Efficacy of Antiviral Suppression Therapy after Neonatal HSV Infection of the CNS

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 DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infections in infants are deadly, and survivors are at high risk of neurodevelopmental impairment including mental retardation and cerebral palsy. Neonatal HSV involving the central nervous system carries the highest risk of long-term neurodevelopmental impairment (70-86%) among survivors. Oral acyclovir suppressive therapy improves neurodevelopmental outcomes in infants with a history of central nervous system HSV disease; however, the most effective dose and duration of antiviral therapy are unknown. Higher antiviral doses may be beneficial because: 1) antiviral plasma and cerebrospinal fluid (CSF) levels are highly variable in pediatric populations; 2) antiviral CSF concentrations are ≤50% of plasma levels; 3) and oral absorption of acyclovir is low. Although 6 months of acyclovir therapy was shown to be superior to placebo in a small randomized trial, longer and higher dose courses of acyclovir were shown to be safe and potentially more effective. Valacyclovir, which is rapidly converted to acyclovir after oral administration, may be a better alternative due to improved oral absorption and longer dosing intervals. The aim of this proposal is to develop a clinical trial protocol to compare the efficacyof long-term oral valacyclovir therapy with short-term oral acyclovir therapy for improving neurodevelopmental outcomes in infants with a history of central nervous system HSV. This proposal will capitalize on the expertise of the Duke Clinical Research Institute (DCRI) in the following areas: 1) regulatory; 2) pharmacometrics; 3) biostatistics; and 4) trial operations. Dr. Smith will develop a protocol for a prospective multicenter study that will be submitted to NIAID for potential funding. He anticipates enrolling 90 infants with a history of central nervous system HSV infection at approximately 60 clinical sites in an efficacy study of oral antiviral suppressive therapy. Infants will be randomized to 2 groups: group 1 subjects will receive oral acyclovir for 6 months, and group 2 subjects will receive valacyclovir for 2 years. The primary outcome of the study will be neurodevelopmental impairment measured at 28-32 months of age. Secondary end points will include the number of breakthrough HSV infections, mortality, safety, and pharmacokinetics of acyclovir and valacyclovir. This study will be conducted under FDA oversight, and study results will be submitted to the FDA to change the drug labels. Dr. Smith will accomplish the aim of this proposal by: 1) using the expertise at the DCRI to design and finalize a complete protocol for the clinical trial; 2) drafting a template for the informed consen; 3) developing a budget for the proposed clinical trial; 4) obtaining an investigational new drug application for the protocol from the FDA; 5) developing a manual of trial operations, training materials, and clinical trial milestones; 6) developing data collection forms; and 7) establishing data safety monitoring board.