Received: 25 April 2021 | Revised: 15 May 2021 | Accepted: 24 May 2021

DOI: 10.1111/jcpt.13464

REVIEW ARTICLE

Neurotoxicity associated with acyclovir and

valacyclovir: A systematic review of cases

David Brandariz-­Nuñez MPharm1 | Marcelo Correas-­Sanahuja BPharm2 |

Sara Maya-­Gallego MD3 | Isabel Martín Herranz MPharm1

1
Pharmacy Service, A Coruña University
Hospital Complex (CHUAC), A Coruña, Abstract
Spain
What is known and objective: Acyclovir and valacyclovir are commonly used anti-
2
Pharmacy Service, Sagrat Cor Hospital,
Barcelona, Spain
virals with good general tolerance. Despite their good safety profile, they can cause
3
Pediatric Infectious Disease Service, San systemic adverse effects, such as neurotoxicity, which are less frequent and known.
Joan de Deu Hospital, Barcelona, Spain The objective of this review was to collect all the reported cases of neurotoxicity as-
Correspondence sociated with acyclovir and valaciclovir published in the literature and characterize
Brandariz-­Nuñez D MPharm, Pharmacy their clinical course and interventions.
Service, A Coruña University Hospital
Complex (CHUAC), A Coruña, Spain. Methods: A systematic review of cases was carried out following the guidelines es-
Email: vrandariz@gmail.com tablished by “Preferred Reporting Items for Systematic Reviews and Meta-­Analyses”
(PRISMA). The research was carried out using the PubMed-­Medline and Embase da-
tabases, between July 1984 and March 2021.
Results and discussion: A total of 119 cases with neurotoxicity mainly related to acy-
clovir (n = 88; 73.9%), followed by valaciclovir (n = 35; 29.4%) were analysed. 49.6%
(n = 59) were men with a mean age of 59.5 years ± 21.1 (0.5–­88). In 83.3% of the cases,
renal impairment was documented and 57.1% (n = 68) with end-­stage renal disease.
The administered dose was higher than the renal adjustment recommendations in
59.7% of the cases. The global mean of onset of symptoms was 3.1 days ± 4.3 (0.2–­28)
after the start of antivirals. The mean recovery time was 9.8 days ± 21.7 (0.2–­180).
74.4% of the patients had a recovery of ≤7 days, 15.9% between 8 and 15 days and
9.8% > 15 days.
What is new and conclusion: The neurotoxicity induced by acyclovir and its deriv-
ative valacyclovir is a poorly known and rare adverse effect that can occur mainly
in patients with advanced age and impaired renal function. The most characteristic
symptoms are confusion, altered level of consciousness, hallucinations, agitation and
dysarthria. The basis of treatment is the discontinuation of the antiviral, and in some
cases, it may require additional clearance by dialysis.

KEYWORDS
acyclovir, dialysis, neurotoxicity, renal failure, valacyclovir

918 | © 2021 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jcpt J Clin Pharm Ther. 2021;46:918–926.
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BRANDARIZ-­NUÑEZ et al. 919

1 | W H AT I S K N OW N A N D O B J EC TI V E out using the PubMed-­Medline and Embase databases between July

1984 and March 2021, using the following search criteria: (acyclovir
The varicella-­zoster virus (VZV) included within the herpesviridae and neurotoxicity) OR (valacyclovir and neurotoxicity) OR (acyclovir
family is the cause of a high prevalence of infections in humans.1 and neuropsychiatric symptoms) OR (valacyclovir and neuropsychi-
Acyclovir is a guanosine nucleoside analog approved in the 1970s atric symptoms) OR (acyclovir and epilepsy) OR (valacyclovir and
(1974), widely used in the treatment of VZV and herpes simplex virus epilepsy) OR (acyclovir and altered mental status) OR (valacyclovir
(HSV). It also has inhibitory capacity in vitro in the replication of and altered mental status) OR (acyclovir and encephalopathy) OR
other viruses such as Epstein-­Barr virus (EBV) and cytomegalovirus (valacyclovir and encephalopathy). Two authors (DBN and MCS) in-
(CMV). To develop its activity, it needs to be converted into its active dependently and in parallel conducted the initial title/abstract selec-
form, acyclovir triphosphate, which is incorporated into the DNA tion from original articles. Articles with no limits on language were
chain and inhibiting DNA polymerase. 2 There are presentations for reviewed. For studies not located or with incomplete information,
intravenous and oral administration. The latter has a considerably corresponding authors were contacted. We included all published
low oral bioavailability, around 15%–­30% of the administered dose. studies (clinical cases and case series) with cases of neurotoxicity
The volume of distribution of acyclovir molecule is large allowing related to the administration of acyclovir or valacyclovir and that
good tissue penetration, including the central nervous system (CNS), provided data associated with neurological adverse effects. Articles
reaching high levels in the cerebrospinal fluid (CSF). Its elimination in which neurotoxicity could be caused by other drugs, animal stud-
is mainly renal through filtration and tubular excretion; therefore, ies, brief communications to congresses, reviews or articles with in-
kidney damage can cause drug accumulation and systemic adverse complete data were excluded. Risk of bias was assessed using the
effects. 9-­carboxymethyl methylguanine (CMMG) is the only metab- Cochrane Collaboration tool.
olite of acyclovir with 10%–­15% renal elimination.3
In 1995, valacyclovir was approved by the FDA. It is the L-­valine
ester of acyclovir, which after oral administration suffers a first-­pass 2.2 | Data extraction and variables
effect on the liver and is rapidly and extensively converted to acy-
clovir. The main advantage of valacyclovir over Acyclovir is its oral DBN and MCS parallel and independently were responsible for ex-
bioavailability, which allows it to achieve plasma levels of acyclovir 3 tracting data from publications. Variables collected and analysed
to 5 times higher. In consequence, it is possible to use less frequent were age, sex, renal dysfunction, creatinine, urea, creatinine clear-
dose regimens but retaining the highly acceptable safety profile es- ance (CrCl), concomitant nephrotoxic drugs, kidney transplant, cor-
tablished for acyclovir.4,5 rect dose adjusted to CrCl, obesity, antiviral exposure time until
Both are drugs frequently used and with good general tolerance. symptom onset, grade of neurological recovery, time to full recov-
Despite their good safety profile, they can cause systemic adverse ery of symptoms, stay in the critical care unit, death, interventions:
effects. The most frequent toxicity is acute renal failure associated withdrawal of antiviral, dialysis, peritoneal dialysis or extracorporeal
with the deposit of crystals in the renal tubule.6 Another lesser renal replacement therapies (ERRT). Also, the number of cases as-
known but no less important side effect is neurotoxicity, character- sociated with acyclovir and/or valacyclovir, route of administration,
ized by confusion, dizziness, drowsiness, stupor, coma and psychiat- indication, total daily dose, levels of acyclovir and determination of
ric symptoms, among others. The reported incidence is very low, and 9-­carboxymethoxymethylguanine (CMMG) metabolite in serum and
the main associated risk factors are renal deterioration, high doses CSF. In addition, neurological clinical characteristics such as enceph-
of antivirals and age.7 On the other hand, the presence of CMMG in alopathy, epileptic status, seizures/myoclonus, disorientation, hal-
cerebrospinal fluid has been related to the appearance of psychiatric lucinations, tremor, asterixis, ataxia, aphasia, dysarthria, agitation,
symptoms.8 photophobia, decreased level of consciousness, delirium, peripheral
The objective of this review was to collect all the reported cases neuropathy, dizziness, depression, insomnia and irritability were col-
of acyclovir-­ and valacyclovir-­associated neurotoxicity published in lected, among others.
the literature and to analyse the demographic, clinical and neurolog- Renal dysfunction was defined as the presence of at least 1 of the
ical characteristics collected. following criteria: glomerular filtration rate less than 60 ml/min, serum
creatinine greater than 2 mg/dl, or a description in the text such as
kidney failure or chronic kidney failure. End-­stage renal disease (ESRD)
2 | M E TH O D S was defined as the presence of renal replacement therapy or a text de-
scription. The “correct dose adjusted to renal function” was considered
2.1 | Study selection to be the dose received in accordance with the recommendations set
out in Table 1. A “decreased level of consciousness” was defined as a re-
A systematic review of cases was carried out following the guidelines duction in alertness, which includes sleepiness, drowsiness and stupor.
established by “Preferred Reporting Items for Systematic Reviews The “coma” state was recorded as another independent variable. The
and Meta-­Analyses” (PRISMA). A retrospective observational study variable seizures / myoclonus was considered as any involuntary move-
was followed with all the data obtained. The research was carried ment or fasciculation, presence of alteration in electroencephalogram
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920 BRANDARIZ-­NUÑEZ et al.

TA B L E 1 Recommended acyclovir and valacyclovir dosage based on renal function

Acyclovir Valacyclovir

Intravenous Oral

CrCl >50 ml/min 5-­15 mg/kg/8 h 200-­8 00 mg/5 times a day 1 g/8 h
CrCl 25–­50 ml/min 5-­10 mg/kg/12 h 200-­8 00 mg/5 times a day 1 g/12 h
CrCl 10–­25 ml/min 5-­10 mg/kg/24 h 800 mg/8 h 1 g/24 h
CrCl <10 ml/min 2.5-­5 mg/kg/24 h 800 mg/12 h 500 mg/24 h
Dialysis 5 mg/kg/24 h 400-­8 00 mg/24 h 500 mg/24 h, after dialysis session.
ERRT 7.5-­10 mg/kg/24 h 600-­1200 mg/24 h 500 mg/24 h
Peritoneal dialysis 5 mg/kg/24 h 400-­8 00 mg/24 h 500 mg/24 h

Abbreviations: CrCl, creatinine clearance; ERRT, extracorporeal renal replacement therapies.

F I G U R E 1 PRISMA flow diagram of the study selection

(EEG) or through text documentation. The peripheral neuropathy vari- 119 independent patients (Figure 1). The cases were extracted from
able was identified as the presence of neuropathic pain, sensory or 86 clinical cases9-­35,37-­48,50-­54,56-­63,65-­71,73,75-­77,80-­83,85-­100,102,103 and
muscular alterations or through text documentation. 11 case series.36,49,55,64,72,74,78,79,84,101,113 Figure 1 shows the case
selection flow diagram.
The demographic and clinical characteristics of the 119 patients
2.3 | Statistical analysis with acyclovir-­ and valacyclovir-­associated neurotoxicity can be
seen in Table 2. In most cases, neurotoxicity was related to acy-
A descriptive analysis was performed using the SPSS program (version clovir (n = 88; 73.9%), followed by valacyclovir 35 (29.4%). The oral
20.0), and the qualitative variables were expressed in percentages and route was the most frequent form of administration (n = 85; 71.4%).
the quantitative variables in mean, standard deviation and range. The population mean age was 59.5 years ± 21.1 (0.5–­88), with 9.2%
(n = 11) of paediatric patients (<18 years)38,53,69,70,81,84-­86,93 and
61.3% (n = 73) of patients older than 65 years.
3 | R E S U LT S In 83.2% of the cases, renal impairment was documented at the
time of administration, and in 57.1% (n = 68), they presented ESRD
During this research, a total of 2719 articles were identified. Ninety-­ or undergoing renal replacement therapy. Serum creatinine was re-
seven of those were included in the analysis, representing a total of corded in 47 patients, with a mean of 5.6 mg/dl ± 3.6 (0.6–­17) and
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BRANDARIZ-­NUÑEZ et al. 921

TA B L E 2 Demographic and clinical characteristics of acyclovir

CrCl in 23, with a mean of 34.5 ml/min ±34.7 (5–­131). On the other
and valacyclovir neurotoxicity patients
hand, the administered dose was incorrect in more than half of the
N = 119 patients (59.7%), being higher than the recommendations for renal
Acyclovir, n (%) 88 (73.9) adjustment. In 2 obese patients, 25,94 the dose of intravenous acy-
IV, n (%) 57 (47.9) clovir was estimated according to the real weight instead of the ad-
Oral, n (%) justed ideal weight with the consequent overdose.

Valacyclovir, n (%) 35 (29.4) The global mean onset of symptoms was 3.1 days ± 4.3 (0.2–­
28) after the start of antivirals. All patients suffered neurological
Acyclovir and valacyclovir, n (%) 12 (10.1)
alterations, and the majority recovered their baseline state (93.3%).
Mean age, years (± SD) 59.5 ± 21.1
Only 3 cases had an incomplete reversal of symptoms.61,75,93 Lastly,
Male gender, n (%) 59 (49.6)
5 patients died, of those, 4 were older than 65 years with significant
Renal dysfunction, n (%) 99 (83.2)
comorbidity and 3 presented ESRD under renal replacement ther-
Dialysis 53 (44.5)
apy. The last dead patient was only 29 years old however diagnosed
ERRT 3 (2.5) with leukaemia and under treatment with chemotherapy.12,18,69,78,84
Peritoneal dialysis 15 (12.6) The neurological symptoms collected are described in Figure 2.
Kidney transplant, n (%) 11 (9.2) The most frequently described symptoms were disorientation
Mean cr, mg/dl (± SD) 5.6 ± 3.6 (n = 69; 58%), decrease level of consciousness (n = 45; 37.8%),
Mean crcl, ml/min (± SD) 34.5 ± 34.7 hallucinations (n = 46; 36.1%), agitation, (n = 32; 26.9%) and dys-
Mean urea, mg/dl (± SD) 89.0 ± 53.5 arthria (n = 23; 19.3%). In 5 cases, 21,27,48,54,89 although the authors
Dose not adjusted to crcl, n (%) 71 (59.7) attributed the neurological symptoms to antivirals, viral encephalitis

Co-­administered nephrotoxic drugs, n (%) 20 (16.8)

cannot be definitively ruled out, since a positive result was obtained
in the PCR of HZV in CSF (Table 3).
Co-­administered nephrotoxic drugs, n (%) 23 (19.3)
Interventions in the treatment of neurotoxicity included antiviral
Obesity, n (%) 5 (4.2)
discontinuation (n = 98; 82.3%), dose adjustment to renal function
Mean of neurotoxicity onset time, days (± SD) 3.1 ± 4.3
(n = 6; 5.0%), clearance of acyclovir by dialysis (n = 61; 51.3%), perito-
Treatment, n (%)
neal dialysis (n = 11; 9.2%) and ERRT (n = 3; 2.5%). The mean recovery
Antiviral withdrawal 98 (82.3)
time was documented in 100 cases, with a mean of 9.8 days ± 21.7
Received dialysis 61 (51.3) (0.15–­180). 74.4% of the patients had a recovery of ≤7 days, 15.9%
Received ERRT 4 (3.4) between 8 and 15 days and 9.8%> 15 days.
Received peritoneal dialysis 11 (9.2) Detection of acyclovir levels in plasma was requested in 53 cases
Complete recovery, n (%) 111 (93.3) (44.5%), with a mean of 17.2 mcg/ml ±25.3, and levels in CSF in 10
Critical care stage, n (%) 26 (21.8) cases,15,17,18,26,31,113 with a mean of 1.2 mcg/ml ±1.6. The CMMG
Death, n (%) 5 (4.2) metabolite was also obtained in 10 cases, 25,31,34,37,51,113 with 8 de-

Mean time to clinical improvement, days (± SD) terminations in plasma, 8 in CSF and 1 in urine.

All patients 9.8 ± 21.7

Treatment whit dialysis 5.9 ± 6.8
4 | DISCUSSION
Mean of total daily iv acyclovir dose, mg (± SD) 2121.2 ±
1553.8
This work is the first systematic review, to our knowledge, that joins
Mean of total daily oral acyclovir dose, mg (± SD) 2251.9 ±
1411.4 up and describes the neurotoxicity associated with acyclovir and its

Mean of total daily valacyclovir dose, mg (± SD) 2488.9 ± derivative, valacyclovir published in the literature. It was found that
1291.2 age (> 65 years) and renal impairment, especially ESRD, behaved as
Mean of acyclovir serum levels, mcg/ml (± SD) the main related risk factors. As already commented, the clearance

Indication, n (%) of acyclovir is fundamentally renal and crosses the blood-­brain bar-
rier; therefore, a decrease in glomerular filtration can increase CSF
HSV 26 (21.8)
levels and produce neurotoxicity.4 Despite the fact that the neuro-
VZV 86 (72.3)
toxicity mechanism is not completely clear, a proposed hypothesis
HSV prophylaxis 2 (1.7)
would be the cellular alteration through the inhibition of DNA poly-
CMV 4 (3.4)
merase at the mitochondrial level.104
EBV 1 (0.8)
An alternative treatment in patients with mucocutaneous HSV
Abbreviations: CMV, cytomegalovirus; Cr, creatinine; CrCl, creatinine or VZV and risk factors associated with neurotoxicity could be
clearance; EBV, Epstein-­Barr virus; ERRT, extracorporeal renal famciclovir. It has been used previously with success in patients
replacement therapies; HSV, herpes simplex virus; IV, intravenous; VZV,
who developed renal toxicity secondary to acyclovir, and although
varicella-­zoster virus.
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922 BRANDARIZ-­NUÑEZ et al.

Disorientaon F I G U R E 2 Clinical manifestations of

Decrease level of consciousness acyclovir and valacyclovir neurotoxicity
Hallucinaons were tabulated and reported as a
Agitaon percentage of the total cohort (n = 119),
Dysarthria from most to least frequently observed
Seizures/myoclonus
Encephalopathy
Coma
Tremor
Ataxia
Aphasia
Delirium
Dizziness
Insomnia
Irritability
Peripheral neuropathy
Photophobia
Epilepc status
Delusion
Asterixis
Slurred/incoherent speech
Mania
Somnambulism
Amnesia
Echopraxia
Depression
Obscene language
Anxiety
0 10 20 30 40 50 60 70

n (%)

TA B L E 3 Acyclovir-­and valacyclovir-­
Risk factors Signs and symptoms Interventions
induced neurotoxicity: A clinical picture
• Renal dysfunction • Disorientation • Drug discontinuation
• Older age • Decrease level of consciousness • Dialysis
• Drug overdose • Hallucinations • Peritoneal dialysis
• Agitation • ERRT
• Dysarthria
• Coma
• Seizures/myoclonus
• Encephalopathy
• Tremor
• Ataxia
• Delirium
• Aphasia
• Dizziness
• Irritability
• Insomnia
• Peripheral neuropathy

Abbreviation: ERRT, extracorporeal renal replacement therapies.

it is not without neurological adverse effects, its incidence seems in the calculation of the initial dosage. On the contrary, the other
more limited, with only one case of neurotoxicity reported to half of the patients developed neurotoxicity despite an apparently
date.105,106 adequate adjustment. Watson Wa, et al, in a case of this series, used
It came as a surprise to observe that the administered dose was a Bayesian method to adjust the dose and showed an overestimation
higher than the renal adjustment recommendations in more than of the real renal function when estimated with a traditional popula-
half of the patients. This can be partly explained by the fact that tion formula. 21 Therefore, caution can be advised in the use of tradi-
renal function is dynamic and in some patients the test was re- tional formulas to evaluate renal function due to their limitations in
quested when the neurotoxicity was already established, and errors elderly patients or those with renal failure.107
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BRANDARIZ-­NUÑEZ et al. 923

In patients with HZV treated with acyclovir or valacyclovir and calculation of the dose adjustment were performed inconsistently,
neurological symptoms, it is very difficult to establish a correct dif- which limits the confirmation of renal failure and overdose, as risk
ferential diagnosis of neurotoxicity with respect to viral encephalitis. factors related to neurotoxicity. Finally, the observational design of
In this study, it has been observed that the most frequent neuro- our study describes the documented interventions in the manage-
logical manifestations were psychiatric symptoms, confusion, al- ment of neurotoxicity but does not allow us to conclusively evaluate
tered level of consciousness and hallucinations and dysarthria. This their efficacy. Despite its limitations, this study provides a complete
symptomatology is compatible with other reviewed studies with pa- compilation that summarizes and describes the characteristics of the
tients with neurological toxicity secondary to both antivirals.36,72,108 neurotoxicity associated with acyclovir and its derivative.
However, viral encephalitis is characterized by the presence of fever,
headache, meningeal symptoms, such as a stiff neck and cranial neu-
ropathy. Furthermore, the presence of pleocytosis and a positive 6 | W H AT I S N E W A N D CO N C LU S I O N
PCR or antibodies to HZV in CSF are indicators of viral infection.109
The onset of neurotoxicity symptoms in our population was 3 days The neurotoxicity induced by acyclovir and its derivative valacy-
after starting the antiviral, whereas encephalitis appeared 7 days clovir is a poorly known and rare adverse effect that can occur
after the skin lesions appeared.75 On the opposite, although in most mainly in patients with advanced age and impaired renal function.
patients the toxicity was reversible with a recovery equal to or less The most characteristic symptoms are confusion, altered level of
than 7 days, it was reported considerable severity, with 26% of the consciousness, hallucinations, agitation and dysarthria. Toxicity
cases admitted to the critical care unit and 4.2% mortality. appears after 3 days of treatment and reverses completely after
Withdrawal or discontinuation of the antiviral is the basis of 7 days or less. The basis of treatment is the discontinuation of the
treatment, as it has been described in the vast majority of our pa- antiviral and in some cases an additional intervention such as dialy-
tients. On the other hand, acyclovir is almost 50% dialysed due to its sis may be needed. To minimize the risk of developing neurotoxic-
110
low molecular weight, low protein binding and high solubility. HD ity in patients with risk factors, we recommend monitoring renal
was the treatment used in almost half of the patients, and a clear- function to make a correct dose adjustment and avoid overdoses.
ance of 40%–­60% of the antiviral level has been documented with Determination of the metabolite CMMG can be useful in the di-
sessions of 3-­5 h of HD. 24,26,35,110,111 Another treatment technique agnosis of neurotoxicity. To conclude, more studies are needed to
used was PD. Despite the fact that HD appears more effective than clarify the role of monitoring acyclovir plasma levels in the diagnosis
PD in extraction, good results were obtained in reversing neuro- of neurological toxicity.
logical symptoms with intensified PD.33 Finally, another extraction
method described with therapeutic utility was ERRT.12,17,20 C O N FL I C T O F I N T E R E S T
Regarding acyclovir levels, in almost half of the cases it was doc- None declared.
umented that they were obtained. Its relationship with neurotoxicity
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