Neonatal herpes simplex virus (HSV) occurs in 1 in 3000 births in the United States. It most often results from exposure at delivery and can manifest as: 1) disseminated disease (25%); 2) central nervous system (CNS, 30%) disease; or 3) skin, eye, mouth (SEM, 45%) disease. Untreated neonatal HSV carries a mortality rate of 60–80%.
Institution of high-dose acyclovir therapy (60 mg/kg/day) for 21 days has reduced neonatal HSV mortality from 57% to 31% for disseminated disease and from 20% to 6–14% for CNS disease. In spite of this dramatic reduction, however, morbidity remains high. Survivors often suffer from HSV cutaneous recurrences (41%), and infants with disseminated or CNS disease are at high risk of neurodevelopmental impairment. Long-term complications can include microcephaly, hydrocephalus, encephalomalacia, spasticity, paresis, blindness, deafness, or seizures.
Despite the common use of high-dose acyclovir in infants admitted to the neonatal intensive care unit, safety, efficacy and pharmacokinetic (PK) studies to define optimal dosing are lacking. The purpose of this PTN study is to characterize safety of high-dose acyclovir given to infants per standard of care. Because high-dose acyclovir is widely used in clinical practice, a randomized controlled trial of high-dose vs. standard-dose acyclovir therapy is untenable. Therefore, an externally controlled trial design was chosen to assess acyclovir efficacy.
In an earlier PTN study of acyclovir pharmacokinetics (NCT00942084), target acyclovir systemic exposures were simulated with the following dosing regimen:
- 20 mg/kg every 12 hours in infants <30 weeks postmenstrual age (PMA)
- 20 mg/kg every 8 hours in infants 30 – <36 weeks PMA
- 20 mg/kg every 6 hours in infants 36–41 weeks PMA
Acyclovir systemic exposures in infants were similar to observed adult exposures, and the surrogate pharmacodynamic (PD) target (steady-state concentrations for 50% of dosing interval ≥3 mg/L) was achieved in 91% of infants ≤41 weeks PMA.
To provide the FDA with additional safety data to support labeling of high-dose acyclovir for the treatment of neonatal HSV, we will assess the safety of high-dose acyclovir in infants with HSV via a review of the Pediatrix Medical Group database and a retrospective chart review of infants with HSV treated at 3 medical centers. We also will conduct a secondary data analysis comparing clinical outcomes in infants enrolled in an earlier trial that used a high-dose regimen against those of infants enrolled in another study that used a standard-dose regimen. Acyclovir exposures in these 2 trials will be characterized through PK/PD simulations based on a PK model generated from the prior PTN PK study of acyclovir.