International Journal of Antimicrobial Agents 59 (2022) 106562
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International Journal of Antimicrobial Agents
journal homepage: www.elsevier.com/locate/ijantimicag
Letter to the Editor
Hepatitis delta treatment with bulevirtide in real life: a
case report
Editor: Professor A Tsakris
Sir,
Co-infection with hepatitis delta virus (HDV) in patients in-
fected with hepatitis B virus (HBV) worsens chronic hepatitis
compared with HBV infection alone and is a global health con-
cern [1,2]. Until recently, there was only one off-label drug,
pegylated-interferon alpha-2a/-2b (PEG-IFN-alpha), available for
hepatitis delta treatment [1]. Rates of virological response (≥2
log10 copies/mL reduction of HDV RNA level at end of treatment)
and sustained virological response are low with this treatment and
are mostly observed in <60% and <50% of patients, respectively,
including when combined with adefovir, entecavir, or tenofovir
disoproxil fumarate (TDF) that control HBV replication [1]. In ad-
dition, PEG-IFN-alpha is associated with substantial toxicity. Bule-
virtide is a long, 47-amino-acid, synthetic N-myristoylated and C-
amidated lipopeptide derived from the large HBV surface protein
preS1-domain [1,3]. This antiviral drug inhibits virus entry into
hepatocytes by competing with HDV and HBV for their cellular re-
ceptor, the solute carrier family 10 member 1 (SLC10A1) or sodium
taurocholate co-transporter polypeptide (NTCP), thus blocking hep-
atocyte infection by both viruses. In a clinical trial, bulevirtide was
associated with a decline of HDV RNA ≥2 log10 after 24 weeks
of treatment in 46%, 47% and 77% of the 2, 5 and 10 mg/day
groups, respectively [1]. Here, we report the real-world case of
an HBV/HDV-co-infected patient treated with bulevirtide combined
with PEG-IFN-alpha-2a and TDF.
The patient is a 36-year-old male from Georgia who presented
in 02/2016 with liver cytolysis (alanine aminotransferase [ALT],
698 IU/L) and was diagnosed with HBV/HDV-co-infection. Hepati-
tis C and HIV serologies were negative. Transient elastography in-
dicated fibrosis at Metavir stage 3 (12 kPa). HDV RNA load deter-
mined using an in-house, real-time reverse transcription-PCR as-
say [4] was 7.0 log10 copies/mL, and HBV DNA load determined us-
ing the DxN Veris assay (Beckman Coulter, Brea, CA, USA) was 1.8
log10 IU/mL. HDV genotype was 1A, as determined by Sanger pop-
ulation sequencing with an in-house protocol [4] (Supplementary
Figure S1). HBV genotype could not be determined because of the
very low HBV DNA level. The patient received PEG-IFN-alpha-2a
from 02/2016 to 12/2019, and TDF from 01/2018. In 2017, tran-
sient elastography indicated cirrhosis (Metavir stage 4, 20 kPa). In
12/2019, HDV RNA load was 7.4 log10 copies/mL, HBV DNA load
was 2.6 log10 IU/mL, and ALT was 81 IU/L (Figure 1). Bulevirtide
(2 mg/day) was started in 01/2020, in addition to PEG-IFN-alpha-
2a (180 μg/week) and TDF (245 mg/day). PEG-IFN-alpha dosage
was reduced to 135 μg/week in 02/2020 because of a fall in platelet
counts from 117 to 57/mm3 . Virological response was observed,
https://doi.org/10.1016/j.ijantimicag.2022.106562
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with HDV RNA load decreasing to 4.9 log10 copies/mL (-2.5 log10 ) at
3 months, and to 4.4 log10 copies/mL (-3.0 log10 ) at 4 months. PEG-
IFN-alpha dosage was further reduced to 90 μg/week in 06/2020
because of thrombocytopenia (43 G/L). HDV RNA load increased
to 5.5 log10 copies/mL in 07/2020. PEG-IFN-alpha was discontin-
ued in 09/2020 because the platelet count remained low (44 G/L),
and platelet count subsequently increased above 90 G/L. Between
09/2020 and 04/2021, HDV RNA load fluctuated between 6.1 and
7.7 log10 copies/mL, and ALT and prothrombin index fluctuated be-
tween 42 and 68 IU/mL and 53 and 58%, respectively. HBV DNA
level was systematically detectable at a low level between 02/2016
and 12/2019 (mean±standard deviation, 2.6±0.4 log10 IU/L [range,
1.6-2.9]), whereas it was undetectable on bulevirtide in 04/2020
and remained undetectable until 04/2021, except for one measure
of 1.1 log10 IU/mL in 06/2020. In addition, mean ALT was 318±206
IU/L (range, 78-714 IU/L) between 06/2016 and 12/2019 and was
then 60±15 IU/L (36-81 IU/L). No clinical side effects were noted
during bulevirtide treatment apart from thrombocytopenia that
was attributed to PEG-IFN-alpha.
Real-life data on bulevirtide therapy for HDV infection, particu-
larly for patients with a follow-up duration ≥12 months, are scarce.
The present case shows virological failure of bulevirtide 2 mg/day
combined with PEG-IFN-alpha-2a and TDF, with an initial response
at 3 months (-2.5 log10 copies/mL) then a virologic rebound at 6
months. This failure could be at least partly due to PEG-IFN-alpha
dosage reduction at 4 months then PEG-IFN-alpha discontinuation
at 8 months because of thrombocytopenia. Loglio et al. recently re-
ported that real-life, high-dose (10 mg/day) bulevirtide monother-
apy was effective in three patients with compensated cirrhosis [4].
HDV RNA became undetectable after 28-52 weeks then remained
undetectable on treatment at 144 weeks of follow-up in two of the
patients despite bulevirtide dosage reduction after 76-108 weeks
[4]. In contrast, virological rebound occurred in the third patient,
for whom bulevirtide was discontinued because of chemotherapy
initiation [4]. Asselah et al. reported a 2 log10 -decline of HDV RNA
at the end of follow-up in three of four patients who received
bulevirtide (2 mg/day) plus PEG-IFN-alpha (180 μg/week) for 12-
68 weeks [5]. These three patients concurrently received TDF. HDV
RNA became undetectable in all three cases but virologic rebound
occurred in one of the patients. Two other patients who received
bulevirtide monotherapy experienced a ≥2 log10 -HDV RNA decline
at weeks 8 and 28, with levels becoming undetectable in one case
[5].
Few data are available on the effect of adding PEG-IFN-alpha
and TDF to bulevirtide HDV therapy. In the 48-week MYR203
study, HDV RNA was undetectable in 80% of patients on bulevirtide
(2 mg/day) plus PEG-IFN-alpha (180 μg/week) versus 13% of pa-
tients on bulevirtide (2 mg/day) monotherapy [6]. Bulevirtide alone
or in combination therapy was generally well tolerated in clinical
trials [7] and in real-life reports after a maximum of three years
M.-A. GIORDAN, J.G. BENGONE ABOGOURIN, S. AHERFI et al.
Figure 1. Evolution of virological, biochemical and hematological parameters in the case-patient
ALT, alanine aminotransferase; GGT, gamma-glutamyl-transferase; HDV, hepatitis delta virus; HBV, hepatitis B virus
[4,5], with injection site reactions and asymptomatic, reversible in-
creases in bile acids being the most frequently reported adverse ef-
fects. Simplification of hepatitis delta treatment is hindered by the
route and frequency of bulevirtide administration (daily subcuta-
neous injection) and the occurrence of relapse after treatment dis-
continuation. Further real-life reports of patients co-infected with
HBV/HDV who received bulevirtide-based therapies are needed to
evaluate the efficacy of this drug at different dosages and in differ-
ent drug combinations on HBV and HDV in terms of on-treatment
and sustained virological responses.
Funding
This work was supported by the French Government under the
“Investments for the Future” program managed by the National
Agency for Research (ANR), Méditerranée-Infection 10-IAHU-03.
Competing Interests
The authors have no conflicts of interest to declare. Funding
sources had no role in the design and conduct of the study; col-
lection, management, analysis, and interpretation of the data; and
preparation, review, or approval of the manuscript.
Ethical Approval
All data were generated as part of the routine work at Assis-
tance Publique-Hôpitaux de Marseille (Marseille University Hospi-
tals), and the study is the result of routine standard clinical man-
agement. The study was approved by the institution’s ethics com-
mittee (N°2019-001).
Sequence Information: 2548175 (GenBank)
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Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
International Journal of Antimicrobial Agents 59 (2022) 106562
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ijantimicag.2022.
106562.
References
[1] Brancaccio G, Gaeta GB. Treatment of chronic hepatitis due to hepatitis B and
hepatitis delta virus coinfection. Int J Antimicrob Agents 2019;54:697–701.
[2] Zhang Z, Urban S. New insights into HDV persistence: The role of inter-
feron response and implications for upcoming novel therapies. J Hepatol
2021;74:686–99.
[3] Petit PR, Borentain P, Aherfi S, Gérolami R, Colson P. Hepatitis Delta recurrence
post-liver transplantation in absence of detectable hepatitis B surface antigen
and hepatitis B virus DNA in peripheral blood. Clin Res Hepatol Gastroenterol
2020;44:e41–4.
[4] Loglio A, Ferenci P, Uceda Renteria SC, Tham CYL, Scholtes C, Holzmann H,
et al. Safety and effectiveness of up to 3 years’ bulevirtide monotherapy in pa-
tients with HDV-related cirrhosis. J Hepatol 2022;76:464–9.
[5] Asselah T, Loureiro D, Le Gal F, Narguet S, Brichler S, Bouton V, et al. Early vi-
rological response in six patients with hepatitis D virus infection and compen-
sated cirrhosis treated with Bulevirtide in real-life. Liver Int 2021;41:1509–17.
[6] Wedemeyer H, Schoneweis K, Bogomolov PO, Voronkova N, Chulanov V,
Stepanova T, et al. Final results of a multicenter, open-label phase 2 clinical trial
(MYR203) to assess safety and efficacy of Myrcludex B in with PEG-interferon
alpha 2a in patients with chronic HBV/HDV co-infection. [abstract no. GS-13]. J
Hepatol 2019;70(1):e81.
[7] Kang C, Syed YY. Bulevirtide: First Approval. Drugs 2020;80:1601–5.
Marc-Antoine GIORDAN
Aix-Marseille Univ., Institut de Recherche pour le Développement
(IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), Microbes
Evolution Phylogeny and Infections (MEPHI), 27 boulevard Jean
Moulin, 13005, Marseille, France
M.-A. GIORDAN, J.G. BENGONE ABOGOURIN, S. AHERFI et al. International Journal of Antimicrobial Agents 59 (2022) 106562

Jessica Grace BENGONE ABOGOURIN Philippe COLSON∗

Aix-Marseille Univ., Institut de Recherche pour le Développement
(IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), Microbes
Evolution Phylogeny and Infections (MEPHI), 27 boulevard Jean
Moulin, 13005, Marseille, France
IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005,
Marseille, France
Aix-Marseille Univ., Institut de Recherche pour le Développement
(IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), Microbes
Evolution Phylogeny and Infections (MEPHI), 27 boulevard Jean
Moulin, 13005, Marseille, France
IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005,
Marseille, France

Sarah AHERFI ∗ Correspondingauthor: Philippe Colson, IHU Méditerranée

Aix-Marseille Univ., Institut de Recherche pour le Développement Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France.
(IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), Microbes Tel.: +33 413 732 401, Fax: +33 413 732 402.
Evolution Phylogeny and Infections (MEPHI), 27 boulevard Jean E-mail address: philippe.colson@univ-amu.fr (P. COLSON)
Moulin, 13005, Marseille, France
Isabelle ALLEMAND
IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005,
Marseille, France

Descargado para Luis Hurtado (lhurtados@gmail.com) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en mayo 07, 2023.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.