Acyclovir suppressive therapy after treatment of neonatal herpes

Neonatal infection with herpes simplex virus (HSV) presents in various ways with varying outcomes. It may be fairly benign with skin, eye and mouth involvement only, no risk of death, and a very low risk of neurological impairment although there may be skin recurrences. Disseminated disease, however, is associated with a 30% mortality and a 20% risk of neurological sequelae among survivors. Central nervous system (CNS) infection is associated with a 6% mortality but a 70% risk of permanent neurological sequelae. The virus may become latent in sensory ganglia with later reactivation and it has been suggested that there may be subclinical reactivation within the brain. The value of 6 months of suppressive oral therapy with acyclovir, after initial parenteral treatment, has been assessed in two parallel US multicentre trials reported together (David W Kimberlin and colleagues. New Engl J Med 2011;365:1284–72; see also Editorial, ibid: 1338–9). The trials included 74 neonates with HSV infection, 45 with CNS involvement (with or without disseminated disease) and 29 with only skin, eye and mouth involvement. Randomisation was to oral acyclovir (300 mg/m² of body surface area) or placebo, three times daily for 6 months after initial parenteral acyclovir for 14 days (skin, eye and mouth disease) or 21 days (CNS disease). The trials were affected by slow recruitment (74 infants in 11 years), attrition and incomplete data.

Infants were withdrawn from the studies if they had two cutaneous recurrences. The time to withdrawal for this reason was significantly longer with acyclovir treatment rather than placebo in the CNS disease study but not in the skin, eye and mouth disease study. Among the 45 infants in the CNS disease study, three had a recurrence of CNS disease within 12 months of enrolment (one assigned to acyclovir and two to placebo). Mental development at 12 months of age was assessed in 28 of the 45 infants using the Mental Development Index of the Bayley Scales of Infant Development, with mean scores of 88.24 (acyclovir) versus 68.12 (placebo), a significant difference (p=0.046). There was a non-significant trend towards more neutropenia with acyclovir suppression therapy.

Six months of oral suppressive treatment with acyclovir after initial parenteral acyclovir reduces the risk of skin recurrences in all children with neonatal HSV disease and may improve neurodevelopmental outcomes in those with CNS disease. The editorialist suggests treating all children with neonatal herpes in this way.