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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,2 Ho Chi Minh City, Vietnam; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom3; and Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand4 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.
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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 Trop. Dis. 4:e854.
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 cerebrospinal fluid after oral administration of valacyclovir. Antimicrob.
Agents Chemother. 47:2438–2441.
leading to quick accumulation in the CSF after the acute 6. Poirier, J. M., N. Radembino, and P. Jaillon. 1999. Determination of acy-
plasma exposure following intravenous (IV) administration of clovir in plasma by solid-phase extraction and column liquid chromatogra- the drug. An important observation, previously reported (5, 9), phy. Ther. Drug Monit. 21:129–133.
7. Sangdara, A., and P. Bhattarakosol. 2008. Acyclovir susceptibility of herpes
is that concentrations in CSF vary less over dose intervals than simplex virus isolates at King Chulalongkorn Memorial Hospital, Bangkok.
those in plasma. These results suggest that acyclovir slowly J. Med. Assoc. Thai. 91:908–912.
crosses the blood-brain barrier and is then actively transported 8. Skoldenberg, B., et al. 1984. Acyclovir versus vidarabine in herpes simplex
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cerebrospinal fluid and systemic circulation after administration of high-dose the CSF/plasma ratio.
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tion of valacyclovir, the L-valyl ester of acyclovir, following oral administra- litis achieved therapeutic levels in the CSF throughout the tion to humans. Antimicrob. Agents Chemother. 39:2759–2764.
course of treatment. The higher levels of acyclovir in CSF at 11. Svensson, J. O., L. Barkholt, and J. Sawe. 1997. Determination of acyclovir
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- J. Chromatogr. B Biomed. Sci. Appl. 690:363–366.
clovir should be considered an alternative to intravenous acy- 12. Weller, S., et al. 1993. Pharmacokinetics of the acyclovir pro-drug valacyclo-
clovir for treatment of herpes simplex encephalitis when the vir after escalating single- and multiple-dose administration to normal vol-
unteers. Clin. Pharmacol. Ther. 54:595–605.
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14. Whitley, R. J., M. R. Blum, N. Barton, and P. de Miranda. 1982. Pharma-
Consideration should be given to making oral valacyclovir cokinetics of acyclovir in humans following intravenous administration. A available and encouraging its use immediately after a patient model for the development of parenteral antivirals. Am. J. Med. 73:165–171.
Εργαστήριο Σπουδών Φύλου και Ισότητας Λ. Συγγρού 134, 1ος όροφος, 17671 Αθήνα, τηλ. 210 9210177-8, fax 210 9210178 http://www.genderpanteion.gr, e-mail: [email protected] ΕΙΣΗΓΗΣΗ 22 Μαΐου 2007 Elizabeth Dermody Leonard, καθηγήτρια κοινωνιολογίας στο Πανεπιστήµιο Vanguard της Νότιας Καλιφόρνιας, Η.Π.Α