Antiviral Therapy of CMV Disease in Children

  • Mike SharlandEmail author
  • Suzanne Luck
  • Paul Griffiths
  • Mark Cotton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 697)


Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in infants and children. The main burden of disease occurs in congenital infection, postnatal infection in premature infants and in older immunocompromised children (now predominantly following transplantation) in developed countries. In lower income countries, CMV is a major co-pathogen in human immunodeficiency virus [HIV]-infected infants. Antiviral treatment options remain very limited. The guanosine analogue ganciclovir (GCV) was first used in children over 20 years ago, but the optimal dose, duration and route of administration remain poorly evidence based. In particular there are very limited data in premature infants and older children. Direct comparison studies between the intravenous ganciclovir and the oral valyl-ester valganciclovir (VGCV) have not been performed. CMV disease is important, but not very common and there remains a need to identify useful surrogate markers of successful antiviral therapy to facilitate clinical trials. Cidofovir and foscarnet have very significant toxicity. No other anti-CMV agent has successfully completed phase III studies. There remain few other antiviral agents effective against CMV on the horizon. This chapter reviews the current clinical spectrum of CMV disease in childhood and the evidence base for both GCV and VGCV use in clinical practice. It also discusses the antiviral studies currently being performed and those that need to be performed.


Viral Load Sensorineural Hearing Loss Hearing Outcome Neonatal Herpes Simplex Virus Infection Infected Baby 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17:253–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Griffiths PD, Baboonian C, Rutter D, Peckham C. Congenital and maternal cytomegalovirus infections in a London population. Br J Obstet Gynaecol. 1991;98:135–40.PubMedGoogle Scholar
  4. 4.
    Barbi M, Binda S, Caroppo S, Ambrosetti U, Corbetta C, Sergi P. A wider role for congenital cytomegalovirus infection in sensorineural hearing loss. Pediatr Infect Dis J. 2003;22:39–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Nance WE, Lim BG, Dodson KM. Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss. J Clin Virol. 2006;35:221–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Rivera LB, Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics. 2002;110:762–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Noyola DE, Demmler GJ, Nelson CT, Griesser C, Williamson WD, Atkins JT, Rozelle J, Turcich M, Llorente AM, Sellers-Vinson S, Reynolds A, Bale JF Jr, Gerson P, Yow MD. Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J Pediatr. 2001;138:325–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet. 2000;355:2032–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Cope AV, Sweny P, Sabin C, Rees L, Griffiths PD, Emery VC. Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation. J Med Virol. 1997;52:200–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Stagno S, Reynolds DW, Tsiantos A, Fuccillo DA, Long W, Alford CA. Comparative serial virologic and serologic studies of symptomatic and subclinical congenitally and natally acquired cytomegalovirus infections. J Infect Dis 1975;132:568–77.PubMedGoogle Scholar
  11. 11.
    Bradford RD, Cloud G, Lakeman AD, Boppana S, Kimberlin DW, Jacobs R, Demmler G, Sanchez P, Britt W, Soong SJ, Whitley RJ. Detection of cytomegalovirus (CMV) DNA by polymerase chain reaction is associated with hearing loss in newborns with symptomatic congenital CMV infection involving the central nervous system. J Infect Dis. 2005;191:227–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Boppana SB, Fowler KB, Pass RF, Rivera LB, Bradford RD, Lakeman FD, Britt WJ. Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr. 2005;146:817–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Lanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, Landini MP, Faldella G. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006;117:e76–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Walter S, Atkinson C, Sharland M, Rice P, Raglan E, Emery VC, Griffiths PD. Congenital cytomegalovirus: association between dried blood spot viral load and hearing loss. Arch Dis Child Fetal Neonatal Ed. 2008;93:F280–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Ross SA, Novak Z, Fowler KB, Arora N, Britt WJ, Boppana SB. Cytomegalovirus blood viral load and hearing loss in young children with congenital infection. Pediatr Infect Dis J. 2009;28:588–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Halwachs-Baumann G, Genser B, Pailer S, Engele H, Rosegger H, Schalk A, Kessler H, Truschnig-Wilders. M. Human cytomegalovirus load in various body fluids of congenitally infected newborns. J Clin Virol. 2002;25(Suppl 3):S81–S87.CrossRefPubMedGoogle Scholar
  17. 17.
    Kohyama J, Kajiwara M, Shimohira M, Iwakawa Y, Okawa H. Human cytomegalovirus DNA in cerebrospinal fluid. Arch Dis Child. 1994;71:414–18.CrossRefPubMedGoogle Scholar
  18. 18.
    Stagno S, Reynolds DW, Pass RF, Alford CA. Breast milk and the risk of cytomegalovirus infection. N Engl J Med. 1980;302:1073–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Vochem M, Hamprecht K, Jahn G, Speer CP. Transmission of cytomegalovirus to preterm infants through breast milk. Pediatr Infect Dis J. 1998;17:53–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Hamprecht K, Maschmann J, Vochem M, Dietz K, Speer CP, Jahn G. Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding. Lancet. 2001;357:513–18.CrossRefPubMedGoogle Scholar
  21. 21.
    Hamprecht K, Maschmann J, Jahn G, Poets CF, Goelz R. Cytomegalovirus transmission to preterm infants during lactation. J Clin Virol. 2008;41:198–205.CrossRefPubMedGoogle Scholar
  22. 22.
    Kumar ML, Nankervis GA, Cooper AR, Gold E. Postnatally acquired cytomegalovirus infections in infants of CMV-excreting mothers. J Pediatr. 1984;104:669–73.CrossRefPubMedGoogle Scholar
  23. 23.
    Cheong JL, Cowan FM, Modi N. Gastrointestinal manifestations of postnatal cytomegalovirus infection in infants admitted to a neonatal intensive care unit over a five year period. Arch Dis Child Fetal Neonatal Ed. 2004;89:F367–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Paryani SG, Yeager AS, Hosford-Dunn H, Johnson SJ, Malachowski N, Ariagno RL, Stevenson DK. Sequelae of acquired cytomegalovirus infection in premature and sick term infants. J Pediatr. 1985;107:451–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Vollmer B, Seibold-Weiger K, Schmitz-Salue C, Hamprecht K, Goelz R, Krageloh-Mann I, Speer CP. Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants. Pediatr Infect Dis J. 2004;23:322–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Emery VC, Hassan-Walker AF, Burroughs AK, Griffiths PD. Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts. J Infect Dis 2002;185:1723–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Cope AV, Sabin C, Burroughs A, Rolles K, Griffiths PD, Emery VC. Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation. J Infect Dis 1997;176:1484–90.CrossRefPubMedGoogle Scholar
  28. 28.
    Gor D, Sabin C, Prentice HG, Vyas N, Man S, Griffiths PD, Emery VC. Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease. Bone Marrow Transplant. 1998;21:597–605.CrossRefPubMedGoogle Scholar
  29. 29.
    Jeena PM, Coovadia HM, Chrystal V. Pneumocystis carinii and cytomegalovirus infections in severely ill, HIV-infected African infants. Ann Trop Paediatr. 1996;16:361–8.PubMedGoogle Scholar
  30. 30.
    Rabie H, de Boer A, van den Bos S, Cotton MF, Kling S, Goussard P. Children with human immunodeficiency virus infection admitted to a paediatric intensive care unit in South Africa. J Trop Pediatr. 2007;53:270–3.PubMedGoogle Scholar
  31. 31.
    McNally LM, Jeena PM, Gajee K, Thula SA, Sturm AW, Cassol S, Tomkins AM, Coovadia HM, Goldblatt D. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet. 2007;369:1440–51.CrossRefPubMedGoogle Scholar
  32. 32.
    O’Connell N, Rabie H, Freeman N, Cotton M Cytomegalovirus retinitis in HIV-1 infected South African children. 2009. In 5th International AIDS Society Conference on pathogenesis and treatment, Cape Town, South Africa.Google Scholar
  33. 33.
    Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, Dankner W, Starr S, Pass R, Stagno S et al. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Clin Pharmacol Ther. 1993;53:15–21.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhou XJ, Gruber W, Demmler G, Jacobs R, Reuman P, Adler S, Shelton M, Pass R, Britt B, Trang JM, Whitley RJ, Sommadossi JP. Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Antimicrob Agents Chemother. 1996;40:2202–5.PubMedGoogle Scholar
  35. 35.
    Pacifici GM. Pharmacokinetics of antivirals in neonate. Early Hum Dev. 2005 Sep;81(9):773–80.Google Scholar
  36. 36.
    Luck S, Sharland M, Griffiths P, Jenkins S. Advances in the antiviral therapy of herpes virus infection in children. Amend Expert Rev Anti Infect Ther. 2006;4(6):1005–20.Google Scholar
  37. 37.
    Kimberlin DW, Acosta EP, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang D, Romero JR, Griffin J, Cloud GA, Lakeman FD, Whitley RJ. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis 2008;197:836–45.CrossRefPubMedGoogle Scholar
  38. 38.
    Jacqz-Aigrain E, Macher MA, Sauvageon-Marthe H, Brun P, Loirat C. Pharmacokinetics of ganciclovir in renal transplant children. Pediatr Nephrol. 1992;6:194–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang D, Lapeyraque AL, Popon M, Loirat C, Jacqz-Aigrain E. Pharmacokinetics of ganciclovir in pediatric renal transplant recipients. Pediatr Nephrol. 2003;18:943–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Vethamuthu J, Feber J, Chretien A, Lampe D, Filler G. Unexpectedly high inter- and intrapatient variability of ganciclovir levels in children. Pediatr Transplant. 2007;11:301–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Sugawara M, Huang W, Fei YJ, Leibach FH, Ganapathy V, Ganapathy ME. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci. 2000;89:781–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Razonable RR, Paya CV. Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts. Expert Rev Anti Infect Ther. 2004;2:27–41.CrossRefPubMedGoogle Scholar
  43. 43.
    Acosta EP, Brundage RC, King JR, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang D, Romero JR, Griffin J, Cloud G, Whitley R, Kimberlin DW. Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation. Clin Pharmacol Ther. 2007;81:867–72.CrossRefPubMedGoogle Scholar
  44. 44.
    Meine Jansen CF, Toet MC, Rademaker CM, Ververs TF, Gerards LJ, van Loon AM. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med. 2005;33:364–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhao W, Baudouin V, Zhang D, Deschenes G, Guellec CL, Jacqz-Aigrain. E. Population pharmacokinetics of ganciclovir following administration of valganciclovir in paediatric renal transplant patients. Clin Pharmacokinet. 2009;48:321–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Strazielle N, Ghersi-Egea JF. Factors affecting delivery of antiviral drugs to the brain. Rev Med Virol. 2005;15:105–33.CrossRefPubMedGoogle Scholar
  47. 47.
    Fletcher C, Sawchuk R, Chinnock B, de Miranda P, Balfour HH Jr. Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986;40:281–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Lycke J, Malmestrom C, Stahle L. Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir. Antimicrob Agents Chemother. 2003;47:2438–41.CrossRefPubMedGoogle Scholar
  49. 49.
    Nigro G, Scholz H, Bartmann U. Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience. J Pediatr 1994;124(2):318–22.CrossRefPubMedGoogle Scholar
  50. 50.
    Whitley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF, Dankner W, Spector SA, Starr S, Pass RF, Stagno S, Britt WJ, Alford C Jr, Soong S, Zhou XJ, Sherrill L, FitzGerald JM, Sommadossi JP. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1997;175:1080–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Cinque P, Baldanti F, Vago L, Terreni MR, Lillo F, Furione M, Castagna A, Monforte AD, Lazzarin A, Linde A. Ganciclovir therapy for cytomegalovirus (CMV) infection of the central nervous system in AIDS patients: monitoring by CMV DNA detection in cerebrospinal fluid. J Infect Dis 1995;171:1603–6.PubMedGoogle Scholar
  52. 52.
    Emery VC, Cope AV, Bowen EF, Gor D, Griffiths PD. The dynamics of human cytomegalovirus replication in vivo. J Exp Med. 1999;190:177–82.CrossRefPubMedGoogle Scholar
  53. 53.
    Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci USA. 2000;97:8039–44.CrossRefPubMedGoogle Scholar
  54. 54.
    Boivin G, Goyette N, Rollag H, Jardine AG, Pescovitz MD, Asberg A, Ives J, Hartmann A, Humar A. Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antivir Ther. 2009;14:697–704.PubMedGoogle Scholar
  55. 55.
    Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000;356:645–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Kiell JM, Soong SJ, Whitley RJ. 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.CrossRefPubMedGoogle Scholar
  57. 57.
    Tomicic MT, Bey E, Wutzler P, Thust R, Kaina B. Comparative analysis of DNA breakage, chromosomal aberrations and apoptosis induced by the anti-herpes purine nucleoside analogues aciclovir, ganciclovir and penciclovir. Mutat Res. 2002;505:1–11.PubMedGoogle Scholar
  58. 58.
    Michaels MG, Greenberg DP, Sabo DL, Wald ER. Treatment of children with congenital cytomegalovirus infection with ganciclovir. Pediatr Infect Dis J 2003;22:504–8.Google Scholar
  59. 59.
    Rojo P and Ramos JT. Ganciclovir treatment of children with congenital cytomegalovirus infection. Pediatr Infect Dis J 2004;23:80–8.Google Scholar
  60. 60.
    Tanaka-Kitajima N, Sugaya N, Futatani T, Kanegane H, Suzuki C, Oshiro M, Hayakawa M, Futamura M, Morishima T and Kimura H. Ganciclovir therapy for congenital cytomegalovirus infection in six infants. Pediatr Infect Dis J 2005;24:782–5.Google Scholar
  61. 61.
    Oliver S, Cloud G, Sánchez P, Demmler G, Dankner W, Shelton M, Jacobs R, Vaudry W, Pass R, Soong S, Whitley R, Kimberlin D. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009 Dec;46(Suppl 4):S22–S26.Google Scholar
  62. 62.
    Muller A, Eis-Hubinger AM, Brandhorst G, Heep A, Bartmann P, Franz AR. Oral valganciclovir for symptomatic congenital cytomegalovirus infection in an extremely low birth weight infant. J Perinatol. 2008;28:74–6.CrossRefPubMedGoogle Scholar
  63. 63.
    Takahashi R, Tagawa M, Sanjo M, Chiba H, Ito T, Yamada M, Nakae S, Suzuki A, Nishimura H, Naganuma M, Tominaga N, Moriuchi M, Moriuchi H. Severe postnatal cytomegalovirus infection in a very premature infant. Neonatology. 2007;92:236–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Fischler B, Casswall TH. Malmborg P and Nemeth A. Ganciclovir treatment in infants with cytomegalovirus infection and cholestasis. J Pediatr Gastroenterol Nutr. 2002;34:154–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Nigro G, Krzysztofiak A, Bartmann U, Clerico A, Properzi E, Valia S, Castello M. Ganciclovir therapy for cytomegalovirus-associated liver disease in immunocompetent or immunocompromised children. Arch Virol. 1997;142:573–80.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mike Sharland
    • 1
    Email author
  • Suzanne Luck
    • 2
    • 3
    • 4
  • Paul Griffiths
    • 5
  • Mark Cotton
    • 6
  1. 1.Paediatric Infectious Diseases UnitSt. George’s HospitalLondonUK
  2. 2.Kingston HospitalLondonUK
  3. 3.University College LondonLondonUK
  4. 4.Royal Free HospitalLondonUK
  5. 5.University College London, Centre for Virology, Royal Free HospitalLondonUK
  6. 6.Children’s Infectious Diseases Clinical Research Unit (KID-CRU)University of StellenboschCape TownSouth Africa

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