This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since the introduction of antiviral therapy for neonatal Herpes simplex virus (HSV) (type 1 and type 2) infection, dramatic improvements in morbidity and mortality have been realized. Improvements have been seen in disease limited to the skin, eye, and mucous membranes (SEM), disseminated disease, and central nervous system (CNS) disease. While mortality from SEM disease is essentially non-existent, neurologic morbidity can result from this form of HSV infection. Neurologic impairment occurs in almost 40% of untreated SEM infected infants even without clinically apparent central nervous system involvement. This is likely the consequence of insidious infection of the central nervous system during the neonatal period with undetected clinical reactivation later in life. Neurologic morbidity following SEM disease can be decreased with intravenous antiviral therapy, such that over 90% of such infants develops normally at one year of life. The impairment, which appears by one year of age, is not subtle, consisting of spasticity, microcephaly, and chorioretinitis. Even with the administration of antiviral therapy there is a direct correlation between the frequency of cutaneous recurrences following antiviral therapy and development of neurologic impairment among infants with SEM disease. Specifically, during the first year of life, the likelihood of developing normally is only 64% if there are three or more recurrences as opposed to no impairment with fewer recurrences. This, despite rigorous follow-up both clinically and frequent findings of normal cerebrospinal fluid (CSF) examinations), would imply the possibility of viral reactivation at sites other than the skin. The occurrence of neurologic sequelae in patients with disease localized to the SEM despite normal CSF findings and prompt treatment illustrates the inadequacies of current therapies. To try to further improve the neurologic outcome of infants with SEM disease, a pilot study of oral acyclovir at 300 mg/m2/dose given either twice daily or three times daily following 10 days of intravenous acyclovir was done. Infants remained on oral acyclovir for 6 months and were neurologically evaluated for outcome at 12 months of age. Eighteen infants were studied. Thirteen (81%) of the 16 who received acyclovir three times a day had no cutaneous recurrences (54% of untreated historical controls). Two (12%) of the 16 had one or two recurrences and one was lost to follow-up. Thirteen of the 18 patients were available for evaluation at one year of age and all were developing normally. The purpose of this study is to determine the outcome of infants with disease limited to the SEM who are treated intravenously with standard therapy (14 days of acyclovir at 20 mg/kg/dose every 8 hours) and then randomized to placebo or oral acyclovir (300 mg/m2/dose three times per day) for 6 months. The hypothesis is that acyclovir suppressive therapy will reduce significantly the number of recurrences and will result in better neurological outcomes. Primary endpoint is the neurologic assessment at 12 months of age. Secondary endpoints will be the number of cutaneous recurrences and CSF parameters during those recurrences. With each recurrence 'study drug' (acyclovir or placebo) will be stopped and 'open label' acyclovir oral or intravenous, depending on CSF findings, will be given which is standard of care at the present time. Safety monitoring and stopping rules with the offering of open label acyclovir are part of the protocol. Enrollees will be followed to age 5 years. Two interim analyses with appropriate statistical considerations are planned.
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