Prolonged Oral Acyclovir Improves Neurodevelopment of Infants With CNS Herpes Simplex

Daniel M. Keller, PhD

November 03, 2010

November 3, 2010 (Vancouver, British Columbia) — Infants with neonatal herpes simplex virus (HSV) infection with central nervous system (CNS) involvement have better neurodevelopmental outcomes at 1 year if they are started on oral acyclovir suppressive therapy immediately after parenteral acyclovir than if oral therapy is delayed.

Survivors of neonatal HSV disease have unacceptably high rates of poor neurodevelopmental outcomes and skin recurrences. Therefore, the Collaborative Antiviral Study Group (CASG) of the National Institute of Allergy and Infectious Diseases assessed the efficacy of oral acyclovir suppressive therapy in modifying these outcomes. The CASG is a multicenter clinical trials group of 104 participating institutions around the world, headquartered at the University of Alabama at Birmingham School of Medicine (UAB).

Lead author David Kimberlin, MD, professor and codirector of the Division of Pediatric Infectious Diseases at UAB, said the study enrolled 74 neonates with HSV disease in 2 parallel, phase 3, double-blind, placebo-controlled trials — 1 for infants with CNS disease with or without dissemination and the other for infants with skin, eye, and mouth disease (SEM), but without CNS disease.

All patients received intravenous acyclovir. Once parenteral acyclovir treatment was completed, the infants were randomly assigned to receive either placebo or oral acyclovir 300 mg/m2 3 times a day for 6 months. For a first cutaneous recurrence, an infant received oral open-label episodic treatment. For a second cutaneous recurrence, the blinded treatment was discontinued, and open-label acyclovir was allowed.

Reporting here at the Infectious Diseases Society of America 48th Annual Meeting, Dr. Kimberlin and coinvestigators said between 1997 and 2008, 45 study infants had CNS involvement, and 29 had SEM disease. When adjusted for covariates, the infants who had been randomly assigned to receive immediate acyclovir oral therapy had significantly better mean performance on Bayley Scales of Infant Development Mental Scores at 12 months compared with infants who received placebo and deferred antiviral suppressive therapy (88.24 vs 68.12, respectively; P = .046).

"They had improved neurodevelopmental outcomes — they were smarter, in other words — at a year of life," Dr. Kimberlin said.

"For babies with [SEM] disease — more limited disease — we also found that the antiviral suppression kept it from coming back on the skin as well." Infants on oral acyclovir stayed on blinded study medication 2 months longer before discontinuation because of recurrent skin lesions compared with infants receiving placebo (P = .009). Therapy with acyclovir raises concerns about neutropenia, but the incidence of this adverse effect did not differ between the infants receiving acyclovir vs those receiving placebo (P = .94 for infants with CNS disease; P = .24 for those with SEM disease). Dr. Kimberlin said neutropenia may still be a possibility, adding: "However, it's a lot less likely than we were concerned that it might be."

Neonatal herpes is a rare disease, affecting about 1 in 3000 babies. Dr. Kimberlin mentioned that significant improvements in its management occurred from the 1970s through the 1990s, but most of the improvements were in mortality. "We still had problems related to morbidity — babies who survived and yet had damaged brains and had difficulty with respect to meeting developmental milestones," Dr. Kimberlin said.

Although this study did not investigate the effect of cesarean delivery, Dr. Kimberlin said studies during the past several years have shown that it can help reduce the risk for neonatal HSV disease, but does not prevent it entirely.

He said any baby who develops neonatal CNS or SEM herpes disease "should be treated with intravenous acyclovir...regardless of whether it's limited to the...[CNS] or whether it's full-blown disseminated disease, or whether it's limited to the skin, the eyes, or the mouth. Once they've completed that course of [intravenous] acyclovir therapy, I believe that our data would strongly support that they should then be started on 6 months of oral acyclovir suppressive therapy with periodic monitoring of the white blood cell count through just a regular routine blood test."

Richard J. Whitley, MD, president of Infectious Diseases Society of America and professor of pediatrics, microbiology, medicine, and neurosurgery and chief of pediatric infectious diseases at UAB, and project director of the CASG since 1980, said taking care of babies with HSV disease is "one of the most distressing of all circumstances for a couple.... Simply, the recurrence of skin vesicles is a reminder to the couple that somebody gave this disease to one another to lead to disease in the baby."

He said this situation can lead to stress in the couple's relationship, and one offshoot of the present study will be to see whether neonatal suppressive therapy improves the well-being of the relationship.

"[A] second component of [the disease] is the 3-month-old who is in daycare," Dr. Whitley continued. "As soon as they get a vesicle, they're thrown out," so parents lose time from work, he concluded.

Dr. Kimberlin has disclosed no relevant financial relationships. Dr. Whitley was a coinvestigator on the study but has reported no other relevant disclosures.

Infectious Diseases Society of America 48th Annual Meeting: Abstract 810. Presented October 22, 2010.


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