Acyclovir in HSV Meningitis
Critical Distinction: Meningitis vs. Encephalitis
For immunocompetent adults with confirmed HSV meningitis (without encephalitic features), supportive care alone is recommended—acyclovir is not indicated. 1
The UK Joint Specialist Societies guideline explicitly states there is no evidence supporting acyclovir or valacyclovir for herpes meningitis in immunocompetent patients, as these patients recover completely without neurologic sequelae. 1 This contrasts sharply with US practice patterns, where many clinicians treat despite acknowledging the lack of efficacy data. 2
However, immediate escalation to full IV acyclovir therapy is mandatory if any encephalitic features develop: personality changes, behavioral alterations, cognitive impairment, confusion beyond post-ictal state, or altered level of consciousness. 1, 3, 4
When to Start Acyclovir: The Encephalitis Threshold
Immediate Initiation Required When:
- Any encephalitic signs present (altered mental status, confusion, behavioral changes, focal neurological deficits, seizures) 1, 3, 4
- Clinical deterioration or severe illness even if initial CSF/imaging normal 3, 4
- Cannot distinguish meningitis from encephalitis clinically 3, 4
Start within 6 hours of admission when suspicion exists—do not wait for PCR confirmation. 3, 4 Delays beyond 48 hours significantly worsen outcomes. 3, 4 Untreated HSV encephalitis carries 70% mortality versus 20-30% with treatment. 5, 3
Do NOT Start Acyclovir When:
- Pure meningitis syndrome in immunocompetent adults: headache, photophobia, fever, meningismus, normal mental status 1, 6
- Simple febrile seizure without encephalitic features 3
Dosing Regimens
Standard Adult Dosing (Normal Renal Function):
10 mg/kg IV every 8 hours for 14-21 days 5, 4
- Infuse over 1 hour to prevent crystal nephropathy 5
- Maintain adequate hydration throughout treatment 5, 4
Pediatric Dosing:
- Neonates (0-3 months): 20 mg/kg IV every 8 hours for 21 days 5, 4
- Children 3 months-12 years: 500 mg/m² IV every 8 hours (≈20 mg/kg) for minimum 21 days 5, 3, 4
- Adolescents ≥12 years: 10 mg/kg IV every 8 hours for 14-21 days 5, 4
Critical pitfall: Shorter courses (<21 days) in children 3 months-12 years result in 26-29% relapse rates. 5, 3, 4
Renal Dose Adjustments
Acyclovir is 62-91% renally excreted—dose adjustment is mandatory in renal impairment. 5, 4
IV Acyclovir Renal Dosing:
| Creatinine Clearance | Recommended Dose |
|---|---|
| >50 mL/min | 10 mg/kg IV every 8 hours (no adjustment) |
| 25-50 mL/min | 10 mg/kg IV every 12 hours |
| 10-24 mL/min | 10 mg/kg IV every 24 hours |
| <10 mL/min | 5 mg/kg IV every 24 hours |
| Hemodialysis | 5 mg/kg IV every 24 hours; dose after dialysis |
Monitoring Requirements:
- Monitor renal function (creatinine, urine output) regularly throughout treatment 5, 4
- Nephrotoxicity occurs in up to 20% of patients after approximately 4 days of therapy, presenting as crystalluria, rising creatinine, or obstructive nephropathy 5, 3, 4
- Maintain aggressive hydration to prevent crystal precipitation 5, 4
Duration and Treatment Monitoring
Standard Duration:
- Adults: 14-21 days IV acyclovir 5, 4
- Children 3 months-12 years: Minimum 21 days before repeat LP 5, 3, 4
End-of-Treatment Assessment:
Obtain repeat lumbar puncture with HSV PCR at 14-21 days: 5, 4
- If PCR negative: Discontinue therapy 4
- If PCR positive: Continue IV acyclovir and repeat PCR weekly until negative 5, 4
Important caveat: CSF PCR may remain positive for 7-10 days after starting therapy—this does not indicate treatment failure. 5, 4
Alternatives When Acyclovir is Contraindicated
For Acyclovir-Resistant HSV (Immunocompromised Patients):
Foscarnet 40 mg/kg IV every 8 hours (or 60 mg/kg IV every 12 hours) 5
- Suspect resistance when persistent lesions occur despite acyclovir therapy 5
- Primarily seen in immunocompromised hosts 5
Oral Valacyclovir:
Valacyclovir is NOT appropriate for acute HSV meningitis or encephalitis as primary therapy—it does not achieve therapeutic CSF concentrations. 5, 4
Exception: After 10-14 days of IV acyclovir in HSV meningitis (not encephalitis), may switch to valacyclovir 1 g PO three times daily to complete 14 days total when IV access is problematic. 5
Special Populations
Immunocompromised Patients:
Antiviral therapy significantly improves neurologic outcomes in immunocompromised patients with HSV meningitis (P<0.05), unlike immunocompetent patients who show no benefit. 7
- Consider prolonged courses beyond 21 days if CSF PCR remains positive 5
- Higher doses may be required 5
- Monitor closely for acyclovir resistance 5
Recurrent HSV-2 Meningitis (Mollaret's Meningitis):
Prophylactic valacyclovir 500 mg twice daily is NOT recommended for preventing recurrences. 1 A placebo-controlled RCT showed no reduction in recurrence rates and higher relapse rates after discontinuation. 1
Critical Pitfalls to Avoid
Never use oral acyclovir for acute CNS HSV infections—CSF concentrations are inadequate. 5, 4
Do not delay treatment for lumbar puncture in severely ill patients—HSV PCR remains detectable for 7-10 days after starting therapy. 5, 4
Do not stop therapy prematurely—10-day regimens led to 26-29% relapse rates in children. 5, 3, 4
Do not forget renal dose adjustments—failure to adjust markedly increases nephrotoxicity risk. 5, 4
Do not treat pure meningitis in immunocompetent adults—risks of drug toxicity and prolonged hospitalization outweigh unproven benefits. 1
Do not miss the transition to encephalitis—any personality change, confusion, or altered consciousness mandates immediate full-dose IV acyclovir. 1, 3
Guideline Divergence: UK vs. US Practice
There is clear divergence between UK and US recommendations. The UK Joint Specialist Societies explicitly recommend no antiviral treatment for immunocompetent HSV meningitis due to lack of evidence and excellent outcomes with supportive care alone. 1 US-based guidance often recommends treatment despite acknowledging the same evidence gap. 2 A 2022 survey showed substantial variation in practice, with 61% using IV-then-oral regimens and 19% using oral monotherapy. 2
In real-world practice, err on the side of caution: If you cannot confidently exclude encephalitis or the patient is immunocompromised, treat with IV acyclovir. 7 For clearly isolated meningitis in immunocompetent adults, supportive care is appropriate. 1, 7