ArticlePDF Available

Entecavir Induced Severe Myopathy: An Uncommon Side Effect



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.
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:
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.
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.
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
Tanoğlu A and Sarı O. J Mol Virol Immunol 2021; 2(1): 15-17.
side effect [4]. In this paper, we aimed to present
a patient with severe myopathy due to entecavir
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.
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
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.
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].
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
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.
1. Wilkins T, Sams R, Carpenter M. Hepatitis B:
Screening, Prevention, Diagnosis, and Treatment. Am
Fam Physician 2019; 99(5): 314-23.
2. Karagoz E, Tanoglu A. Clinical Usefulness of HBsAg
Quantification in Patients with Chronic Hepatitis B
Infection. Hepat Mon 2017; 17(4): e12293. [Crossref]
3. Koklu S, Gulsen MT, Tuna Y, Koklu H, Yuksel O, Demir
M, et al. Differences in nephrotoxicity risk and renal
effects among anti-viral therapies against hepatitis B.
Aliment Pharmacol Ther 2015; 41(3): 310-9. [Crossref]
4. Tu T, Douglas MW. Hepatitis B Virus Infection: From
Diagnostics to Treatments. Viruses 2020; 12(12): 1366.
5. Findlay AR, Goyal NA, Mozaffar T. An overview of
polymyositis and dermatomyositis. Muscle Nerve 2015;
51(5): 638-56. [Crossref]
6. Chang TT, Gish RG, de Man R, Gadano A, Sollano J,
Chao YC, et al; BEHoLD AI463022 Study Group. A
comparison of entecavir and lamivudine for HBeAg-
positive chronic hepatitis B. N Engl J Med 2006;
354(10): 1001-10. [Crossref]
7. Zou XJ, Jiang XQ, Tian DY. Clinical features and risk
factors of creatine kinase elevations and myopathy
associated with telbivudine. J Viral Hepat 2011; 18(12):
892-6. [Crossref]
8. Yuan K, Guochun W, Huang Z, Lin B, Zhou H, Lu X.
Entecavir-associated myopathy: a case report and
literature review. Muscle Nerve 2014; 49(4): 610-4.
9. Dolce V, Fiermonte G, Runswick MJ, Palmieri F,
Walker JE. The human mitochondrial deoxynucleotide
carrier and its role in the toxicity of nucleoside
antivirals. Proc Natl Acad Sci U S A 2001; 98(5): 2284-
8. [Crossref]
10. Bridges EG, Jiang Z, Cheng YC. Characterization of
a dCTP transport activity reconstituted from human
mitochondria. J Biol Chem 1999; 274(8): 4620-5.
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
In this Special Issue, we have brought together a broad range of studies on hepatitis B virus (HBV) covering diagnosis, pathogenesis, monitoring, and treatment. In doing so, we have highlighted the many challenges that remain unaddressed, including limitations in technical, virological, clinical, and public health-related resources. HBV diagnosis and living with HBV. Although highly sensitive, specific, widely available, and inexpensive tests are now available to diagnose HBV infection, Freeland et al. highlight some of the major hurdles that still prevent affected people from entering the health care system [1]. They focus on African immigrants to the United States and find (as with many other communities) that stigma and discrimination play a key role in preventing patient engagement in diagnosis and treatment. Tu et al. further explore these issues in a review of the non-physical impacts of diagnosis on people living with hepatitis B [2]. They combine academic literature with first-hand accounts of lived experiences to show that chronic HBV infection affects more than physical health, with significant psycho-social impacts on those affected. One major impact on the mental health of people living with hepatitis B is the fear of disease progression. Fortunately, there is renewed interest in updating HBV treatment guidelines, which could reduce this fear dramatically. Hall et al. review recent evidence for early initiation of antiviral therapy [3], which could empower people who do not meet current guidelines for treatment and thereby decrease their fear of disease progression. They also provide an update on when to stop nucleo(s/t)ide analogue treatment while maintaining virological response, a highly-anticipated goal for those currently on lifelong antiviral therapy. Pathogenesis. Most HBV-associated liver disease appears to be linked to aberrant expression of viral proteins (e.g., mutated HBV surface or x proteins, HBsAg or HBx) or to dysregulated, chronically activated immune attack of infected cells. Lee et al. [4] focus on HBx as a potential contributor to HBV-associated liver cancer. Here, they find that over-expression of HBx induces downregulation of selenium binding protein 1, which is reduced in many cancers, including (as they report) HBV-associated HCCs. However, the underlying mechanisms by which HBx effects these changes in the chronically infected liver remain unclear. With respect to the dysregulated immune response, Vinhaes et al. use high-dimensionality analyses of inflammatory perturbation to compare immune markers in the blood of people with chronic HBV infection and those who have undergone spontaneous HBsAg-seroconversion [5]. They find significant differences not only between chronic HBV and HBsAg-negative states but also between people who have cleared HBV infection and those who are HBV-naïve. While it is yet to be demonstrated if any of these markers are linked to HCC risk in patients who have cleared HBsAg, the observed
Full-text available
Context: Quantitative hepatitis B surface antigen (qHBsAg) levels have been shown to assist the management of patients with chronic hepatitis B virus (HBV) infection and reflect the level of transcriptional activity of covalently closed circular DNA (cccDNA). It has been indicated the importance of co-operative use of qHBsAg and HBV-DNA for diagnosis and monitoring of CHB treatment. Evidence Acquisition: In order to achieve a comprehensive approach in HBsAg quantification, an extensive search was done using relevant keywords in major medical libraries to collect, categorize, and summarize data in different sections. Results: A combination of qHBsAg < 1000 IU/mL and HBV-DNA < 2000 IU/mL can identify inactive carriers. qHBsAg levels are changed during the natural history of HBV infection that progressively declines from the immune tolerance to the inactive phase. Conclusions: The use of qHBsAg in chronic hepatitis B (CHB) patients may bring about important complementary information regarding HBV DNA during treatment and help predict the treatment outcome.
Full-text available
A protein fraction of mitochondria from human acute lymphocytic leukemia cells, which could be reconstituted into proteoliposomes to have dCTP transport activity, has been partially purified by hydroxyapatite and blue Sepharose chromatography. The dCTP transport activity in proteoliposomes was time-dependent and could be activated by Ca2+ and to a lesser extent by Mg2+. None of the other divalent cations tested could activate the transport activity. The K m value of dCTP in the presence of Ca2+ was shown to be 3 μm. dCDP but not dCMP or dCyd could inhibit the transport activity. Other deoxynucleoside triphosphates could also inhibit the uptake of dCTP with the potency dGTP = dATP > TTP. Although ATP could competitively inhibit dCTP uptake with aK i value of 8 μm, the reconstituted dCTP uptake activity was not sensitive to the ATP/ADP carrier inhibitor atractyloside or the sulfhydryl reagent N-ethylmaleimide. This suggests that the dCTP transport system studied is not the same as the ATP/ADP carrier. In conclusion, these studies describe the first functionally reconstituted mitochondrial carrier that displays an efficient transport activity for dCTP.
Full-text available
The synthesis of DNA in mitochondria requires the uptake of deoxynucleotides into the matrix of the organelle. We have characterized a human cDNA encoding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles where it catalyzed the transport of all four deoxy (d) NDPs, and, less efficiently, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. The physiological role of this deoxynucleotide carrier is probably to supply deoxynucleotides to the mitochondrial matrix for conversion to triphosphates and incorporation into mitochondrial DNA. The protein is expressed in all human tissues that were examined except for placenta, in accord with such a central role. The deoxynucleotide carrier also transports dideoxynucleotides efficiently. It is likely to be medically important by providing the means of uptake into mitochondria of nucleoside analogs, leading to the mitochondrial impairment that underlies the toxic side effects of such drugs in the treatment of viral illnesses, including AIDS, and in cancer therapy.
Full-text available
Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level. Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72 percent) and 195 of 314 patients in the lamivudine group (62 percent, P=0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67 percent vs. 36 percent, P<0.001) and normalization of alanine aminotransferase levels (68 percent vs. 60 percent, P=0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P<0.001). HBeAg seroconversion occurred in 21 percent of entecavir-treated patients and 18 percent of those treated with lamivudine (P=0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. ( number, NCT00035633.).
Hepatitis B virus (HBV) is a partly double-stranded DNA virus that causes acute and chronic liver infection. Screening for hepatitis B is recommended in pregnant women at their first prenatal visit and in adolescents and adults at high risk of chronic infection. Hepatitis B vaccination is recommended for medically stable infants weighing 2,000 g or more within 24 hours of birth, unvaccinated infants and children, and unvaccinated adults requesting protection from hepatitis B or who are at increased risk of infection. Acute hepatitis B is defined as the discrete onset of symptoms, the presence of jaundice or elevated serum alanine transaminase levels, and test results showing hepatitis B surface antigen and hepatitis B core antigen. There is no evidence that antiviral treatment is effective for acute hepatitis B. Chronic hepatitis B is defined as the persistence of hepatitis B surface antigen for more than six months. Individuals with chronic hepatitis B are at risk of hepatocellular carcinoma and cirrhosis, but morbidity and mortality are reduced with adequate treatment. Determining the stage of liver disease (e.g., evidence of inflammation, fibrosis) is important to guide therapeutic decisions and the need for surveillance for hepatocellular carcinoma. Treatment should be individualized based on clinical and laboratory characteristics and the risks of developing cirrhosis and hepatocellular carcinoma. Immunologic cure, defined as the loss of hepatitis B surface antigen with sustained HBV DNA suppression, is attainable with current drug therapies that suppress HBV DNA replication and improve liver inflammation and fibrosis. Pegylated interferon alfa-2a, entecavir, and tenofovir are recommended as first-line treatment options for chronic hepatitis B.
Background Results are conflicting with respect to the renal effects of anti-viral agents used for hepatitis B virus infection.AimTo compare short and long-term renal effects in real-life settings and to determine risk factors for renal impairment during treatment.Methods2221 treatment-naïve patients were enrolled. Among these, 895 (302 lamivudine, 27 telbivudine, 282 entecavir, 273 tenofovir and 11 adefovir initiated patients) had ‘repeated measures’ of creatinine (baseline, 1st, 6th, 12th and 24th month of treatment). Telbivudine and adefovir groups were excluded from further analysis because of the low number of patients. We calculated the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula at each time point. Hypophosphataemia was also recorded. Risk factors for renal impairment were analysed.ResultsTenofovir caused a decline in GFR at each time point when compared to baseline levels. However, lamivudine and entecavir did not change GFR. GFR-shifting from ≥90 to 60–89 mL/min/1.73 m2 was comparable among groups. The proportion of patients whose baseline creatinine increased more than 25% was comparable among all anti-virals. GFR showed a decline in patients who switched from entecavir to tenofovir. One patient with compensated cirrhosis needed to change from tenofovir because of renal safety. Seven and three patients developed transient hypophosphataemia in the tenofovir and lamivudine groups, respectively.Conclusions Although tenofovir caused a decline in GFR, differences between the anti-viral agents do not appear to be so impressive. In patients with and without renal risk factors at baseline, there is no impact of anti-virals, including tenofovir.
Polymyositis and dermatomyositis are inflammatory myopathies that differ in their clinical features, histopathology, response to treatment, and prognosis. While their clinical pictures differ, they both present with symmetrical, proximal muscle weakness. Treatment relies mainly upon empirical use of corticosteroids and immunosuppressive agents. A deeper understanding of the molecular pathways that drive pathogenesis, careful phenotyping, and accurate disease classification will aid clinical research and the development of more efficacious treatments. This review discusses current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of polymyositis and dermatomyositis. This article is protected by copyright. All rights reserved.
Introduction: Entecavir, a nucleoside analog (NA), is effective for treatment of chronic hepatitis B virus (HBV) infection. Methods: We report the case of a patient we encountered with entecavir-associated myopathy. We also performed a literature review of myopathies associated with nucleoside analogs. Results: A 44-year-old man presented with a 3-month history of myalgia and progressive weakness. He had HBV infection and had received entecavir antiviral treatment for 5 years. Laboratory tests showed that serum creatine kinase levels were significantly elevated. Muscle histopathology showed abundant T-lymphocyte infiltration of muscle fibers, and HBV surface antigen and HBV core antigen were not present in muscle fibers. Entecavir-associated myopathy was subsequently diagnosed. The patient's symptoms eventually resolved, and serum CK levels decreased rapidly after he stopped receiving entecavir treatments. Conclusions: Patients who receive NA therapy should be closely monitored for myopathic side effects. Muscle Nerve 49:610-614, 2014.
With the extensive use of telbivudine, more and more studies reported its association with creatine kinase (CK) elevations and myopathy. However, clinical features of these adverse effects were poorly understood. The aim of the present study was to investigate the clinical features and risk factors of CK elevations and myopathy associated with telbivudine. The serum CK levels of 200 patients who were treated with telbivudine for chronic hepatitis B (CHB) between January 2007 and July 2010 were monitored and analysed along with clinical manifestations. The 3-year cumulative incidence of CK elevations and myopathy was 84.3% and 5%, respectively. CK elevations occurred more frequently in men than in women, and patients aged ≤45 years and with negative HBeAg had higher incidence of CK elevations. There was no difference in CK elevations among patients with different HBV DNA levels. Male, younger age and HBeAg negativity were independent predictors of CK elevations by multivariate Cox regression analysis. There was no association between the occurrence of myopathy and variables including age, sex, HBeAg and HBV DNA. No risk factors of myopathy were identified. CK elevations usually occurred 21 months after starting treatment, and most patients resolved spontaneously without interruption of telbivudine therapy except three patients who had to switch to other agents. In conclusion, CK elevations are common adverse reactions associated with telbivudine therapy, while myopathy is rare. Male, younger age and HBeAg negativity might be risk factors of CK elevations.