Question

• In infants ages 0 to 2 months of age being treated for presumed meningoencephalitis, do the risks of IV acyclovir outweigh the risks for complications of severe HSV infections?

Clinical Bottom Lines

1. Acyclovir prescribed at 60 mg/kg/day for 21days appears more effective in the treatment of disseminated and CNS herpes simplex infections than does 30 mg/kg/day for 10days (the relative effects of length of treatment and dose are unknown).
2. The side effects of high dose acyclovir are likely limited to neutropenia, which resolves with moderation or cessation of therapy. Other side effects, including liver/kidney dysfunction and thrombocytopenia, are likely related to some combination of disease severity and acyclovir, but they usually resolve if monitored and treated appropriately.

Summary of Key Evidence

1. Prospective, non-randomized, non-blinded, multi-center clinical trial using historical controls. Compared sequentially accrued patients with documented HSV infections (either skin/eye/mucocutaneous (SEM), CNS, or disseminated) treated with intermediate dose acyclovir (45mg/kg/day for 21days) or high dose (60mg/kg/day for 21days) to historical controls who received standard dose (30mg/kg/day for 10days) therapy.¹
2. Patients were accrued over an 8 year period (1989-1997) and compared to controls enrolled in a previous trial from 1981-1988.
3. The intermediate treatment group had 16 patients, which was too small to adequately assess for meaningful differences between intermediate and high dosing.
4. The 72 patients treated with high dose therapy were compared to 107 standard dose controls.
5. Overall, patients treated with high dose acyclovir had substantially improved mortality compared to patients who had previously received standard dosing.
6. Patients with disseminated HSV had improved mortality (31% compared to 61%, NNT=3) when treated with high dose acyclovir compared with standard dose treatment.
7. Elevations in AST, bilirubin, creatinine, and thrombocytopenia were noted in patients with disseminated disease treated with high dose acyclovir but were not compared to controls.
8. Neutropenia was found in both patients with disseminated disease and localized CNS disease treated with high dose acyclovir. The neutropenia resolved with moderation of therapy.

Additional Comments

• The study was limited by small sample size, variations in group characteristics, and improvements in supportive care over the study time periods.
• The study was unable to demonstrate differences in subgroup mortality and long term follow-up morbidity because of the small sample size and significant (undefined) lost to follow-up of enrolled patients.
• Improved mortality with high dose therapy was dramatic and at a minimal cost of side effects. The side effects of standard dose acyclovir, however, were not compared to those patients who received high dose therapy in the study.
• Mortality and long term sequelae of neonatal HSV infections are severe.

Citation

1. Kimberlin DW, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001;108:230-238.

CAT Author: Brian Benneyworth, MD

CAT Appraisers: James Gurney, PhD

Date appraised: January 24, 2007