Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates
Condition: Herpes Simplex
MeSH terms: Herpes Simplex
Intervention: Acyclovir; Placebo
Intervention description: Oral banana flavored acyclovir suspension: 300 mg/m^2/dose three times a day (TID), to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area.; Oral banana flavored placebo suspension: to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area.
Intervention MeSH terms: Acyclovir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 46.0
Sex: All
Maximum age: 28 Days
Healthy volunteers: No
Keywords: acyclovir, central nervous system, Herpes Simplex Virus

Summary:

      The purpose of this study is to test whether long term treatment with acyclovir given orally
      (by mouth) improves the outcome for infants with herpes simplex virus infection of the brain
      or spinal cord (known as the central nervous system [CNS]). Infants with herpes viral
      infection of the CNS that has or has not spread to other parts of the body will be enrolled
      in this study. All participants will receive treatment in a hospital for 21 days with
      acyclovir, given intravenously (by a needle inserted into a vein). Participants will then be
      divided into two groups: those with CNS disease that has or has not spread to the skin, and
      those whose viral infection has spread and involves the CNS. Both groups will be randomly
      assigned to receive either oral acyclovir or placebo (inactive substance) for 6 months.
      Infants in the US and Canada will participate for 5 years. A physical exam, hearing exam, eye
      exam, and an evaluation of the nervous system will be performed throughout the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Viral Culture:

               1. If cutaneous lesions are present, then isolation of Herpes Simplex Virus (HSV)-1
                  or HSV-2 by viral culture from any site (skin, oropharynx, cerebral spinal fluid
                  [CSF], urine, etc.) will be required for study entry.

               2. If cutaneous lesions are not present, then viral isolation by culture is adequate
                  for study entry but is not required. In the case of no cutaneous lesions and
                  negative viral cultures, however, the CSF polymerase chain reaction (PCR) must be
                  positive.

               3. Additional sites from which HSV culture will be attempted include conjunctivae,
                  oropharynx, blood buffy coat, urine, and CSF.

          -  Evidence for central nervous system (CNS) HSV disease during the acute illness,
             including one or more of the following:

               1. Abnormal CSF indices for term infants: greater than 22 white blood cells
                  (WBCs)/mm^3 and protein greater than 115mg/dl.

               2. Abnormal CSF indices for preterm infants: greater than 25 WBCs/mm^3 and protein
                  greater than 220 mg/dl.

               3. Abnormal neuroimaging study (computed tomography [CT] with contrast, magnetic
                  resonance imaging [MRI] with gadolinium, or head ultrasound) [NOTE: CT with
                  contrast is the preferred imaging study].

               4. Abnormal electroencephalography (EEG), if performed (NOTE: EEG is suggested for
                  the evaluation of infants with HSV disease but is not required for this study].

               5. Positive CSF PCR for HSV deoxyribonucleic acid (DNA) [NOTE: If no cutaneous
                  lesions are present and all viral cultures are negative, the CSF PCR must be
                  positive. If lesions are present and are culture-positive, abnormal CNS
                  neurodiagnostic studies or abnormal CSF indices are sufficient for study entry].

          -  Negative CSF PCR result within 48 hours prior to completion of intravenous acyclovir
             therapy.

          -  Less than or equal to 28 days of age at the time of initial presentation with CNS
             disease.

          -  Birth weight greater than or equal to 800 grams.

        Exclusion Criteria:

          -  Infants with either a grade 3 or grade 4 intraventricular hemorrhage (IHV) prior to
             study enrollment.

          -  Breast feeding infants whose mothers are taking acyclovir, valacyclovir, or
             famciclovir for greater than 120 hours (greater than 5 days). If at any point
             following enrollment the mother takes these antiviral drugs for greater than 120 hours
             (greater than 5 days), she will be asked to refrain from breast feeding while taking
             the drug.

          -  Infants known to be born to women who are human immunodeficiency virus (HIV) positive
             (but HIV testing is not required for study entry). These infants are at known risk of
             acquiring HIV, which would alter their immune response to other infections, including
             herpes simplex virus (HSV) infection. Additionally, they may be receiving
             antiretroviral and/or antiviral drugs during the time in which the study of
             suppressive oral acyclovir is being conducted. As such, they will be excluded if the
             mother's positive HIV status is known at the time of evaluation for study inclusion.
             If at any point following enrollment it is learned that an infant is HIV positive,
             however, he/she will be continued on the study protocol.

          -  Infants with HSV infection limited to the skin, eyes, or mouth (SEM). Patients with
             SEM HSV infection will be considered for enrollment and randomization in the ongoing
             Collaborative Antiviral Study Group (CASG) evaluation of oral suppressive acyclovir
             therapy following neonatal HSV infections limited to the SEM.

          -  Infants with creatinine greater than 1.5 mg/dl at time of study enrollment.