Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates

A Placebo-Controlled Phase III Evaluation of Suppressive Therapy With Oral Acyclovir Suspension Following Neonatal Herpes Simplex Virus Infections Involving the Central Nervous System

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.

Neonatal herpes simplex virus (HSV) disease complicates approximately 1 in every 3,000 deliveries in the United States, resulting in an estimated 1, 500 cases annually in this country. HSV-1 and HSV-2 infections in the neonate can manifest as: disseminated disease; central nervous system (CNS) disease; or disease limited to the skin, eyes, and mouth (SEM disease). This study will evaluate the efficacy of long term suppressive therapy with oral acyclovir in infants with CNS disease, with or without evidence of dissemination to other organs (including the skin). It will determine if suppressive oral acyclovir therapy improves neurologic outcome in infants following HSV disease with CNS involvement and address the significance of a positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) result when all other CSF parameters either remain normal or show improvement. Comparisons will be made between groups with respect to post-randomization time to first positive CSF PCR result during the initial 12 months of life, and results will be correlated with clinical neurological assessments. It will determine if continuous administration of oral acyclovir suspension suppresses recurrent skin lesions in infants following HSV disease with CNS involvement, and it will confirm the safety of long-term administration of oral acyclovir therapy in a cohort of infants with HSV disease with CNS involvement. Finally, the effects of suppressive acyclovir therapy on issues of pharmacoeconomics and family infrastructure will be assessed and quantitated. Infants with CNS disease (with or without evidence of viral dissemination to other organs, such as the skin, liver, and lungs) will qualify for this study. Following a 21 day course of treatment with intravenous (IV) acyclovir, infants with CNS disease, with or without cutaneous involvement, will be randomized to either continuous oral acyclovir or placebo (CNS Sub-Study). Similarly, infants with disseminated disease with CNS involvement will be randomized to either continuous oral acyclovir or placebo (Disseminated with CNS Involvement Sub-Study). The subset of infants with CNS disease (with or without dissemination) who do not clear their acute infection in 21 days of IV acyclovir therapy will be eligible for enrollment in a Pilot Sub-Study. This group is expected to be of insufficient number to be able to obtain statistical significance for establishing efficacy. Per protocol amendment dated 19-Nov-1998, 66 subjects will be recruited into each sub-study. Subjects will begin oral drug therapy 8 hours after the final IV acyclovir dose and oral drug therapy will be administered for 6 months. Whole blood (1.0 cubic centimeter) will be obtained at study enrollment and at completion of IV antiviral therapy for HSV PCR analysis, per protocol amendment dated 4-May-1998. This amendment replaces the obtaining of serum for HSV PCR analysis. In the event that whole blood is not available, serum will be provided instead. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. Physical examination, hearing assessment, and retinal examination will be performed at each follow-up visit. Standardized neurological evaluations will be performed at 12, 24, 36, 48, and 60 months. The primary study endpoint will evaluate neurological impairment at 12 months of life. The secondary endpoints will evaluate post-randomization detection of HSV DNA in CSF by PCR at any time during the initial 12 months of life and 2 or fewer episodes post-randomization of cutaneous recurrence of HSV disease during the initial 12 months of life.

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.