Oral acyclovir suppression and neurodevelopment after neonatal herpes

Abstract

Background: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease.

Methods: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy.

Results: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09).

Conclusions: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Figure 1. Enrollment, Randomization, and Follow-up in the Two Parallel Studies

The CASG 103 study (Panel A) included neonates who had HSV disease with central nervous system (CNS) involvement. The yellow boxes represent the 15 infants with a Bayley Scales of Infant Development mental-development assessment at 12 months who received active suppression for 6 months, either with the randomly assigned oral acyclovir for the entire 6-month period (10 infants) or with the randomly assigned oral acyclovir for part of the time and open-label oral acyclovir for part of the time (5 infants); the blue boxes represent the 6 infants with a mental-development assessment at 12 months who received acyclovir suppression for only part of the 6-month treatment period; and the pink boxes represent the 7 infants with a mental-development assessment at 12 months who received no acyclovir suppression at any time during the study. The CASG 104 study (Panel B) included neonates who had HSV disease with skin, eye, and mouth involvement.

Figure 2. Time to Discontinuation of Study Drug

Per protocol, the study drug was discontinued if an infant had two cutaneous recurrences. The time to discontinuation of the study drug is shown among subjects in the CASG 103 study (Panel A), which included neonates with HSV disease with central nervous system (CNS) involvement, among subjects in the CASG 104 study (Panel B), which included neonates with HSV disease with skin, eye, and mouth involvement only, and among the subjects in the two groups combined (Panel C).