Valganciclovir in Infants with Hearing Loss and Clinically Inapparent Congenital Cytomegalovirus Infection: A Nonrandomized Controlled Trial

Read article one: Read article two: Read article three: Submitted by: Dr Eloise Silvester, Paediatric Infectious Diseases Advanced Trainee Registrar & Supervising consultant Dr Jeremy Carr; Monash Children’s Hospital, Melbourne Vic, 18/07/24.Background:Congenital cytomegalovirus infection (cCMV) is the leading cause of nongenetic sensorineural hearing loss in children and the most common congenital infection worldwide. Two RCTs have demonstrated improved hearing and neurodevelopmental outcomes at the age of 2 in symptomatic neonates commenced on ganciclovir or valganciclovir (VGV) within 4 weeks of age. Without universal screening there is often a delay in diagnosing cCMV in asymptomatic infants with isolated hearing loss, missing the opportunity to treat and improve outcomes in a group that represents a large burden of cCMV disease. This prospective, non-randomised controlled study assessed the efficacy of 6 weeks of VGV in infants up to 13 weeks of age with hearing loss and clinically inapparent cCMV, identified by a failed newborn hearing tests and a positive dried blood spot CMV PCR. Treatment groups were combined from a prospective cohort (26/37) allocated to treatment or no treatment based on parental decision making, a terminated RCT (n=2), and a retrospective cohort (n=9). A duration of 6-weeks was chosen prior to the publication of an RCT (Kimberlin NEJM 2015) showing benefit of 6-month over 6-week treatment course for symptomatic cCMV.Findings:Of the 24 infants who received 6 weeks valganciclovir treatment, best-ear hearing improved from baseline to follow up (18-22mo) in 13% (3/24), maintained normal hearing in 50% (12/24), was unchanged in 29% (7/24) and deteriorated in 8% (2/24). In the control group, best-ear hearing did not improve in any participants, 17% (2/12) maintained normal hearing, 33% (4/12) were unchanged and 50% (6/12) experienced a deterioration in hearing (p=0.003). On average, hearing deteriorated by 13.7 dB in the control group while the treated group showed a mean improvement of 3.3 dB (difference 17 dB, 95% CI 2.6 to 31.4, P = .020). Of the patients with unilateral hearing loss at baseline, 2/4 control subjects progressed to bilateral hearing loss at follow-up, compared to none of 12 subjects in the treatment arm. For total-ear hearing analyses, control ears showed more deterioration than treated ears (p=0.001). No significant differences in any developmental domain were found between treatment and control groups. Take home message:This prospective cohort study demonstrates that 6 weeks of valganciclovir, when initiated within the first 3 months of life, has a mild beneficial effect on hearing outcomes in children with hearing loss and clinically inapparent cCMV. This study was published in tandem with an RCT of 6 weeks of VGV initiated in infants aged 1 month to 3 years with heterogeneous, and highly symptomatic clinical cCMV that showed no treatment benefit. The current study suggests extension of the treatment initiation window beyond 4 weeks to 13 weeks may be considered. Whilst further evidence comparing 6 weeks vs. 6 months of GCV in cCMV and apparently isolated SNHL is needed, cCMV RCTs are challenging if not infeasible.Twinned paper: Kimberlin et al. Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial. J Pediatr 2024;268:113934.