What is the recommended treatment (drug, dose, route, and duration) for herpes simplex virus type 2 meningitis, including adjustments for renal impairment or immunocompromised patients?

Treatment of HSV-2 Meningitis

For immunocompetent adults with HSV-2 meningitis, supportive care with analgesia and fluids is the primary recommendation, as these patients typically recover completely without neurologic sequelae; however, if any features of encephalitis develop (personality changes, altered consciousness, cognitive impairment), immediately initiate IV acyclovir 10 mg/kg every 8 hours for 14-21 days. 1

Primary Treatment Approach by Patient Population

Immunocompetent Patients

The UK Joint Specialist Societies guideline explicitly states that treatment should be supportive with analgesia and fluids, and if antibiotics have been started, they should be stopped once viral diagnosis is confirmed. 1

• Observational studies support this conservative approach: among 27 immunocompetent patient-episodes, no neurologic sequelae occurred regardless of antiviral use (P = 1.0), suggesting symptomatic treatment alone is appropriate. 2

• If antiviral therapy is initiated despite lack of evidence for efficacy, the most common regimen used in practice is IV acyclovir until fever and headache resolve, then switch to oral valacyclovir 1 g three times daily to complete 14 days total. 3, 4

• Real-world practice shows highly variable treatment ranging from no antivirals (4/23 patients, 17%) to 14-21 days IV acyclovir, with most receiving 1-7 days IV followed by 7-21 days oral therapy. 5

Immunocompromised Patients

Antiviral therapy significantly improves neurologic outcomes in immunocompromised patients (P < 0.05) and is therefore mandatory in this population. 2

• Administer IV acyclovir 10 mg/kg every 8 hours for 14-21 days. 3, 6

• For HIV-infected patients with severe HSV disease, use acyclovir 5 mg/kg IV every 8 hours. 3

• If acyclovir resistance is suspected (persistent lesions despite therapy), switch to foscarnet 40 mg/kg IV every 8 hours. 3

• Immunocompromised patients may require prolonged courses beyond 21 days if CSF PCR remains positive. 3

Critical Distinction: Meningitis vs. Encephalitis

You must immediately escalate to full encephalitis treatment if ANY of the following develop: personality changes, behavioral changes, cognitive impairment, or altered level of consciousness. 1

• HSV encephalitis has 70% mortality untreated versus 20-30% with acyclovir, making this distinction life-saving. 3

• For confirmed or suspected encephalitis, give IV acyclovir 10 mg/kg every 8 hours for the full 14-21 days—do not use oral therapy or shortened courses. 3, 4

• Start acyclovir immediately when encephalitis is suspected, even before lumbar puncture, especially in deteriorating patients. 3

Dosing Specifications

Standard Adult Dosing (Normal Renal Function)

• IV acyclovir: 10 mg/kg every 8 hours 3, 6
• Oral valacyclovir (if used): 1 g three times daily 3

Pediatric Dosing

• Neonates (0-3 months): 20 mg/kg IV every 8 hours for 21 days (higher dose due to worse prognosis) 3, 6
• Children 3 months-12 years: 500 mg/m² (≈20 mg/kg) IV every 8 hours for minimum 21 days 3, 6
• Adolescents ≥12 years: 10 mg/kg IV every 8 hours 3

Renal Dose Adjustments

Acyclovir is 62-91% renally excreted and MUST be dose-adjusted in renal impairment. 3, 6

Creatinine Clearance	IV Acyclovir Dose
>50 mL/min	10 mg/kg every 8 hours (no adjustment)
25-50 mL/min	10 mg/kg every 12 hours
10-24 mL/min	10 mg/kg every 24 hours
<10 mL/min	5 mg/kg every 24 hours
Hemodialysis	5 mg/kg every 24 hours; dose after dialysis

3, 6

Duration of Therapy

First Episode in Immunocompetent Patients (if treated)

• IV acyclovir until fever and headache resolve, then valacyclovir 1 g TID to complete 14 days total. 3
• Survey data shows median total duration of 7 days (IQR 7-10 days) in current practice. 7

Encephalitis or Immunocompromised Patients

• Full 14-21 days of IV acyclovir is mandatory. 3, 4
• Obtain repeat CSF PCR at 14-21 days; if still positive, continue IV therapy and repeat PCR weekly until negative. 3

Monitoring Requirements

Monitor renal function closely throughout treatment, as nephrotoxicity occurs in up to 20% of patients after approximately 4 days of IV therapy. 3, 6

• Maintain adequate hydration throughout treatment to prevent crystalluria and obstructive nephropathy. 3, 4

• CSF PCR remains positive for 7-10 days after starting acyclovir, so delayed lumbar puncture can still confirm diagnosis. 3, 4

• Reassess daily for encephalitis features (altered mental status, focal deficits), which mandate full 14-21 day IV course. 4

Critical Pitfalls to Avoid

Never use oral acyclovir for acute HSV meningitis requiring hospitalization—it does not achieve therapeutic CSF concentrations. 3, 4

• Do not stop treatment prematurely: original 10-day regimens led to relapse rates of 26-29% in children. 3

• Do not assume genital herpes history or current genital lesions will be present: only 8.7% had prior genital herpes history and 4.3% had lesions at presentation. 5

• Do not assume this is a first episode: 30.4% of patients reported previous episodes of meningitis. 5

Recurrent HSV-2 Meningitis (Mollaret's Meningitis)

Prophylactic valacyclovir 500 mg twice daily is NOT recommended for preventing recurrent HSV-2 meningitis. 1

• A placebo-controlled trial showed valacyclovir did not reduce recurrences and patients had greater relapse rates once the trial stopped. 1

• The lack of efficacy was attributed to low CSF drug levels, though higher doses have not been studied. 1

• For recurrent established HSV-2 meningitis, oral antiviral therapy may be used after initial IV course. 3

Adverse Effects

Reversible nephrotoxicity is the primary concern, occurring in up to 20% of patients after 4 days of IV therapy. 3, 6

• Rare adverse events include hepatitis, bone marrow suppression, and encephalopathy. 3

• Adequate hydration and renal function monitoring mitigate these risks. 3, 4

Evidence Quality and Divergence

There is a stark divergence between UK and US guidance: the UK guideline states there is no evidence supporting acyclovir for HSV meningitis and recommends supportive care only 1, while US-based sources recommend treatment despite acknowledging optimal therapies have not been studied. 4

• The observational data strongly support the UK position for immunocompetent patients: no neurologic sequelae occurred regardless of treatment. 2

• However, the risk-benefit ratio favors treatment when encephalitis cannot be excluded, as HSV encephalitis has 70% mortality untreated. 3, 4

• Current practice remains highly variable, with 61% of surveyed ID specialists using IV acyclovir followed by oral valacyclovir. 7