MAJOR ARTICLE

Long-term Valacyclovir Suppressive Treatment

After Herpes Simplex Virus Type 2 Meningitis:
A Double-Blind, Randomized Controlled Trial
E. Aurelius,1 E. Franzen-Rohl,1 M. Glim
ker,1 O. Akre,1 L. Grillner,2 C. Jorup-Ronstrom,3 M. Studahl,4 and the HSV-2
Meningitis Study Group
1Department of Infectious Diseases and 2Department of Microbiology, Karoliniska University Hospital, Stockholm; 3Department of Infectious Diseases,

South General Hospital, Stockholm; and 4Department of Infectious Diseases, Sahlgrenska University Hospital, Goteborg, Sweden

Background. Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis.
Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full
spectrum of neurological complications.

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Methods. One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned
to placebo (n 5 51) or 0.5 g of valacyclovir twice daily (n 5 50) for 1 year after initial treatment with 1 g of
valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome
was time until recurrence of meningitis. The patients were followed up for 2 years.
Results. The first year, no significant difference was found between the valacyclovir and placebo groups.
The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was
significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.0610.21]).
One-third of the patients experienced 14 meningitis episodes during the study period. A considerable
morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was
found in both groups.
Conclusions. Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent
meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against
mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV
activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could
be interpreted as a rebound phenomenon.

Herpes simplex virus type 2 (HSV-2) infection is
a common sexually transmitted disease with a sero-
prevalence of 10%25% in Sweden [1, 2]. The virus
is neurotropic and causes neurological complications,
primarily clinical meningitis with or without muco-
cutaneous lesions [36]. HSV-2 is one of the major
Received 21 August 2011; accepted 20 December 2011; electronically published
28 March 2012.
Correspondence: Elisabeth Aurelius, Infectious Diseases Unit, Department of
Medicine, Karolinska Universitity Hospital, Karolinska Institutet, SE-171 76 Stockholm,
Sweden (elisabeth.aurelius@ki.se).
Clinical Infectious Diseases 2012;54(9):130413
The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/cis031
causes of aseptic meningitis, comprising up to 20% of
consecutive cases tested with polymerase chain reaction
(PCR) on cerebrospinal fluid (CSF) samples [7, 8].
HSV meningitis carries the risk of a broad spectrum
of future neurological morbidity, including recurrent
meningitis, myelitis, and radiculitis [9]. In one study,
one-third of 40 patients suffered from recurrent neu-
rological symptoms within the first year after HSV
meningitis [10]. Recurrent lymphocytic meningitis is
mainly caused by HSV-2 [11] and is estimated to
occur in 20%30% of cases after primary HSV meningitis
[3, 9, 10, 12].
Suppressive antiviral therapy has been studied ex-
tensively in genital herpes and proved to be effective
in diminishing the frequency of genital HSV infection
recurrences [13]. A daily dose of 0.5 g of valacyclovir

1304 d CID 2012:54 (1 May) d Aurelius et al

Table 1. Primary, Secondary and Tertiary Study Objectives

Objective Outcome Measures

Primary
To compare neurological morbidity during 1 year when
active antiviral suppression or placebo is taken
Secondary
To compare effects of active antiviral suppression or
placebo during 1 year
Tertiary
To define the clinical course of HSV meningitis with or
without active long-term suppression (12 months) of
viral replication by valacyclovir during 12 months, and
during the following 12 months after treatment
Length of time until symptoms of a recurrence of herpes simplex virus
type 2 (HSV-2) meningitis
(1) Proportion of patients with at least 1 verified episode of HSV meningitis
during the 12-months period; (2) no. of patients with herpetic mucocutaneous
symptoms from the genital and/or lumbosacral region; (3) no. of episodes
of herpetic mucocutaneous symptoms from the genital and/or lumbosacral
region; and (4) tolerability of treatment during 1 year
(1) All outcome measures stated above; (2) no. of patients with recurrent
attacks of suspected meningitis without verification by cerebrospinal fluid
pleocytosis (pleocytosis not present and/or lumbar puncture not performed);
(3) no. of patients with symptoms from the nervous system indicated at
regular revisits; (4) no. of grouped symptoms from the nervous system
indicated at regular revisits; and (5) duration of symptoms from the nervous
system indicated at regular revisits

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is effective for preventing genital herpes recurrences. In patients
with frequent recurrences, a twice-daily dosage is beneficial [14].
However, in meningitis, neither antiviral treatment in the
acute phase nor suppressive therapy has been assessed in con-
trolled trials. Nevertheless, antiviral treatment with 1 g of vala-
cyclovir 3 times daily for 1 week is often used as acute phase
treatment. Successful prevention of meningitis and other neu-
rological symptoms with antiviral suppression has been reported
in small case series [15, 16].
In this randomized trial, which followed up patients for
2 years after HSV-2 meningitis, the aim was to determine the
impact of antiviral suppression with 0.5 g of valacyclovir twice
daily for 1 year on recurrence of meningitis and to delineate
the full spectrum of neurological complications.
METHODS
Patients
Consecutive patients (.18 years of age) with symptoms of
viral meningitis and CSF pleocytosis levels of .5 3 106 cells/L
with an HSV-2 infection etiology were included. The etiology
was verified by (1) detection of HSV-2 DNA in the CSF by
PCR, (2) preceding or concurrent virologically verified HSV-2
lesions in the genital or lumbosacral region, or (3) a history
of previous aseptic meningitis of herpetic or unknown origin
and positive HSV-2 serology in the acute phase serum sample.
For criteria 2 and 3, negative results in bacterial culture and
PCR for enterovirus in CSF and negative serology results for
tick-borne encephalitis virus were compulsory.
Exclusion criteria included the following: (1) immunosup-
pression, (2) human immunodeficiency virus (HIV) infection,
(3) pregnancy, (4) no protection against pregnancy in female
sexually active patients, (5) hepatic impairment (aspartate
aminotransferase [AST] or alanine aminotransferase [ALT]
levels .5 times the upper limit of normal), (6) impaired renal
function (estimated creatine clearance of #30 mL/minute),
(7) intolerance to acyclovir or valacyclovir, (8) probenicid
treatment, (9) systemic antiviral therapy with an antiherpetic
effect or immunomodulatory therapy, (10) malabsorption, and
(11) other ongoing investigational drug treatment.
The study was approved by the ethics committees of each
institution, and all participants gave their written informed
consent.
Procedures
We conducted a prospective, randomized, double-blind, placebo-
controlled multicenter trial in Sweden. The prespecified
primary, secondary, and tertiary objectives are presented in
Table 1. The study participants were enrolled at 9 depart-
ments of infectious diseases from November 2000 through
January 2005 with a follow-up period of 2 years.
Patients were asked for their history of genital herpes and
any previous meningitis, and thorough neurological examina-
tions as well as assessments of skin and mucous membranes
were performed by the investigating physician. Blood chemistry
analyses (hemoglobin level, leukocyte count, thrombocyte count,
differential counts, sodium level, potassium level, creatinine level,
bilirubin level, AST level, and ALT level) were performed.
CSF samples and vesicle materials were analyzed for HSV-1
and HSV-2 DNA by use of a qualitative nested PCR as described
elsewhere [17, 18] or a quantitative TaqMan PCR [1921] at
the regional clinical virological laboratories at the study sites.
Serum samples were analyzed for HSV-1 and HSV-2 type-
common and type-specific immunoglobulin G (IgG) by use
of antigens from HSV-2 glycoprotein G and HSV-1 glyco-
protein D, respectively [22, 23]. Acute phase treatment of

HSV-2 Meningitis Valacyclovir Trial d CID 2012:54 (1 May) d 1305

HSV meningitis with 1 g of valacyclovir 3 times daily was
initiated at admission or as soon as an HSV-2 infection etiology
was confirmed clinically and/or virologically, and treatment
was continued for 1 week.
Participants were assigned to the placebo group or the vala-
cyclovir suppression group by means of a computer-generated
randomization protocol. The dosage chosen (0.5 g twice daily
orally) is consistent with that often recommended for HSV
suppression in immunocompromised patients [13, 24]. Glaxo-
SmithKline supplied the drug and placebo tablets in sealed
packages.
The stratification was made from a clinical point of view.
Primary HSV-2 meningitis was defined as first episode of
HSV-2 meningitis according to the etiology criteria 1 or 2
described above. Recurrent HSV-2 meningitis was defined as
the presence of at least 1 earlier episode of verified HSV-2
meningitis or viral meningitis of unknown origin along with
positive HSV-2 serology result (criterion 3).
To ensure an even distribution within each stratum,
a randomization request was faxed to the central unit at the
Karolinska Pharmacy, and a stratified randomization in
blocks according to the patient groups was performed. The
study drug was started 03 days after completion of the acute
phase treatment. Participants, clinicians, and pharmacologists
were all unaware of the allocated study treatment. The code
was not disclosed at any time to the study investigators until
the last included patient had been followed up for 2 years
and the statistical analyses were performed.
The patients continued with valacyclovir suppression or
placebo for 1 year. Recurrence of meningitis was treated openly
with 1 g of valacyclovir 3 times daily orally for 1 week, replaced
by 5 mg/kg acyclovir 3 times daily intravenously in case of
nausea or vomiting. Meanwhile, the randomized study treat-
ment was temporarily withdrawn. In mucocutaneous recur-
rences only, treatment was generally avoided. In cases of severe
genital herpes, 0.5 g of valacyclovir twice daily was given for
35 days. A similar policy was applied during the second year
of follow-up.
Clinical investigation and blood chemistry analyses were
performed at weeks 46 and after 12 and 24 months. Episodes
of meningitis as well as episodes of mucocutaneous lesions
were recorded. Verified recurrent meningitis was defined as
clinical symptoms of meningitis and CSF pleocytosis levels
of .5 3 106 cells/L. Probable recurrent meningitis was defined
as clinical acute meningitis (headache, nausea, vomiting, hy-
persensitivity to light and noise neck stiffness) without lum-
bar puncture performed, or lack of pleocytosis, and no
reasonable cause of the symptoms other than HSV infection.
Genital herpes recurrence was defined as genital lesions with
HSV detected by PCR or genital herpetic lesions reported by
the patient.
1306 d CID 2012:54 (1 May) d Aurelius et al
The patients received diary cards to record adverse experi-
ences, recurrences of herpetic lesions, or signs of meningitis,
as well as missed doses of drug, as a memory support. The
study nurse called the patient monthly to check on the tol-
erability of the drug and the presence or absence of any
symptoms, using a structured questionnaire.
The following symptoms were specifically asked about
(1) headache; (2) symptoms from the central nervous system
(CNS) such as concentration difficulties, irritability, fatigue,
hypersensitivity to light and noise, sleep disturbances, and in-
fluence on libido or sexual potency; (3) symptoms from the
peripheral nervous system (PNS) such as radiating pain, skin-
sensitive defects, and muscular weakness; (4) symptoms from
the autonomous nervous system (ANS) such as urinary or
anorectal dysfunction; and (5) herpetic lesions in the genital
or lumbosacral region.
Compliance was controlled in 2 ways: (1) by the patients
report on missed doses at the monthly telephone call and (2) by
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the investigating doctor or nurse who recorded and counted
the tablets every 3 months.
Safety, tolerability, and discontinuation related to adverse
events were recorded, as well as deviations of laboratory test
results. Data were entered into an electronic case report form
from a written one. Thereafter a central review of the data-
was performed and discrepancies were returned to the
investigational sites for clarification.
Statistical Analyses
We assessed time to recurrence, the primary endpoint, by use
of Kaplan-Meier estimation and log-rank tests. In this anal-
ysis, participants with .1 recurrence were censored on their
first recurrence. Categorical data were analyzed using v2 tests.
Hazard ratios (HRs) and 95% confidence interval (CIs) were
estimated through Cox proportional hazards regression. Sta-
tistical significance was set at a 5 .05.
The sample size for this study was predicated on detection
of a difference of 20% of recurrences of HSV-2 meningitis be-
tween the valacyclovir and placebo groups. On the basis of
a calculated power of 80% and a significance level of 5%, we
estimated that a minimum sample size of 86 patients would
be needed. To compensate for patients who were not fully
evaluable, the number of patients was increased by about 20%.
RESULTS
A total of 101 patients met the eligibility criteria. All patients
had symptoms of viral meningitis and CSF pleocytosis levels
of .5 3 106 cells/L. The HSV-2 infection diagnoses were
based on DNA detection by PCR in the CSF samples in 87 case
patients (valacyclovir group, n 5 44; placebo group, n 5 43), or
concurrent virologically verified HSV-2 lesions or a history of
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Figure 1. Trial profile. Abbreviation: bid, twice daily.

previous aseptic meningitis of herpetic or unknown origin psychosocial reasons (n 5 5), new diagnosis of syringomyelia
and positive HSV-2 IgG result at inclusion in 14 case patients (n 5 1), frequent recurrences of genital herpes (n 5 1),
(valacyclovir group, n 5 6; placebo group, n 5 8). Patients and new episode of acute meningitis (n 5 1). The median
were randomly allocated to treatment with study drug or time to discontinuation of therapy was 2 months (range,
placebo (Figure 1). Thirty-eight additional patients with
diagnosed herpes meningitis were not included due to con-
sent refusal or withdrawal, desire to become pregnant, im- Table 2. Baseline Demographic Data, Clinical History of Herpes
Infection, and Type-Specific Serology at Baseline in Valacyclovir
munosuppression, hepatic impairment or impaired renal
and Placebo Groups
function, severe anemia, intolerance to valacyclovir, geo-
graphical inconvenience, and missed or incorrect screening No. (%) of Patients
procedure. No patient had other neurological disease at in-
Valacyclovir Group Placebo Group
clusion or exclusion. Characteristic (n 5 50) (n 5 51)
Demographic data, clinical history of meningitis and/or gen- Sex
ital herpes, and type-specific HSV-1 and HSV-2 serology results Male 14 (28) 10 (20)
at baseline are presented in Table 2. The patients with recurrent Female 36 (72) 41 (80)
herpetic disease had a history of herpes for 131 years (median, Median age at enrollment, years 38 38
12 years). The majority of the patients were female. However, the Previous genital herpes 21 (43) 25 (49)
sex distribution was equal in both groups, as was the number of No previous meningitis 24 (49) 27 (53)
patients with a clinical history of previous meningitis and/or Previous meningitis 25 (51) 24 (47)
Previous genital herpes 21 (43) 25 (49)
genital herpes. The majority of patients tested negative for HSV-
HSV-1 IgG positive and 7 (15) 4 (9)
1 IgG, and the small number of patients who tested positive for HSV-2 IgG positive
HSV-1 IgG at baseline were equally distributed. HSV-1 IgG positive and 0 (0) 0 (0)
Eighty-three of the 101 patients were $ 75% compliant HSV-2 IgG negative
during 12 months of follow-up. Eighteen patients discontinued HSV-1 IgG negative and 6 (13) 12 (27)
HSV-2 IgG negative
the medication, 5 in the valacyclovir group and 13 in the placebo
HSV-1 IgG negative and 35 (73) 29 (64)
group (Figure 1). HSV-2 IgG positive
The reasons for discontinuation were pregnancy (n 5 4) Abbreviations: HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex
or desire to become pregnant (n 5 1), side effects (n 5 5), virus type 2; IgG, immunoglobulin G.

HSV-2 Meningitis Valacyclovir Trial d CID 2012:54 (1 May) d 1307

 A Year 1 - during VACV suppression/placebo

00
1.0
0.75
Percent relapse free

0
0.50
0.25
0.00

0 3 6 9 12
Time since start of VACV treatment/placebo
Number at risk
VACV 50 50 45 41 37
Placebo 51 50 46 45 44
VACV Placebo

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B Year 2 - after the end of VACV/placebo
1.00
0.75
Percent relapse free

0.50
0.25
0.00

0 3 6 9 12
Time since end of VACV/placebo
Number at risk
VACV 49 44 42 40 37
Placebo 49 48 47 47 45
VACV Pl
Placebo
b

Figure 2. Kaplan-Meier functions for relapse-free survival during active treatment in the treatment arm or placebo (A), and during follow-up after
cessation of active treatment and placebo administration (B ). Abbreviation: VACV, valacyclovir.

07 months) in the valacyclovir group and 3.5 months (range,
17 months) in the placebo group. All patients underwent
the scheduled monthly assessments and doctors visits during
the first year. During the second year, 4 patients were lost to
follow-up.
Recurrence of HSV meningitis, verified and probable, was
found in a nonsignificantly higher rate in the valacyclovir
group than in the placebo group (HR, 1.86 [95% CI, .784.43])
(Figure 2; Table 3) during the first year when subjects were
taking the study drug. During the second year, the risk was

1308 d CID 2012:54 (1 May) d Aurelius et al

Table 3. Meningitis, Headache, and Associated Symptoms Other significantly higher among patients previously exposed to
Than Meningitis From the Central, Peripheral, and Autonomous valacyclovir (HR, 3.29 [95% CI, 10.0610.21]) (Figure 2;
Nervous Sytems During the Study Period Table 3). The difference remained when verified and probable
meningitides were analyzed separately (data not shown). As
No. (%) of Patients
an ancillary analysis, a comparison between the subgroups of
Valacyclovir Placebo
patients who were .90% compliant within the groups (valacy-
Group Group
Parameter (n 5 50) (n 5 51) P Value clovir group, n 5 21; placebo group, n 5 16) was made and
Year 1
yielded results equivalent to those in the analysis of the patients
No. of patients with 14 (29) 8 (16) .12 with .75% compliance (data not shown).
suspected 1 verified In total, 48 meningitis episodes (16 verified and 32 prob-
HSV meningitis
able) occurred during the 2 years of observation. Thirty-two
No. of attacks of headache
patients (31.6%) had 14 episodes of meningitis. A cluster
0 21 (42) 18 (35) .57
of episodes was observed in the valacyclovir group after drug
12 17 (34) 16 (31)
$3 12 (24) 17 (33) cessation. The distribution of the meningitis episodes in the
No. of days with headache 2 groups during the first and second year is shown in Figure 3.
019 15 (30) 17 (33) .72 With regard to headache and symptoms other than menin-
$20 35 (70) 34 (67) gitis from the CNS, PNS, or ANS, a considerable morbidity
Other symptoms from was noted in both groups, but no statistically significant
the CNS

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difference was shown between the groups (Table 3).
Lowest tertile 19 (38) 15 (30)
Mucocutaneous recurrences occurred frequently during the
Middle tertile 16 (32) 17 (34) .68
Highest tertile 15 (30) 18 (36)
first year in both groups, but significantly more patients
Symptoms from the PNS had recurrences in the placebo group than in the valacyclovir
Lowest tertile 19 (38) 15 (30) group (Table 4). In the total cohort, 78% of the patients had
Middle tertile 14 (28) 19 (38) .53 recurrent herpetic manifestations, genital and/or meningeal,
Highest tertile 17 (34) 16 (32) during the study period of 2 years.
Symptoms from the ANS Meningitis treatment was given without any significant dif-
No 35 (70) 28 (55) .12 ference in the type of antiviral, administration, or duration
Yes 15 (30) 23 (45) between the groups during the first and second years. During
Year 2
the first year, 3 treatments were given to 3 patients in the vala-
No. of patients with 12 (24) 4 (8) .03
suspected 1 verified cyclovir group and 8 treatments to 7 patients in the placebo
HSV meningitis group. During the second year, 6 treatments were given to
No. of attacks of headache 5 patients in the valacyclovir group and 3 treatments to 3 patients
0 24 (48) 20 (40) in the placebo group.
12 16 (33) 16 (32) .51
Genital herpes treatments were nonsignificantly more common
$3 10 (19) 15 (28)
in the placebo group than in the valacyclovir group (27 vs 20
No. of days with headache
patients, respectively; P 5 .19). In total, there were 96 reported
019 27 (54) 24 (44) .48
$20 23 (46) 27 (53)
recurrences in the placebo group and 49 in the valacyclovir group,
Symptoms from the CNS and the number of treatment episodes was 27 and 15, respectively.
Lowest tertile 16 (33) 16 (33) 1.0 Adverse events possibly related to the study were recorded in
Middle tertile 16 (33) 16 (33) 15 patients (30%) in the valacyclovir group and 9 (17.6%) in the
Highest tertile 16 (33) 16 (33) placebo group (P 5 .14). Exanthema was the most commonly
Symptoms from the PNS recorded adverse event. Two men, one in each group, suffered
No 21 (42) 20 (39) from profound sweating. Other adverse events were loose stools,
Yes 29 (58) 61 (22) .76 angioedema, and palpitations.
Symptoms from the ANS
Serious adverse events occurred in 6 patients; none were
No 39 (78) 43 (84) .51
considered to be related to the study medication. In the vala-
Yes 1 (22) 8 (16)
cyclovir group, 1 patient developed serious kidney disease,
Abbreviations: ANS, autonomous nervous system; CNS, central nervous
system; HSV, herpes simplex virus; PNS, peripheral nervous system.
1 patient was diagnosed with syringomyelia, and 3 others were
hospitalized due to surgical abortion, surgery for inguinal hernia,
or pyelonephritis. In the placebo group, 1 patient was hospital-
ized due to a probable postpunctional headache.

HSV-2 Meningitis Valacyclovir Trial d CID 2012:54 (1 May) d 1309

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Figure 3. Time points of recurrent meningitis episodes during years 1 and 2 in the valacyclovir group (A) and placebo group (B ).

DISCUSSION patients with primary and recurrent HSV-2 meningitis. The

2-year study also allowed delineation of the natural course of
This large prospective, double-blind, randomized controlled trial symptoms, including a broad spectrum of neurological mor-
is the first to investigate the impact of antiviral suppression in bidity following HSV meningitis, which was hitherto lacking.

1310 d CID 2012:54 (1 May) d Aurelius et al

Table 4. Patients With Genital Recurrences During the Study
Period
No. (%) of Patients
Valacyclovir Group Placebo Group
Parameter (n 5 50) (n 5 51) P Value
Year 1
No. of genital
recurrences
0 30 (60) 24 (47) .01
1 14 (28) 8 (16)
$2 6 (12) 19 (37)
Year 2
No. of genital
recurrences
0 20 (40) 20 (39) .99
1 10 (20) 10 (20)
$2 20 (40) 20 (41)
We found no effect of antiviral suppression with 0.5 g of
valacyclovir twice daily on the risk of recurrence of meningitis.
The lack of a prohibiting effect was not due to any of the fol-
lowing confounding factors: age, sex, stratum, or previous her-
petic disease (clinically and serologically determined), which
were equally distributed in the 2 groups. The suppressive dose
might not have been adequate for preventing meningitis re-
currences in this particular cohort of patients, although it was
higher than normal for genital recurrences [14], being equal
to the one recommended for immunocompromised patients
[13, 24] and given twice daily, which has been found to be
beneficial compared with once-daily regimens [25]. The dosage
was, however, sufficient for decreasing recurrences of genital
herpes. The acyclovir concentrations were not measured in
the present study, but the levels achieved may have been sub-
optimal in protecting against further spread to the CNS. Pre-
vious studies have shown that even valacyclovir in the dosage
of 1 g 3 times daily given to patients with multiple sclerosis
resulted in only moderate concentrations in the CSF [26]. Re-
currences were actually found in a greater number of patients
during the first year in the actively treated group, but the dif-
ference was not statistically significant. The tendency of a higher
risk of meningitis might reflect the possibility that these in-
dividuals, although randomly allocated, happened to be more
prone to reactivation of meningitis.
During the second year after cessation of suppression, men-
ingitis episodes occurred earlier and significantly more often
in the group of patients previously treated with valacyclovir.
The occurrence of a cluster of meningitis episodes at the be-
ginning of the second year in the arm of patients with previous
antiviral suppression is suggestive of a rebound effect of cessa-
tion of active drug, which might indicate that the drug has had
some, but not a sufficient, suppressive effect during the first
year. In the valacyclovir group, the immune system was less
stimulated by mucocutaneous recurrences; such stimulation
might play a protective role against meningitis recurrences.
The cohort studied seems to be at high risk of symptom-
atic herpes recurrences in general, as 78% of patients had
recurrences (meningeal and/or genital) during the study
period. One reason for this might be the female predominance
in HSV-2 meningitis as demonstrated in this and previous
studies [4, 8, 10, 27]. Women have been reported to have
a higher degree of viremia in primary genital herpes [28]. With
their larger total genital surface to be infected, women might
receive a higher viral load that is forwarded to a larger number
of cells within the nerve ganglions. Furthermore, factors in-
volving the specific constitutive or adaptive immune defense may
contribute to the development of symptomatic infection and/or
recurrences in otherwise immunocompetent individuals [29].
A preexisting humoral immune response to HSV-1 is
a marker of protection against genital herpes [30]. The same
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seems true in HSV-2 meningitis according to previous observa-
tions of ours [31]. In this study, a low percentage of the patients
were previously infected with HSV-1, thereby lacking this
protection and at risk of meningitis when infected with HSV-2.
Considerable morbidity, comprising additional symptoms,
from the CNS, PNS, and ANS occurred with and without
a temporal relation to meningitis but did not differ between
the groups. Recurrent limited attacks of headache without
overt signs of meningitis and without CSF pleocytosis after
herpes meningitis have been reported elsewhere [3, 9, 10].
In analogy with reactivation patterns in genital recurrences
[32], a nervous system viral reactivation might not always
lead to migration of virus to the meninges with overt clinical
meningitis but might be the basis for attacks of headache as
well as transient radiating pain or skin sensitivity defects.
Furthermore, recurrent attacks of meningitis may not only be
followed by a sometimes protracted convalescent phase but
also induce secondary symptoms such as tension headache
and sleeping disturbances.
Our data do not provide support for antiviral suppression
at the dosage tested (ie, 0.5 g of valacyclovir twice daily) following
HSV-2 meningitis. However, it cannot be ruled out that tailored
suppressive treatment may be of benefit to some patients with
frequent recurrences. Further pathophysiological studies of the
complex mechanisms of reactivation of HSV-2 in the CNS are
desired as well as studies on suppressive antiviral treatment
to prohibit recurrent meningitis. While we await a safe and
effective HSV vaccine, appropriate use of antivirals is justified.
Notes
Author contributions. E. A. was the principal investigator and re-
sponsible for the design of the study in which M. G. was involved. The
study investigators, members of the HSV-2 Meningitis Study Group, were
HSV-2 Meningitis Valacyclovir Trial d CID 2012:54 (1 May) d 1311
responsible for patient recruitment and management. I. H. performed the
structured interviews. E. A., E. F. R., and C. J. R. were responsible for the
data acquisition. M. G. and E. F. R. were involved in the interpretation of
data. E. A. and M. S. were responsible for the final interpretation of the data
and writing of the paper. O. A. was responsible for the statistical analysis
and participated in its interpretation. L. G. and E. S. were responsible for
the microbiological analyses. All authors revised and approved the final
version of the manuscript.
Acknowledgments. We thank B. Skoldenberg for expert counseling
and support in the planning of the study, T. Bergstrom for constructive
discussions, and E. Lundberg and G. Ekberg at the Karolinska Pharmacy
for the pharmaceutical management.
Members of the HSV-2 Meningitis Study Group: E. Aurelius, E. Franzen-
Rohl, M. Glimaker, E. Gille, and I. Harviden, Department of Infectious
Diseases, Karolinska University Hospital, Solna, Stockholm; E. Skoog, and
L. Grillner, Department of Microbiology, Karolinska University Hospital,
Stockholm; M. Studahl, Department of Infectious Diseases, Sahlgrenska
University Hospital, Goteborg; C. Jorup-Ronstrom, Department of
Infectious Diseases, South Hospital, Stockholm; B.-M. Eriksson,
Department of Infectious Diseases, Uppsala University Hospital;
H. Ekwall, Department of Infectious Diseases, Sundsvall Hospital;
H. Eliasson, Department of Infectious Diseases, Orebro University
Hospital; B. Olofsson, Department of Infectious Diseases, Central
Hospital Vasteras; and E. Johansson, Department of Infectious
Diseases, Karlstad Hospital, Sweden.
Financial support. This work was supported as an academic study
by GlaxoSmithKline and by grants from Karolinska Intstitutet.
The trial was initiated and undertaken by the investigators. The funding
sources approved the design and protocol but were not involved in the
study design except for determination of the dosage of the study drug. The
funding sources had no involvement in the collection, analysis, or in-
terpretation of the data. GlaxoSmithKline was responsible for the supply
of the drug and placebo as well as for printing of the case report form.
The sponsor had no role in the interpretation of data, writing of the
manuscript, or decision to submit the data for publication.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
References
1. Jonsson MK, Levi M, Ruden U, Wahren B. Minimal change in HSV-2
seroreactivity: a cross-sectional Swedish population study. Scand J
Infect Dis 2006; 38:35765.
2. Berntsson M, Tunback P, Ellstrom A, Krantz I, Lowhagen GB. De-
creasing prevalence of herpes simplex virus-2 antibodies in selected
groups of women in Sweden. Acta Derm Venereol 2009; 89:6236.
3. Skoldenberg B, Jeansson S, Wolontis S. Herpes simplex virus type 2
and acute aseptic meningitis. Clinical features of cases with isolation of
herpes simplex virus from cerebrospinal fluids. Scand J Infect Dis 1975;
7:22732.
4. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex
virus infections: clinical manifestations, course, and complications.
Ann Intern Med 1983; 98:95872.
5. Sasadeusz JJ, Sacks SL. Herpes latency, meningitis, radiculomyelopathy
and disseminated infection. Genitourin Med 1994; 70:36977.
6. Schlesinger Y, Tebas P, Gaudreault-Keener M, Buller RS, Storch GA.
Herpes simplex virus type 2 meningitis in the absence of genital lesions:
improved recognition with use of the polymerase chain reaction. Clin
Infect Dis 1995; 20:8428.
7. Kupila L, Vuorinen T, Vainionpaa R, Hukkanen V, Marttila RJ,
Kotilainen P. Etiology of aspetic meningitis and encephalitis in an
adult population. Neurology 2006; 66:7580.
8. Franzen-Rohl E, Larsson K, Skoog E, et al. High diagnostic yield by
CSF-PCR for entero-and herpes simplex viruses and TBEV serology in
1312 d CID 2012:54 (1 May) d Aurelius et al
adults with acute aseptic meningitis in Stockholm. Scand J Infect Dis
2008; 40:91421.
9. Bergstrom T, Vahlne A, Alestig K, Jeansson S, Forsgren M, Lycke E.
Primary and recurrent herpes simplex virus type 2-induced meningitis.
J Infect Dis 1990; 162:32230.
10. Aurelius E, Forsgren M, Gille E, Skoldenberg B. Neurologic morbidity
after herpes simplex virus type 2 meningitis: a retrospective study of
40 patients. Scand J Infect Dis 2002; 34:27883.
11. Tedder DG, Ashley R, Tyler KL, Levin MJ. Herpes simplex virus in-
fection as a cause of benign recurrent lymphocytic meningitis. Ann
Intern Med 1994; 121:3348.
12. Kallio-Laine K, Seppanen M, Kautiainen H, et al. Recurrent lympho-
cytic meningitis positive for herpes simplex virus type 2. Emerg Infect
Dis 2009; 15:111922.
13. Martinez V, Caumes E, Chosidow O. Treatment to prevent recurrent
genital herpes. Curr Opin Infect Dis 2008; 21:428.
14. Reitano M, Tyring S, Lang W, et al. Valaciclovir for the suppression
of recurrent genital herpes simplex virus infection: a large-scale dose
range-finding study. J Infect Dis 1998; 178:60310.
15. Bergstrom T, Alestig K. Treatment of primary and recurrent herpes
simplex virus type 2 induced meningitis with acyclovir. Scand J Infect
Dis 1990; 22:23940.
16. Berger JR. Benign aseptic (Mollarets) meningitis after genitalis herpes.
Lancet 1991; 337:13601.
Downloaded from http://cid.oxfordjournals.org/ by guest on June 14, 2016
17. Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M. Rapid
diagnosis of herpes simplex encephalitis by nested polymerase chain
reaction assay of cerebrospinal fluid. Lancet 1991; 337:18992.
18. Aurelius E, Johansson B, Skoldenberg B, Forsgren M. Encephalitis in
immunocompetent patients due to herpes simplex virus type 1 or 2 as
determined by type-specific polymerase chain reaction and antibody
assays of cerebrospinal fluid. J Med Virol 1993; 39:17986.
19. Schmutzhard J, Merete Riedel H, Zweygberg Wirgart B, Grillner L.
Detection of herpes simplex virus type 1, herpes simplex virus type 2
and varicella-zoster virus in skin lesions. Comparison of real-time PCR,
nested PCR and virus isolation. J Clin Virol 2004; 29:1206.
20. Franzen-Rohl E, Tiveljung-Lindell A, Grillner L, Aurelius E. Increased
detection rate in diagnosis of herpes simplex virus type 2 meningitis
by real-time PCR using cerebrospinal fluid samples. J Clin Microbiol
2007; 45:251620.
21. Namvar L, Olofsson S, Bergstrom T, Lindh M. Detection and typing of
herpes simplex virus (HSV) in mucocutaneous samples by TaqMan
PCR targeting a gB segment homologous for HSV types 1 and 2. J Clin
Microbiol 2005; 43:205864.
22. Svennerholm B, Olofsson S, Jeansson S, Vahlne A, Lycke E. Herpes
simplex virus type-selective enzyme-linked immunosorbent assay with
Helix pomatia lectin-purified antigens. J Clin Microbiol 1984; 19:2359.
23. Ashley-Morrow R, Krantz E, Wald A. Time course of seroconversion
by HerpeSelect ELISA after acquisition of genital herpes simplex virus
type 1 (HSV-1) or HSV-2. Sex Transm Dis 2003; 30:3104.
24. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H.
Guidelines for prevention and treatment of opportunistic infections
in HIV-infected adults and adolescents: recommendations from CDC,
the National Institutes of Health, and the HIV Medicine Association of
the Infectious Diseases Society of America. MMWR Recomm Rep
2009; 58:613.
25. Leung DT, Sacks SL. Current recommendations for the treatment of
genital herpes. Drugs 2000; 60:132952.
26. Lycke J, Malmestrom C, Stahle L. Acyclovir levels in serum and cere-
brospinal fluid after oral administration of valacyclovir. Antimicrob
Agents Chemother 2003; 47:243841.
27. Read SJ, Kurtz JB. Laboratory diagnosis of common viral infections of
the central nervous system by using a single multiplex PCR screening
assay. J Clin Microbiol 1999; 37:13525.
28. Johnston C, Magaret A, Selke S, Remington M, Corey L, Wald A.
Herpes simplex viremia during primary genital infection. J Infect Dis
2008; 198:314.
29. Franzen-Rohl E, Schepis D, Lagrelius M, et al. Increased cell-mediated
immune responses in patients with recurrent herpes simplex virus
type 2 meningitis. Clin Vaccine Immunol 2001; 18:65560.
30. Langenberg AG, Corey L, Ashley RL, Leong WP, Straus SE. A pro-
spective study of new infections with herpes simplex virus type 1 and
type 2. Chiron HSV Vaccine Study Group. N Engl J Med 1999; 341:
14328.
31. Aurelius E. Neurological disease in herpes simplex virus type 2
meningitis (HSV-2) infection. In: Studahl M, Cinque P, Bergstrom T,
eds. Herpes simplex viruses. New York, NY: Taylor and Francis,
2006:31732.
32. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex
virus type 2 infection in asymptomatic seropositive persons. N Engl
J Med 2000; 342:84450.
Downloaded from http://cid.oxfordjournals.org/ by guest on June 14, 2016
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