ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2011, p. 3624–3626
Copyright 2011, American Society for Microbiology. All Rights Reserved.
Valacyclovir for Herpes Simplex Encephalitis䌤
Thomas Pouplin,1* Julie Nguyen Pouplin,1 Pham Van Toi,1 Niklas Lindegardh,4 H. Rogier van Doorn,1
Tran Tinh Hien,1 Jeremy Farrar,1 M. Este
¨k,3 and Tran Thi Hong Chau1,2
Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit,
1 and Hospital for Tropical Diseases,
Ho Chi Minh City, Vietnam; Cambridge University Hospitals NHS Foundation Trust, Cambridge,
3; and Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Received 26 July 2010/Returned for modification 2 March 2011/Accepted 28 April 2011
The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In
resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report
the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral
prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentra-
tions in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.
Viral encephalitis is a common neurological condition in
cluded CSF cell count, chemistry, microscopy with Gram,
southern Vietnam, accounting for more than 200 admissions
Ziehl-Neelsen, and India ink stains, and routine culture for
annually to the Hospital for Tropical Diseases (HTD) in Ho
bacterial and fungal pathogens. Patients were excluded when
Chi Minh City. Herpes simplex virus type 1 (HSV-1) is the
an alternative microbiological diagnosis was made or renal
etiological agent in 10% of all viral encephalitis cases (3).
impairment was proven. All patients or patients' relatives gave
HSV-1 is the most common cause of encephalitis in adults
informed consent prior to entering the study. Ethical approvals
worldwide, with a high acute-case fatality rate and devastating
were obtained from the Scientific and Ethical Committees of
neurological sequelae in a significant proportion of survivors
the HTD and the Oxford Tropical Research Ethics Committee
(13). The recommended treatment is intravenous acyclovir, 10
(OXTREC). Treatment was initiated immediately upon en-
mg/kg of body weight, three times daily for 21 days (2, 8, 13).
rollment (Valtrex, 500 mg; GlaxoSmithKline) at 1,000 mg
Acyclovir is a purine nucleoside analogue with activity against
three times daily for a total of 21 days and was stopped if 2
human herpesviruses, including HSV. Oral acyclovir has poor
consecutive HSV PCR tests were negative after 5 days.
oral bioavailability (approximately 15 to 30%) and low pene-
Venous blood samples (1.5 ml) were obtained prior to and
tration into the central nervous system (CNS). Hence, the
1, 2, 3, 4, 6, and 8 h after dose administration on day 0. On days
treatment of HSV encephalitis, which requires higher drug
2, 10, and 20, blood samples were collected at predose and at
levels to achieve antiviral efficacy, is dependent on the use of
2 h postdose. Each blood sample was immediately centrifuged
intravenous acyclovir. However, this regimen is unavailable
upon venous collection. Plasma was collected and stored at
and unaffordable for most patients in resource-limited settings,
⫺80°C. Two milliliters of CSF was obtained from all patients
including in Vietnam ($3,700 for a full treatment course in
2 h postdose on days 0, 2, 10, and 20 and stored at ⫺80°C until
Vietnam and rarely available).
use. Acyclovir concentrations in plasma and CSF were mea-
Valacyclovir, the prodrug L-valyl ester of acyclovir, is con-
sured by high-performance liquid chromatography (HPLC)
verted in vivo
to acyclovir by hepatic and plasma esterase. Oral
with UV detection after solid-phase extraction according to
bioavailability of acyclovir is 3- to 5-fold higher (about 54%)
standard methods (6, 11). The limit of quantification was 50
when given as the prodrug than when given as acyclovir (10).
ng/ml, and the interassay variation was less than 10% in both
Orally administered valacyclovir is very well tolerated, with few
plasma and CSF.
reported adverse events, even at a dose of 2,000 mg four times
Nine patients (5 males, 4 females) were enrolled in the
daily (12). Valacyclovir is 20 times less expensive than intra-
study. Two patients had negative CSF HSV PCR tests, and
venous acyclovir ($185 for a full treatment course in Vietnam)
valacyclovir was discontinued. One patient withdrew from the
and is readily available in pharmacies in countries with limited
study. Two patients died on days 2 and 3 after study enrollment
resources. We investigated the pharmacokinetics of orally ad-
(both had positive HSV-1 PCR, and acyclovir CSF concentra-
ministered valacyclovir in the plasma and cerebrospinal fluid
tions were not different from those of other patients). The
(CSF) of patients with herpes simplex encephalitis (HSE).
other four patients had a positive PCR for HSV-1 and received
Adult patients aged ⱖ18 years with a presumptive clinical
the full 21-day course of valacyclovir. No serious adverse
diagnosis of encephalitis were eligible to enter the study. All
events were observed in the four patients. Routine hematology
patients underwent routine diagnostic investigations that in-
and biochemistry tests were within normal ranges, and nodrug-related adverse events were observed throughout the
* Corresponding author. Mailing address: Oxford University Clini-
cal Research Unit, Hospital for Tropical Diseases, Wellcome Trust
In all patients, the 2-h-postdose concentrations of acyclovir
Major Overseas Programme, 190 Ben Ham Tu, District 5, Ho Chi
in plasma remained stable from day 2 to the end of the treat-
Minh City, Vietnam. Phone: (84.83) 9237954. Fax: (84.83) 9238904.
ment, with the mean steady-state concentration around 28.1
䌤 Published ahead of print on 16 May 2011.
9.8 M, whereas the 2-h-postdose concentrations in CSF
VALACYCLOVIR FOR HERPES SIMPLEX ENCEPHALITIS
FIG. 1. Acyclovir concentrations 2 h postdose in plasma (mean [f] ⫹ standard deviation) and in CSF (individual plots [F]). Two CSF samples
(on day 2) were not taken at the correct time postdose and were excluded from the analysis.
reached maximum levels on day 2 (6.5 ⫾ 4.5 M) and then on
steady state (ranges of albumin CSF/plasma ratio ⫻ 1,000 were
days 10 (4.2 ⫾ 3.8 M) and 20 (3.5 ⫾ 1.7 M M) decreased
2.3 to 10.5 at day 0, 0.6 to 5.7 at day 2, 1.9 to 3.0 at day 10, and
to concentrations similar to and lower than that of the first day
1.0 to 2.4 at day 20).
of treatment (3.6 ⫾ 1.7 M) (Fig. 1).
Our study showed that orally administered valacyclovir at
The CSF/plasma concentration ratio was calculated to de-
1,000 mg three times daily in patients with HSV-1 encephalitis
termine the blood/CSF levels of acyclovir over the treatment
achieved a high mean CSF peak concentration of 6.5 ⫾ 4.5 M
period (Table 1). The concentrations of acyclovir in plasma
on day 2. This is higher than the reported 50% inhibitory
remained stable from the beginning of steady state (day 2) to
concentration (IC ) for clinical isolates of HSV-1 and HSV-2
the end of the treatment, whereas the concentrations in CSF
(range, 0.1 to 3.9 M) after day 2 of therapy (1, 7). All patients
decreased after day 2. The 2-h-postdose CSF/plasma acyclovir
remaining in the study at day 10 (n ⫽ 4) had negative PCR
concentration ratio was 22.9% on day 2, 14.5% on day 10, and
tests, supporting an effective exposure of acyclovir in the CSF.
12.0% on day 20. The acyclovir CSF/plasma ratio dropped to
Over the period of treatment, the CSF acyclovir concentrations
approximately 50% within 18 days of steady state.
found were higher than concentrations previously reported,
The albumin ratio between CSF and plasma is frequently
using the same dosage of valacyclovir but in patients with
used as a surrogate marker of brain inflammation resulting in
multiple sclerosis. In the study by Lycke et al. (5), the acyclovir
an impaired blood-brain barrier (BBB). The influence of the
CSF/plasma ratio 2 h postdose at steady state was 11%, and the
BBB function on the penetration of acyclovir in the CSF was
mean CSF concentration was 2.5 ⫾ 0.7 M. In our study in
investigated. We found that an increase in albumin CSF/
CSF, acyclovir concentrations did not remain stable over the
plasma ratios was correlated with higher acyclovir CSF levels
treatment period. A peak was found after 2 days of treatment,
(Pearson's r ⫽ 0.53; P ⫽ 0.02). This correlation is partially
followed by a rapid decrease from days 2 to 10 and a slight
weak (95% confidence interval range, 0.11 to 0.79) but can be
decline from days 10 to 20. Interestingly, final CSF concentra-
explained by the fact that albumin ratios were highest at day 0,
tions were similar to levels found in other studies where no
when acyclovir concentrations in the CSF were not yet at
evidence of BBB damage was shown (5). The mean CSF acy-clovir concentration on day 20 of 3.5 ⫾ 1.7 M was still higherthan the IC
of most clinical isolates of HSV-1 and HSV-2.
TABLE 1. Acyclovir concentrations at 2 h postdose in
The differences in acyclovir concentration kinetics in CSF
compared to those of plasma during the treatment suggest a
dynamic process of repair of the BBB during treatment for
(M; mean ⫾ SD) in:
acyclovir concn (%)
acute HSV encephalitis. The acute-phase injury leads to dam-
age to the BBB function, increasing its permeability to acyclo-
vir, resulting in the peak concentration seen early in the treat-
ment course (day 2). After 10 days of treatment, the lower
concentrations of acyclovir in CSF compared to baseline levels
suggest that the disease-induced permeability of the BBB had
POUPLIN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
been partially corrected. As the active inflammation in the
presents with suspected encephalitis, particularly in provincial
CNS decreases, the BBB function returns to normal, and drug
and rural settings where molecular diagnostic tests and intra-
levels in the CSF are expected to be lower. The hypothesis that
venous acyclovir are not available.
the BBB is impaired during acute HSV encephalitis and re-covers its function at the end of the disease course is similarly
This study was supported by the Wellcome Trust, United Kingdom.
supported by Lycke et al (5). In their study, patients had
We are grateful to the director, nurses, and technicians of the Hos-
normal renal function and no evidence of BBB dysfunction,
pital for Tropical Diseases, Ho Chi Minh City, Viet Nam, for theirsupport and to all the patients who participated in the study for their
and the CSF concentration at 2 h (2.5 ⫾ 0.9 M) was similar
to the levels on day 20 of valacyclovir at the same dose regimenas that used in our study.
There are very few data describing the CSF/plasma ratio
1. Collins, P. 1983. The spectrum of antiviral activities of acyclovir in vitro and
obtained after an intravenous administration of acyclovir.
in vivo. J. Antimicrob. Chemother. 12(Suppl. B):19–27.
When these have been described, they vary from 25% to 70%
2. Crumpacker, C. S., R. G. Gonzalez, and R. S. Makar. 2003. Case records of
the Massachusetts General Hospital. Weekly clinicopathological exercises.
(14). In most cases, these levels were determined after a short
Case 26-2003. A 50-year-old Colombian man with fever and seizures.
treatment course, in small case series or case reports, and were
N. Engl. J. Med. 349:789–796.
rarely done on simultaneous sampling of blood and CSF (CSF
3. Le, V. T., et al. 2010. Viral etiology of encephalitis in children in southern
Vietnam: results of a one-year prospective descriptive study. PLoS Negl.
levels were measured and the plasma values were predicted). A
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consistent mean value would be approximately 30% (4). De-
4. Lycke, J., O. Andersen, B. Svennerholm, L. Appelgren, and C. Dahlof. 1989.
livering the drug by the oral or intravenous route should not
Acyclovir concentrations in serum and cerebrospinal fluid at steady state. J.
Antimicrob. Chemother. 24:947–954.
change the CSF/plasma ratio, unless there is a saturable mech-
5. Lycke, J., C. Malmestrom, and L. Stahle. 2003. Acyclovir levels in serum and
anism (which would decrease the ratio) or a specific kinetic
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leading to quick accumulation in the CSF after the acute
6. Poirier, J. M., N. Radembino, and P. Jaillon. 1999. Determination of acy-
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course of treatment. The higher levels of acyclovir in CSF at
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the early stage of treatment potentially reflected an impaired
and its metabolite 9-carboxymethoxymethylguanine in serum and urine usingsolid-phase extraction and high-performance liquid chromatography.
and more permeable BBB. In resource-poor settings, valacy-
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clovir should be considered an alternative to intravenous acy-
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Consideration should be given to making oral valacyclovir
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