While both vidarabine and acyclovir are efficacious therapies for neonatal HSV infection, acyclovir is the treatment of choice in spite of not being licensed for this disease because of established safety for other indications (77). Acyclovir is an acyclic analog of guanosine. Virusspecified thymidine kinase phosphorylates acyclovir to its monophosphate derivative, an event that does not occur to any significant extent in uninfected cells. Acyclovir is then phosphorylated by cellular enzymes to its triphosphate derivative. Acyclovir triphosphate binds viral DNA polymerase, acting as a DNA chain terminator (78, 79). At levels 30 times higher than those used clinically, acyclovir can be teratogenic in the in vitro limb-bud assay, but other animal studies indicate that acyclovir is not a significant teratogen (80). Acyclovir is not a significant mutagen in the Ames test but induces chromosomal mutagenic events in a manner similar to that of caffeine (80). Because of the occasional need for acyclovir therapy during pregnancy, as well as the likelihood of frequent first trimester exposures to drug before pregnancy is recognized, an ''Acyclovir in Pregnancy Registry" is established to gather data on all reported prenatal exposures to oral acyclovir. Though no significant risk to the mother or fetus has been documented, the total number of monitored pregnancies remains too small to detect any epidemiologic risk that is not overwhelming (81). The safety of acyclovir in pregnancy, therefore, has not been unequivocally established. Since acyclovir crosses the placenta and can concentrate in amniotic fluid, there is valid concern about the potential for renal toxicity in the fetus (82). Limited data suggest the safety of acyclovir administration near term for mother and fetus (83).
The efficacy of vidarabine therapy (15 mg per kg per day over 12 hr as a continuous infusion for 10–14 days) rests on the demonstration of a decrease in mortality from 75% to 40% in infants with either disseminated or isolated central nervous system disease, and ≈50% of survivors developed normally (76). Furthermore, therapy decreased progression of disease from localized skin, eye, and mouth involvement to either encephalitis or disseminated disease from 70% in placebo recipients to 32% in vidarabine-treated babies. A subsequent clinical trial at 30 mg per kg per day for 10–14 days decreased progression to 4%. Although there were no deaths among infants with skin, eye, and mouth infection, severe neurologic impairment was decreased from 30% to 10% with vidarabine therapy (74).
Subsequent clinical trials have compared vidarabine to acyclovir for neonatal HSV infections. The NIAID CASG compared outcome for 202 babies with neonatal HSV infection who were randomly treated with