Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han JY, Palmer A, Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths PD, Luck S, Gutierrez K, Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban I, Kuo H, James SH, Prichard MN, Griffin J, Giles D, Acosta EP, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015 Mar 5;372(10):933-43. doi:10.1056/NEJMoa1404599. PMID: 25738669
Francesco Cardona MD
Medical University Vienna
TYPE OF INVESTIGATION
In a randomized trial, does prolonged therapy (6 months vs. 6 weeks) valganciclovir treatment of symptomatic congenital cytomegalovirus infection improve hearing in the better ear from baseline to 6 months?
- Design: Phase III multi-center randomized, placebo-controlled double-blinded trial. gov number: NCT00466817
- Allocation: concealed through web-based enrollment system, handled by the Biostatistics Unit of the University of Alabama
- Blinding: Study subjects, investigators and staff were blinded
- Follow-up period: 24 months of age
- Setting: 40 study sites in the USA and UK participated, 31 contributed patients; each contributing only few patients from June 2008 to May 2011
- Patients: 96 Neonates with symptomatic congenital CMV disease were eligible; CMV was detected in urine or throat-swab specimens by means of culture, shell-vial culture of polymerase-chain-reaction assay; Symptomatic disease was defined as one or more of the following: thrombocytopenia, petechiae, hepatomegaly, splenomegaly, intrauterine growth restriction, hepatitis, or CNS involvement such as microcephaly, intracranial calcifications, abnormal cerebrospinal fluid indexes, chorioretinitis, sensorineural hearing loss, or detection of CMV DNA in cerebrospinal fluid. Inclusion criteria were gestational age 32 weeks or more, less than 30 days old, weight > 1800g at initiation of therapy; no screening for CMV mentioned, although protocol mentions use of advertisements/leaflets at wards participating in the study
- Therapy with valganciclovir: 6 months vs. 6 weeks; 1:1 randomization, stratified according to CNS involvement at study entry; all patients received 6 weeks of open label valganciclovir, randomization then decided if patients would either receive valganciclovir up to 6 months or placebo; valganciclovir dose of 16mg per kilogram of body weight, orally twice daily; dose of medication was adjusted monthly for growth. Study drug and placebo were provided by Hoffmann-La Roche Inc.
- Hearing assessment: Brain-stem auditory evoked response (AER) was assessed at entry. Outcome assessments of (AER) or visual-reinforcement audiometry was performed at 6, 12, and 24 months; hearing was classified as normal hearing (0 – 20 dB), mild hearing loss (21 – 45 dB), moderate hearing loss (46 – 70dB), or severe hearing loss (>71 dB). The result of the better ear at each time point was used for further assessment. The audiologist was blinded to randomization assignment.
- Primary outcome: Change in best ear hearing assessments between baseline and 6 months (improvement vs. no change vs. worsening)
- Secondary outcomes: Change in best ear hearing assessments between baseline and 12 months as well as 24 months; adverse events leading to discontinuation of valganciclovir therapy, neurologic impairment at 12 and 24 months of life (Bayley-III scales), viral loads, safety assessment
- Analysis and Sample Size: Wilcoxon-Mann-Whitney test: sample of 37 participants per group would provide the study with 85% power to detect an effect size of 0.169 from the 0.5 value of the null hypothesis; however it was also estimated that 15% would drop out before randomization, with 10% to drop out before hearing evaluation at 6 months. Therefore the original sample was calculated to be 94 participants. However DSMB advice was to increase study size during the study by 10% to accommodate for an unanticipated higher rate of un-analyzable with inadequate hearing data at baseline or 6 months. In addition a pre-specified adjustment for the primary outcome was to be performed for cognitive impairment. The analysis was a “modified intention to treat” analysis for patients who were randomized and received at least one dose of modified treatment. Finally patients who were treated with cochlear implants were excluded. The pre-specified levels of significance were then P values of less than 0.05 for hearing outcomes and less than 0.0071 for neurodevelopmental outcomes.
- Patient follow-up: 109 participants included; 96 participants were randomly assigned and blinded, 47 participants (6 month group), 49 participants (placebo). Of these 43 participants in each group had baseline and 6-month hearing assessments and could be evaluated for primary outcome at 6 months, meaning 79% of overall participants were included in primary outcome evaluation; 9 (6 participants in the 6-month group, and 3 in the 6-week group) stopped taking the blinded drug before completing 6 months of the study; no participant discontinued the study drug owing to adverse events.
- Funding: NIH contract N01-AI-30025 from the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases
Evaluation of the pre-specified primary outcome “best ear” hearing at 6-months showed no difference between groups (p=0.41 by Mann-Whitney test). 6-month therapy was associated with an adjusted odds ratio of 1.75 (95% confidence interval 0.69 to 4.43, p=0.24) for improved or normal hearing after adjusting for central nervous system involvement at randomization.
Secondary outcome at 12- and 24-month analyses showed a tendency toward improvement in “best ear” hearing after 6-months compared with 6-weeks antiviral treatment (12-months follow-up: aOR for 2.81 (95% CI 0.99 to 7.99) and at 24-months: aOR 3.28 (95% CI 0.91 to 11.9) for 6-month therapy, though results were statistically not significant (p-values of 0.05 and 0.07 respectively). If both ears were considered, hearing showed a 3-fold improvement at 12 months for participants treated for 6 months (aOR 3.04, 95% CI 1.26 to 7.34) and at 24 months (aOR 2.61, 95% CI 1.05 to 6.43).
Participants treated with 6-month valganciclovir showed higher scores compared with the 6-week group in most components of the Bayley-III, although only language composite (87.6±3.0 vs. 76.8±2.9) and receptive-communication scale (7.5±0.5 vs. 6.1±0.5) were statistically significant after use of Bonferroni adjustment for multiple testing.
Viral loads in whole blood decreased initially in both groups but diverged after randomization, such that the 6-week treatment group had significantly higher loads compared to the 6-month group.
Safety assessment revealed that 19% developed grade 3 or 4 neutropenia during the first 6 weeks of treatment. From 6 weeks to 6 months there was no difference in rates of neutropenia between the two study groups (21% vs. 27%). 3 participants had to stop treatment temporarily during the first 6 weeks because of an absolute neutrophil count of less than 500 per cubic millimeter. No other serious adverse events were seen.
The authors state that 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.
Congenital CMV infection occurs in 0.7% of live births in industrialized countries2 and 10% of these infants develop symptomatic disease which is associated with poor outcome.3 Congenital infection with Cytomegalovirus is responsible for one fifth of hearing loss encountered in children and is the leading non-genetic cause of sensorineural hearing loss in children. Other sequelae of congenital infection with CMV may be retinitis and cerebral palsy.1 Antiviral therapy to reduce disability and improve long-term outcome is therefore warranted.
Current recommendations support treatment in infants suffering from symptomatic CMV infection for 6 weeks with either intravenous ganciclovir or oral valganciclovir.4 The only previous randomized controlled study in symptomatic infants with congenital cytomegalovirus disease with CNS involvement compared 6-week ganciclovir therapy with no treatment. That study did not detect any difference between groups related to improved or maintained normal hearing, though fewer ganciclovir patients exhibited deterioration in hearing compared with placebo.5 Therapy with oral valganciclovir, a prodrug of ganciclovir, has been shown to be comparable to intravenous ganciclovir in terms of achieving comparable drug levels over time (AUC).6
The trial reviewed herein adds some new information on the effects of prolonged treatment and suggests that 6-month therapy may lead to better long-term outcome for neonates with symptomatic congenital CMV infection, even if short-term benefits remain marginal. It is also reassuring that prolonged treatment for 6 months did not induce higher rates of side effects. This current study has built on an initial placebo-controlled trial with some indication of benefit. The CMV community is to be congratulated for talking a step-wise approach to rigorously evaluate a new therapy. They should not now baulk at the next definitive step!
- Morton CC, Nance WE. Newborn Hearing Screening — A Silent Revolution. N Engl J Med. 2006;354:2151-2164. doi:10.1056/NEJMra050700.
- Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17:253-276. doi:10.1002/rmv.535.
- Dreher AM, Arora N, Fowler KB, et al. Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr. 2014;164:855-9. doi:10.1016/j.jpeds.2013.12.007.
- Pickering L, Baker C, Long S, Kimberlin D. Cytomegalovirus infection. In: Red Book: 2012 Report of the Committee on Infectious Diseases. 29th Ed. Elk Grove Village, IL: American Academy of Pediatrics.; 2012:300-5.
- Kimberlin DW, Lin CY, Sánchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: A randomized, controlled trial. J Pediatr. 2003;143:16-25. doi:10.1016/S0022-3476(03)00192-6.
- Kimberlin DW, Acosta EP, Sanchez PJ, et al. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis. 2008;197:836-845. doi:10.1086/528376.