Therapeutic studies of rare diseases such as neonatal herpes present unique challenges. Each of the previous major investigations of the management of neonatal HSV conducted by the CASG has spanned the course of a decade.2,3,16,17
The current studies were no exception, requiring 11 years to enroll 74 infants. Many clinicians assumed that oral acyclovir would be efficacious, on the basis of the results of small, uncontrolled studies,18,19
further challenging the conduct of these randomized, controlled trials. The long-term follow-up required to assess neurodevelopmental outcomes also affected the ability to follow all the enrolled infants for the primary protocol end point, with only 43 of the 74 infants (58%) having a Bayley Scales of Infant Development assessment at 12 months ().
Interpretation of the results of the neurodevelopmental assessment should be tempered by the fact that Bayley Scales of Infant Development assessments were not performed in 38% of subjects in the CASG 103 (CNS) study. This substantial attrition renders the primary protocol end point less interpretable. For the 62% of infants in the CASG 103 study with a neurologic evaluation at 12 months, our finding of improved neurodevelopmental outcomes among subjects who started oral acyclovir suppression at the end of the 21-day course of intravenous therapy provides the first controlled data that suggest that ongoing neurologic injury occurs in infants who survive neonatal HSV disease and that it can be decreased by longer-term antiviral suppression. This finding had previously been implied in small, uncontrolled case series.6,19
The distribution of neurologic outcomes among infants in the CASG 103 (CNS) study who were randomly assigned to placebo (normal, 33%; mild impairment, 8%; moderate impairment, 25%; severe impairment, 33%) was similar to that among infants in an earlier trial (in whom the neurologic outcomes were measured by a different tool) who received high-dose parenteral acyclovir for the treatment of acute disease but no subsequent suppression (normal, 31%; mild impairment, 15%; moderate impairment, 15%; severe impairment, 39%).2
Similarly, the distribution of outcomes among infants in the CASG 103 (CNS) study who were randomly assigned to oral acyclovir was virtually identical to that from a small, uncontrolled case series (involving 16 infants) of oral acyclovir suppression after neonatal HSV CNS disease (69% with normal outcomes in both studies).19
The finding of incrementally higher neurodevelopmental scores among infants treated with oral antiviral suppressive therapy for the full 6 months as compared with those treated for only part of the 6 months and as compared with those who received no antiviral suppression (median 12-month Bayley mental-development score of 91 vs. 70 and 58, respectively) also supports the conclusion that oral acyclovir suppressive therapy after treatment of acute neonatal HSV disease confers a benefit. If the infants who were randomly assigned to placebo had not been allowed to switch to active suppression after two cutaneous recurrences, it is possible that the difference between the acyclovir and placebo groups would have been more pronounced. In addition, the subjects with CNS disease who were randomly assigned to acyclovir were smaller in size than were those assigned to placebo, as reflected in the lower birth weights and smaller head circumferences. However, any bias introduced by this difference should be in favor of the null hypothesis, since prematurity or small-for-gestational-age status would be more likely to be associated with worse developmental outcomes.
these studies provided evidence that suppressive therapy with oral acyclovir decreases the number of recurrences of cutaneous lesions after neonatal HSV disease, as has been suggested previously.15
Since skin lesions occur in approximately 70% of all babies with neonatal HSV,1
the positive socioeconomic effect of decreased recurrences should not be underestimated. For example, prevention of skin recurrences can translate to the need for fewer medical evaluations and to more days of child care attendance, which in turn results in fewer days of work missed by the parent.
Previous uncontrolled studies have suggested that acyclovir therapy may be associated with neutropenia.2,15,20–24
In the current placebo-controlled studies, neutropenia was not more likely to develop in infants receiving acyclovir than in infants receiving placebo, although the P values approached significance. It is possible that there is indeed an association that our studies were underpowered to detect; thus, we believe that neutropenia should continue to be considered as a possible toxic effect of longer-term oral acyclovir therapy.15
These data support the use of suppressive therapy with 300 mg of oral acyclovir per square meter per dose administered three times daily for 6 months after initial treatment of neonatal HSV disease. Babies with skin, eye, and mouth disease can benefit because this therapy helps to prevent skin recurrences, whereas babies with CNS disease may have additional benefit with respect to neurodevelopmental outcomes. There are no controlled data that suggest that suppressive therapy administered longer than 6 months or with the use of higher doses of oral acyclovir is beneficial. An extemporaneously compounded oral solution of valacyclovir has not been sufficiently studied in neonates and young infants to warrant its use instead of oral acyclovir for antiviral suppression.25