Valganciclovir for symptomatic congenital cytomegalovirus disease

Abstract

Background: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time.

Methods: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline.

Results: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64).

Conclusions: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Figure 1. Randomization and Follow-up of the Study Participants

The participants who had hearing and developmental assessments that could be evaluated at 12 and 24 months of follow-up did not necessarily constitute subgroups of the preceding groups with follow-up assessments. At 6 months, 4 participants in the 6-month group could not be evaluated because of loss to follow-up (2 participants) and incomplete audiologic data (2), and 6 in the 6-week group could not be evaluated because of loss to follow-up (2), incomplete audiologic data (3), and follow-up assessment that was not performed during the study window (1). At 12 months, 6 participants in the 6-month group could not be evaluated because of cochlear implantation (1 participant), loss to follow-up (3), and incomplete audiologic data (2), and 9 in the 6-week group could not be evaluated because of cochlear implantation (3), loss to follow-up (1), incomplete audiologic data (3), and follow-up assessment that was not performed during the study window (2). At 24 months, 10 participants in the 6-month group could not be evaluated because of cochlear implantation (4 participants), loss to follow-up (4), and concurrent otitis media (2), and 18 in the 6-week group could not be evaluated because of cochlear implantation (6), loss to follow-up (5), incomplete audiologic data (3), follow-up assessment that was not performed during the study window (3), and concurrent otitis media (1). Neurodevelopmental outcomes were assessed with the use of the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III).

Figure 2. Cytomegalovirus DNA Viral Load in Whole Blood in Participants Receiving the Study Therapy

Participants with a viral load of less than 100 were assessed as having a viral load of 10 (i.e., 1.0 in the graph). P values are for the between-group comparisons at the respective time points.