To determine whether active treatment with (val)acyclovir is superior for treatment of viral meningitis compared with placebo assessed by numbers meeting a primary, objective endpoint at 7 days after randomisation

Inclusion Criteria:

• Adults ≥18 years of age admitted on suspicion of viral meningitis defined as:

  1. A clinical presentation consistent with viral meningitis (e.g. headache, nuchal rigidity, photophobia, or fever) AND
  2. Cerebrospinal fluid (CSF) pleocytosis (>4 leukocytes x 106/L) AND
  3. HSV-2 positive by PCR of the CSF
  4. Glasgow Coma Scale score of 15 AND
  5. Ability to absorb oral medications

Exclusion Criteria:

• Patients fulfilling any of the following criteria will be excluded:

  1. Encephalitis as defined by the International Encephalitis Consortium if diagnosed during standard care (see Glossary)20
  2. Transverse myelitis as defined by the Transverse Myelitis Consortium Working Group if diagnosed during standard care (see Glossary)21
  3. Severe immuno-compromise defined as an ongoing need for biological- or chemotherapy (e.g. natalizumab), prednisolone >20 mg/day for ≥14 days, uncontrolled HIV/AIDS (see glossary), haematological malignancies, and organ transplant recipients14,18,22
  4. Moderate to severe concomitant genital herpes requiring systemic aciclovir
  5. Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women)
  6. Hepatic impairment (aspartate aminotransferase or alanine aminotransferase levels >5 times the upper limit of normal)
  7. Impaired renal function (estimated glomerular filtration rate <25 mL/min)
  8. Intolerance to (val)aciclovir
  9. Probenecid treatment
  10. Systemic antiviral therapy with an antiherpetic effect for >24 hours
  11. Previous enrolment into this trial

Data will be deposited at Mendeley Data (https://data.mendeley.com/).

Beginning six months and ending three years after publication, an anonymized dataset can be shared.

Qualified researchers who provide a methodologically sound proposal.

We will use a centralised internet-based computer-generated randomisation schedule prepared and overseen by an experienced statistician. Patients will be randomised in a 1:1 ratio in permuted blocks of two to six and stratified by country, sex, and adjunctive dexamethasone treatment (yes/no).