Entecavir Induced Severe Myopathy: An Uncommon Side Effect

Abstract

Chronic Hepatitis B virus (HBV) infection is a chronic viral illness that affects millions of people around the world and can cause serious consequences such as hepatic failure and hepatocellular carcinoma. Entecavir, a guanosine nucleoside analog (NA), is a commonly used and generally safe therapeutic agent in HBV infection. In this paper, we aimed to present a case of chronic HBV that developed severe myopathy as an extremely rare side effect after the use of entecavir. Patients receiving entecavir therapy for chronic HBV should be closely monitored for the development of myopathy as well as other known and common side effects.

Full text

Open Access Journal [doi: 10.46683/jmvi.2021.26] Case Report
Journal of Molecular Virology and Immunology
Entecavir Induced Severe Myopathy: An Uncommon Side Effect
Entekavir ile İndüklenen Şiddetli Miyopati: Nadir Bir Yan Etki
Alpaslan TANOĞLU1 [ID], Oktay SARI2 [ID]
1Department of Internal Medicine, Gastroenterology, Sancaktepe Şehit Profesör İlhan Varank Education and Research
Hospital, University of Health Sciences, Istanbul, Turkey.
2Department of Family Medicine, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey.
Article Info: Received: 03.04.2021. Accepted: 06.04.2021.
Correspondence: Alpaslan Tanoğlu; Assoc.Prof., Department of Internal Medicine, Gastroenterology, Sancaktepe Şehit
Profesör İlhan Varank Education and Research Hospital, University of Health Sciences, Istanbul, Turkey. E-mail:
alpaslantanoglu@yahoo.com
Abstract
Chronic Hepatitis B virus (HBV) infection is a chronic viral illness that affects millions of people around
the world and can cause serious consequences such as hepatic failure and hepatocellular carcinoma. Entecavir,
a guanosine nucleoside analog (NA), is a commonly used and generally safe therapeutic agent in HBV infection.
In this paper, we aimed to present a case of chronic HBV that developed severe myopathy as an extremely
rare side effect after the use of entecavir. Patients receiving entecavir therapy for chronic HBV should be
closely monitored for the development of myopathy as well as other known and common side effects.
Keywords: Hepatitis B, Antiviral therapy, Nucleoside analog.
Özet
Kronik Hepatit B virusu (HBV) enfeksiyonu, dünya çapında milyonlarca insanı etkileyen ve karaciğer
yetmezliği ve hepatoselüler karsinoma gibi ciddi sonuçlara neden olabilen kronik viral bir hastalıktır. Bir
guanozin nükleozit analoğu (NA) olan entekavir, HBV enfeksiyonunda yaygın olarak kullanılan ve genellikle
güvenli bir terapötik ajandır. Bu yazıda, entekavir kullanımından sonra son derece nadir bir yan etki olarak
şiddetli miyopati gelişen bir kronik HBV olgusunu sunmayı amaçladık. Kronik HBV için entekavir tedavisi alan
hastalar, miyopati gelişimi ve diğer bilinen ve yaygın yan etkiler açısından yakından izlenmelidir.
Anahtar Kelimeler: Hepatit B, Antiviral tedavi, Nükleozit analoğu.
Introduction
Chronic Hepatitis B virus (HBV) infection
influences millions of individuals globally and can
cause serious comorbidities such as cirrhosis, liver
failure and hepatic malignities over time [1,2].
Nucleoside analogs (NA's) and interferons are
therapeutic agents used for chronic HBV infection.
The mechanism of action of NA's is based on
inhibiting viral polymerase activity [3,4].
Administration of NA in the management of
chronic HBV, the risk of development of HBV-
related complications has been significantly
reduced. Entecavir is a guanosine nucleoside
analog used for this purpose [1,3]. It is a globally
used and safe agent in the management of HBV,
but this drug has some side effects. Usually seen
side effects are nausea, headache, malaise, and
flu like symptoms. All these side effects are
usually mild to moderate [4]. However, entecavir-
associated severe myopathy is an extremely rare
©Copyright JMVI. Licenced by Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).

Tanoğlu A and Sarı O. J Mol Virol Immunol 2021; 2(1): 15-17.
16
side effect [4]. In this paper, we aimed to present
a patient with severe myopathy due to entecavir
use.
Case Report
A 50-year-old male patient who was followed
up for chronic HBV was admitted to the
gastroenterology outpatient clinic with complaints
of muscle pain in both lower extremities and
muscle weakness. He stated that myalgia and
progressive weakness in the lower extremities
had started 2 months ago and he did not have
these complaints before. The patient had difficulty
to climbing the stairs and he was complaining
about getting up from a sitting position. However,
there was no weakness in the upper extremities,
and did not describe dysphagia or dyspnea. The
patient had a known history of chronic HBV
infection for 3 years and had been using entecavir
tablet therapy at a dose of 0.5 mg/day for HBV
infection for the last 1 year. Since the first
diagnosis of chronic HBV infection, the patient
declared that telbivudine treatment was used for
the first two years and that the entecavir tablet
therapy was used for the last year. He was not
currently using any other medication other than
entecavir therapy. He denied ever using alcohol,
smoking and other herbal or folk remedies. His
family history was negative for muscle disorders.
The general condition of the patient was good,
conscious, and cooperative. He stated that his
physical activities were not intense. Physical
examination revealed no abnormal findings other
than splenomegaly that slightly crosses the rib
border. In laboratory tests, serum aspartate
aminotransferase and alanine aminotransferase
levels were 96 IU/L and 74 IU/L, respectively.
Serum direct bilirubin level was within normal
range and total bilirubin level was 1.5 mg/dL. The
patient's serum creatine kinase level was 1242
IU/L on admission. Creatine kinase level was
tested again, and the result was 1411 IU/L. His
kidney functional tests and other routine
biochemical tests were normal. HBV-DNA
(deoxyribonucleic acid) levels have been
measured negatively over the past two years. In
line with these tests, the patient was admitted to
the clinic. Among the autoimmune tests studied
during his hospitalization, anti-nuclear antibody,
anti-mitochondrial antibody, anti-smooth muscle
antibody, and rheumatoid factor tests results
were all negative. The erythrocyte sedimentation
rate was normal, and the C-reactive protein level
was slightly elevated. The patient's neurology
consultation was obtained. In the
electrophysiological study performed in the
neurology clinic, it was reported in accordance
with myopathic pattern with normal nerve
conduction. Based on the patient's symptoms,
physical examination, and biochemical tests,
entecavir-induced severe myopathy was thought
to be possible and entecavir treatment was
discontinued. Three weeks after the drug was
discontinued, his serum creatine kinase level was
decreased to 235 IU/L. With the improvement in
the laboratory, all his clinical symptoms were
improved significantly and the patient's exercise
capacity increased. The patient was invited to the
outpatient clinic at frequent intervals until his
condition stabilized and his laboratory findings
returned to totally normal.
Discussion
Some cases of myopathy related to the use
of clevudine, telbivudine or adefovir have been
reported in the literature. In this case report, a
rare case of severe myopathy that developed with
the use of entecavir during chronic HBV treatment
was presented. The distinctive features of the
case were muscle pain, loss of strength in the
proximal muscles of the lower extremities, and
high serum CK (creatine kinase) and AST
(aspartate aminotransferase), ALT (alanine
aminotransferase) levels. The physical
examination and EMG (electromyography)
characteristics performed in the neurology
consultation were very similar to the cases with
polymyositis (PM) [5]. But the absence of
interstitial lung disease and/or dysphagia in our
patient suggested primarily a drug-related side
effect.
Entecavir is a nucleoside analog that
decreases hepatitis B virus replication. It was
approved by the US Food and Drug Administration
for the management of chronic HBV in 2005 [6].
Myopathy has often been reported in patients
receiving clevudine and telbivudine therapy, but
entecavir-associated myopathy is extremely rare.

Tanoğlu A and Sarı O. J Mol Virol Immunol 2021; 2(1): 15-17.
17
Zou et al. evaluated the development of
myopathy due to telbivudine use and increased
CK in a prospective study examining 200 patients,
while high CK was observed in 84.3% of the
patients, while myopathy was found in only 5% of
the patients [7]. The interesting aspect of our
case is that when the initial diagnosis of chronic
HBV was made, obvious myopathy did not
develop despite using telbivudine and severe
myopathy developed while using entecavir.
Entecavir-associated myopathy was first
reported in 2014 by Yuan et al. [8], in a 44-year-
old male chronic HBV patient. Subsequently, very
rare cases were reported. Entecavir-associated
myopathy can be attributed to mitochondrial
toxicity that may develop due to the use of NA
[9,10]. In other words, mitochondrial DNA
polymerases are also inhibited. Thus, inhibition of
mitochondrial functions and finally mitochondrial
toxicity triggered by NA's may cause clinically
seen overt and sometimes severe myopathy
and/or neuropathy [9,10].
Conclusion
Consequently, patients receiving nucleoside
analog treatment should be closely screened for
many kinds of side effects including myopathy.
NA's, as well as entecavir, can induce myopathy
in chronic HBV patients. Sometimes it cannot be
easy to distinguish cases of myopathy from PM,
but detailed analysis and management of all
clinical features will help make the correct
diagnosis.
Consent for publication: Written informed consent was obtained from the patient.
Conflict of interest: The authors declare that there is no conflict of interest. The authors alone are responsible
for the content and writing of the paper.
Financial disclosure: There is no financial support to this study.
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