with 12 weeks of
treatment (8.4% vs. 1.6%), and the incidences
were similar among those receiving NA therapy
and those not receiving NA therapy (6.2% and
5.2%, respectively), except among HBeAg-positive
patients not receiving NA therapy, none of whom
had a response. The loading dose seemed to be
helpful. It is noteworthy that patients with lower
baseline levels of HBsAg had a higher incidence
of response. Thus, among participants receiving
300 mg per week for 24 weeks who had lower
levels of HBsAg at baseline (≤3000 IU per milli­
liter), the incidence of response was 19%, as com-
pared with only 7% of those who had higher
baseline levels.
Further pursuit of bepirovirsen therapy is
certainly warranted, with the use of a dose of
300 mg per week for at least 24 weeks; indeed,
the duration of therapy might be dictated best by
HBsAg levels at baseline. Further trials of bepiro-
virsen also need to include placebo groups, not
just to prove efficacy but also to better define
safety. In this uncontrolled trial, adverse events
were frequent. Of most concern were increased
ALT levels, which were more common in patients
not receiving NA therapy than in those receiving
it (41% vs. 17%). Two serious instances of acute
hepatitis resulting in hospitalization arose in
participants not receiving NA therapy, which
suggests that bepirovirsen should be combined
with NA therapy.
Critical questions remain. Will HBsAg nega-
tivity persist beyond 24 weeks? When can NA
therapy be safely stopped? What other factors
predict response? Will RNA therapy–induced loss
of HBsAg materially improve long-term outcomes?
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of m e dic i n e
Bepirovirsen is just one RNA-based HBV ther-
apy now being pursued.5,7 Several other antisense
RNAs as well as the more malleable small inter-
fering RNA molecules (“-sirans”) are currently in
early-phase clinical trials.7-9 A new era in the
control of hepatitis B may be at hand with these
most modern of therapies for this most ancient
disease.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Liver Disease Research Branch, Division of Digestive
Diseases and Nutrition, National Institute of Diabetes and Di-
gestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD.
This editorial was published on November 8, 2022, at NEJM.org.
1. GBD 2019 Hepatitis B Collaborators. Global, regional, and
national burden of hepatitis B, 1990–2019: a systematic analysis
for the Global Burden of Disease Study 2019. Lancet Gastroen-
terol Hepatol 2022;​7:​796-829.
2. Locarnini SA, Littlejohn M, Yuen LKW. Origins and evolu-
tion of the primate hepatitis B virus. Front Microbiol 2021;​12:​
653684.
3. Roberts H, Ly KN, Yin S, Hughes E, Teshale E, Jiles R. Preva-
lence of HBV infection, vaccine-induced immunity, and suscep-
tibility among at-risk populations: US households, 2013–2018.
Hepatology 2021;​74:​2353-65.
4. Weng MK, Doshani M, Khan MA, et al. Universal hepatitis B
vaccination in adults aged 19–59 years: updated recommenda-
tions of the Advisory Committee on Immunization Practices —
United States, 2022. MMWR Morb Mortal Wkly Rep 2022;​71:​
477-83.
5. Yardeni D, Chang K-M, Ghany MG. Current best practice in
hepatitis B management & understanding long-term prospects
for cure. Gastroenterology 2022 October 12 (Epub ahead of
print).
6. Yuen M-F, Lim S-G, Plesniak R, et al. Efficacy and safety of
bepirovirsen in chronic hepatitis B infection. N Engl J Med. DOI:​
10.1056/NEJMoa2210027.
7. Alexopoulou A, Vasilieva L, Karayiannis P. New approaches
to the treatment of chronic hepatitis B. J Clin Med 2020;​9:​3187.
8. Yuen M-F, Schiefke I, Yoon J-H, et al. RNA interference ther-
apy with ARC-520 results in prolonged hepatitis B surface anti-
gen response in patients with chronic hepatitis B infection.
Hepatology 2020;​72:​19-31.
9. Yuen M-F, Locarnini S, Lim TH, et al. Combination treat-
ments including the small-interfering RNA JNJ-3989 induce
rapid and sometimes prolonged viral responses in patients with
CHB. J Hepatol 2022;​77:​1287-98.
DOI: 10.1056/NEJMe2213449
Copyright © 2022 Massachusetts Medical Society.