Long-term Valacyclovir Suppressive Treatment After Herpes Simplex Virus Type 2 Meningitis: A Double-Blind, Randomized Controlled Trial

Design

Prospective, randomized, double-blind, placebo-controlled, multicenter trial

N= 101

Objective

To determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications

Study Groups

Valacyclovir (n= 50)

Placebo (n= 51)

Inclusion Criteria

Consecutive patients (> 18 years of age) with symptoms of viral meningitis and cerebrospinal fluid (CSF) pleocytosis levels > 5 x 10⁶ cells/L with a herpes simplex virus type 2 (HSV-2) infection etiology (detection of HSV-2 DNA in the CSF by polymerase chain reaction [PCR], preceding or concurrent virologically verified HSV-2 lesions in the genital or lumbosacral region or history of previous aseptic meningitis of herpetic or unknown origin and positive HSV-2 serology in the acute phase serum sample)

Exclusion Criteria

Immunosuppression, human immunodeficiency virus (HIV) infection, pregnancy, no protection against pregnancy in female sexually active patients, hepatic impairment, impaired renal function, intolerance to acyclovir or valacyclovir, probenecid treatment, systemic antiviral therapy with an antiherpetic effect or immunomodulatory therapy, malabsorption, and other ongoing investigational drug treatment

Methods

Acute phase treatment of HSV meningitis with 1 g of valacyclovir TID for 1 week was initiated at admission or as soon as an HSV-2 infection etiology was confirmed clinically and/or virologically for one week. Participants were then randomized to receive valacyclovir (0.5 mg BID orally) or placebo for 1 year initiated 0-3 days after completion of the acute phase treatment. 

In case of nausea or vomiting, the recurrence of meningitis was treated openly with 1 g valacyclovir TID orally for 1 week or 5 mg/kg acyclovir TID intravenously. The randomized study treatment was temporarily withdrawn. In cases of severe genital herpes, 0.5 g of valacyclovir BID was given for 3-5 days. Verified recurrent meningitis was defined as clinical symptoms of meningitis and CSF pleocytosis levels of > 5 x 10⁶ cells/L. Probable recurrent meningitis was defined as clinical acute meningitis (headache, nausea, vomiting, hypersensitivity to light and noise, neck stiffness) without lumbar puncture performed or lack of pleocytosis and no reasonable cause of symptoms other than HSV infection.

Duration

Enrollment: November 2000 to January 2005

Acute phase treatment: 1 week

Randomized treatment: 1 year

Follow-up: 2 years

Outcome Measures

Recurrence of HSV meningitis (verified and probable)

Baseline Characteristics

Valacyclovir (n= 50)

Median age, years

Female

History

Genital herpes

Meningitis

21 (43%)

25 (51%)

25 (49%)

24 (47%)

HSV infection

HSV-1 and HSV-2 positive

HSV-1 and HSV-2 negative

HSV-1 negative and HSV-2 positive

7 (15%)

6 (13%)

35 (73%)

4 (9%)

12 (27%)

29 (64%)

Results

Endpoint

Placebo (n= 51)

Hazard ratio (95% confidence interval)

p-value

Recurrence of HSV meningitis (suspected + verified)

Year 1

Year 2

14 (29%)

12 (24%)

8 (16%)

4 (8%)

1.86 (0.78 to 4.43)

3.29 (10.06 to 10.21)

0.12

0.03

Eighteen patients discontinued the medication, 5 in the valacyclovir group and 13 in the placebo group.

Adverse Events

Common Adverse Events: total (30% vs. 17.6%; p= 0.14); exanthema, profound sweating (one in each group), loose stools, angioedema, and palpitations (undisclosed incidences) 

Serious Adverse Events: none deemed to be related to study medication; 5 in valacyclovir group (serious kidney disease, syringomyelia, hospitalization due to surgical abortion, surgery for inguinal hernia, or pyelonephritis) and 1 in placebo group (hospitalization due to probable postpunctional headache)

Percentage that Discontinued due to Adverse Events: A total of 5 patients discontinued due to adverse events (undisclosed number for each group).

Study Author 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 the active drug could be interpreted as a rebound phenomenon.

InpharmD Researcher Critique

Herpes simplex virus 2 meningitis: a retrospective cohort study

Design

Single-center, retrospective, observational cohort study

N= 28 (33 episodes of meningitis)

Objective

To report the clinical features, cerebrospinal fluid findings, treatment approaches, neurological outcomes, and long-term symptomatic recurrence in patients with herpes simplex virus type 2 (HSV-2) meningitis

Study Groups

Patients with an initial episode (n= 18)

Patients with subsequent episodes (n= 15)

Inclusion Criteria

Patients diagnosed with meningitis by the treating physician and detection of HSV-2 in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) 

Exclusion Criteria

Cases with encephalitis due to HSV-2

Methods

Electronic medical records at a single clinic were retrospectively reviewed to identify eligible patients and collect clinically relevant information, including the history of herpes infections, neurological signs and symptoms, and the number of symptomatic episodes. 

Duration

From January 1, 1995, to December 31, 2008

Outcome Measures

Treatment, prognosis, and recurrence 

Baseline Characteristics

Patients presenting with
an initial episode (n= 18)

Patients presenting with
subsequent episodes (n= 15)

Age, years

Female

History of genital herpes

Clinical presentation of meningitis

Headache

Meningismus

Photophobia

Phonophobia

Nausea and/or vomiting

Fever documented in hospital

100%

22%

33%

16%

33%

6%

100%

71%

64%

0

29%

6%

CSF values

Glucose, mg/dL

Protein, mg/dL

Cells, cells/μL

55 ± 14

163 ± 57

494 ± 460

52 ± 9

125 ± 44

504 ± 412 

Results

Endpoint

Patients with an initial episode (n= 18)

Patients with subsequent episodes (n= 15)

Treatment 

Intravenous acyclovir 

Oral valacyclovir or acyclovir

Prophylaxis 

94%

72%

0%

100%

79%

21%

Prognosis

Recurrence 

Long-term sequelae

9% (not available [NA]= 7)

18% (NA= 7)

36% (NA= 3)

0 (NA= 3)

Most patients were transitioned to oral valacyclovir treatment following intravenous acyclovir. One patient was started on prophylactic valacyclovir after the initial episode, and two patients were started after their second episode. The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily (total daily dose range 500 to 2,000 mg). The most commonly prescribed regimen of oral valacyclovir was 500 mg three times daily following both first and subsequent meningitic episodes.

Three patients developed recurrent episodes during the study period, one with four episodes not taking antiherpetic prophylaxis, one had two episodes taking a prophylactic regimen for 7 months, and the last one had two episodes initiating prophylaxis until the end of the observation period. 

Adverse Events

Study Author Conclusions

It is reasonable to question whether the use of antiviral therapy is warranted in these patients. Questions on treatment and duration would be best answered through a prospective study with randomization. However, given the low number of identified cases of HSV-2 meningitis and the unpredictable nature of recurrence of meningitic episodes, the ideal clinical study of treatment would require several centers and a long recruitment and observation period. 

InpharmD Researcher Critique

While the study described and categorized antiviral treatments and prophylaxis for acute HSV-2 meningitis, it did not address the long-term efficacy and safety of the prophylactic regimen, given the descriptive and retrospective design. The ideal population that would benefit the most from antiviral prophylaxis requires further evaluation. 

Herpes simplex virus type 2 recurrent meningitis (Mollaret's meningitis): a consideration for the recurrent pathogenesis

Design

Case presentation

A 44-year-old female with unremarkable past and familial histories was diagnosed with genital herpes after noticing vesicles and pain in the genital region. Several days later, she had a severe headache, a fever of 39°C, and vomiting, after which she was admitted to the hospital. Her vitals were normal on admission, but she was noted to have nuchal stiffness and lower back pain without Kernig's sign or abnormalities in her extremities. The patient's cerebrospinal fluid (CSF) contained 433/mm³ cells, 144 mg/dL protein, and 40 mg/dL glucose; blood glucose was 79 mg/dL. After identification of herpes simplex virus (HSV) type 2 infection through polymerase chain reaction (PCR), the patient was given a 7-day course of intravenous acyclovir 750 mg/day. Genital herpes and meningeal signs were resolved within a few days. Pleocytosis decreased to 13/mm³ cells one week later, and the patient was eventually discharged.

The patient then experienced genital herpes and headache with vomiting approximately one month and two months following discharge. Her CSF showed mild pleocytosis in the latter episode. In the second episode, the patient was initiated on acyclovir 400 mg/day periodically given as continuous suppressive therapy. However, she experienced a third attack of meningitis without skin eruption a couple of months following her second episode. On this admission, HSV type 2 by HSV PCR and type-specific antibody analysis were confirmed in the patient's CSF. After acyclovir treatment, meningitis resolved within a few days. After discharge, the patient initiated herself on perioral acyclovir treatment as soon as she noticed genital herpes or a headache indicative of meningeal signs. Several months after the third attack, her lymphocyte response to phytohemagglutinin and concanavalin A had normalized.

Study Author Conclusions

The present patient experienced a recurrence very soon after the initial onset. Recurrence frequently occurs within 1 year after onset. Suppressive therapy for genital herpes is becoming popular. Prevention therapy may be necessary in the cases of frequent recurrent meningitis as well as recurrent genital herpes. For the present case, long-term suppressive and patient-oriented therapies were conducted. However, these trials were limited to a few cases. Further cases are needed to evaluate whether these therapies can prevent the recurrence of meningitis.