B. Pfausler

E. Schmutzhard

M. Bergmann

M. Kofler

R. Beer

R. Helbok

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CASE REPORT
Acyclovir resistance in herpes simplex virus type I encephalitis:
a case report
M. Bergmann1 & R. Beer1 & M. Kofler1 & R. Helbok1 & B. Pfausler1 & E. Schmutzhard1
Received: 15 June 2016 /Revised: 30 September 2016 /Accepted: 2 October 2016 /Published online: 27 October 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Acyclovir resistance is rarely seen in herpes sim-
plex virus (HSV) type I encephalitis. Prevalence rates vary
between 0.5 % in immunocompetent patients (Christophers
et al. 1998; Fife et al. 1994) and 3.5–10 % in immunocom-
promised patients (Stranska et al. 2005). We report a 45-year-
old, immunocompetent (negative HIV antigen/antibody test-
ing), female patient, without previous illness who devel-
oped—after a febrile prodromal stage—aphasia and psycho-
motor slowing. Cerebral magnetic resonance imaging (cMRI)
showed right temporal and insular T2-hyperintense lesions
with spreading to the contralateral temporal lobe.
Cerebrospinal fluid (CSF) analysis yielded lymphocytic
pleocytosis and elevated protein level. Polymerase chain reac-
tion testing for HSV type I showed a positive result in repeat
lumbar puncture. HSV type I encephalitis was diagnosed and
intravenous acyclovir treatment was initiated (750 mg t.i.d.).
Acyclovir treatment was intensified to 1000 mg t.i.d., due to
clinical deterioration, ongoing pleocytosis and progression on
cMRI 5 days after initiation of antiviral therapy. In parallel,
acyclovir resistance testing showed mutation of thymidine
kinase gene at position A156V prompting foscarnet therapy
(60 mg t.i.d.). Patient’s condition improved dramatically over
2 weeks. Acyclovir resistance is rare but should be considered
in case of clinical worsening of patient’s condition. To our
knowledge, this is the first report of acyclovir resistance in
HSV type I encephalitis of an immunocompetent and previ-
ously healthy patient in Austria.
Keywords Acyclovir resistance .Herpessimplexvirus typeI .
Encephalitis . Foscarnet
Introduction
Clinically suspected acyclovir resistance of herpes simplex
virus (HSV) type I was first described in 1982 (Burns et al.
1982; Crumpacker et al. 1982; Sibrack et al. 1982) with re-
ported prevalence rates of 0.5% in immunocompetent patients
(Christophers et al. 1998; Fife et al. 1994) and 3.5–10 % in
immunocompromised patients.(Stranska et al. 2005) Even
higher prevalence rates (25 %) of acyclovir resistance have
been published in bone marrow or allogenic hematopoietic
stem cell transplant recipients (Danve-Szatanek et al. 2004;
Morfin et al. 2004). Of note, acyclovir resistance in HSV type
I encephalitis is rare (Gateley et al. 1990; Schulte et al. 2010).
Report of a case
A 45-year-old woman suffering from right frontal headache,
fever, diarrhea, and vomiting, without previous illness, was
admitted to a district hospital. She was evaluated for systemic
viral disease with negative testing for putative pathogens in-
cluding human immunodeficiency virus (HIV). White blood
cell classification revealed left shift with a rise of neutrophils
(neutrophils 8.3 billion cells/L (G/L), total leucocytes 10 G/L,
lymphocytes 1.3 G/L, monocytes 0.38 G/L, eosinophils 0 G/
L, basophils 0 G/L). Blood immunoglobulin levels were nor-
mal. Three days later, she developed psychomotor slowing
and aphasia and, finally, became stuporous, but had no obvi-
ous neck stiffness. Cerebrospinal fluid (CSF) examination re-
vealed lymphocytic pleocytosis (271 cells/μL; reference <4
cells/μL), mild elevated protein (82 mg/dL; normal range
* E. Schmutzhard
erich.schmutzhard@i-med.ac.at
1 Department of Neurology, Neurocritical Care Unit, Medical
University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
J. Neurovirol. (2017) 23:335–337
DOI 10.1007/s13365-016-0489-5
<50mg/dL), but normal glucose concentration. Cerebral mag-
netic resonance imaging (cMRI) showed T2-hyperintense le-
sions, mainly involving the right temporal lobe and the insula,
as well as the frontal and contralateral temporal regions
(Fig. 1). On the following day, a negative PCR testing for
HSV type I in the previously drawn CSF sample was reported.
However, based upon the patient’s clinical presentation, CSF,
and cMRI findings, HSV type I encephalitis was still
suspected and intravenous acyclovir (750 mg t.i.d.) had been
instituted immediately after the diagnostic procedures.
Despite prompt initiation of antiviral therapy, the patient de-
veloped repetitive generalized tonic-clonic seizures and respi-
ratory insufficiency requiring mechanical ventilation.
Consequently, the patient was transferred to our neurological
intensive care unit (ICU). Repeat cMRI 5 days after initiation
of acyclovir treatment showed progressing T2-hyperintense
lesions (Fig. 2). Further, repeat CSF examination yielded on-
going lymphocytic pleocytosis (243 cells/μL) and this time
positive PCR result for HSV type I. To overcome potential
inadequate penetration of acyclovir into the intrathecal com-
partment, the dose of acyclovir was increased to 1000mg t.i.d.
In addition, to rule out suspected resistance to acyclovir, ge-
notype sequencing of thymidine kinase and DNA polymerase
genes was performed. Molecular biology testing confirmed
mutation of thymidine kinase gene at position A156V.
Immediately after positive resistance testing, foscarnet was
added at a dose of 60 mg t.i.d. The combination of increased
acyclovir dose and the initiation of foscarnet led to a marked
improvement of the patient’s condition. The third lumbar
puncture performed at day 24 after hospitalization revealed a
reduction of CSF pleocytosis to 18 cells/μL and HSV type I
DNAwas no longer detectable in the CSF.
The patient was then weaned off the ventilator and
extubated. At transferal to a specialized neurological rehabil-
itation facility 1 month after hospital admission the patient still
showed residual aphasia, left-sided hemiparesis, and cognitive
dysfunction. She left rehabilitation center with modified
Rankin scale of 3 (moderate disability).
Discussion
The patient suffered from HSV type I encephalitis and was
initially treated with an intravenous acyclovir dose of
750 mg t.i.d. Time from onset of symptoms to treatment was
approximately 72 h. Clinical and neuroimaging deterioration
together with the development of intracranial hypertension
prompted further investigations, particularly for potential
presence of acyclovir resistance—even in the case of an im-
munocompetent patient, however, no further investigation
with respect to primary immunodeficiency (Joshi et al.
2009) was carried out. We were able to confirm a mutation
(A156V) of the viral enzyme thymidine kinase which converts
the prodrug acyclovir to acyclovir monophosphate. A156V
mutation is a well-known cause of HSV type I drug resistance.
Acyclovir is the first-line treatment for HSV infections and
requires activation via phosphorylation to the triphosphate
form. Initially, phosphorylation takes place through thymidine
kinase encoded by the human herpesvirus 1 UL23 gene.
Further phosphorylation steps occur through cellular
thymidylate kinases. Activated acyclovir triphosphate is a
competitive inhibitor of the viral DNA polymerase and results
in chain termination. Long-term prophylaxis with acyclovir
may lead to drug resistance, especially in immunocompro-
mised patients (Andrei and Snoeck 2013). The HSV may
become resistant to acyclovir via mutation of the viral
Fig. 1 Turbo inversion recovery magnitude (TIRM) cMRI scan taken at
day three after beginning of symptoms
Fig. 2 Follow-up cMRI scan performed 5 days later from first cMRI
336 J. Neurovirol. (2017) 23:335–337
thymidine-kinase gene, mediating approximately 95 % of
cases of acyclovir resistance, or via mutation of the DNA
polymerase gene. Resistance to acyclovir can be established
by clinical observation, phenotyping (testing the susceptibility
of a viral isolate to different drug doses), or genotyping by the
identification of specific mutations linked with drug resistance
(Andrei and Snoeck 2013).
Foscarnet is a direct inhibitor of the virus DNA polymer-
ases and an alternative drug for the treatment of HSV resistant
patients (Piret and Boivin 2011; Safrin et al. 1991; Schulte
et al. 2010). Alternative therapeutic approaches have been
introduced recently, including viral polymerase inhibition by
brincidofovir (CMX001), valomaciclovir, and n-
methanocarbathymidine. Another option is the inhibition of
the helicase primase complex with pritelivir (AIC316) or
amenamevir (ASP2151) (Scott and Prichard 2014). Finally,
we do not yet know whether increasing the dose of acyclovir
or the initiation of foscarnet led to an improvement of our
patient’s medical condition.
Conclusion
Acyclovir resistance in HSV type I encephalitis is rare in im-
munocompetent patients (Gateley et al. 1990; Schulte et al.
2010) but should be considered in cases of clinical deteriora-
tion despite antiviral therapy and persistent virus load in the
CSF. Here, we report the first case of an immunocompetent
patient with acyclovir resistant HSV type I encephalitis in
Austria. Genotype sequencing reliably reveals mutations of
thymidine kinase as a cause of acyclovir resistance. In our
case, increasing the dose of acyclovir during the assessment
of resistance and the timely initiation of foscarnet proved life-
saving; however, the delay of the appropriate therapy certainly
has contributed to medium-term morbidity.
Acknowledgments Open access funding provided by University of
Innsbruck and Medical University of Innsbruck. We thank Dr. Karin
Pollak from Medical University Vienna, Department of Virology, for
providing genotype sequencing and PD Dr. A. Grams from Medical
University Innsbruck, Department of Neuroradiology, for providing
cMRI.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Open Access This article is distributed under the terms of the Creative
Commons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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Acyclovir resistance in herpes simplex virus type I encephalitis: a case report

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Acyclovir resistance in herpes simplex virus type I encephalitis: a case report

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