Bührer, Christoph

Schulzke, Sven

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Eur J Pediatr (2006) 165: 575–576DOI 10.1007/s00431-006-0109-0SHORT REPORTSven Schulzke . Christoph BührerValganciclovir for treatment of congenital cytomegalovirusinfectionReceived: 27 October 2005 / Accepted: 8 February 2006 / Published online: 14 March 2006# Springer-Verlag 2006Keywords Cytomegalovirus . Congenital . ValganciclovirAbbreviations CMV: Cytomegalovirus . HIV: Humanimmunodeficiency virus . ANC: Absolute neutrophilcounts . PCR: Polymerase chain reactionGanciclovir, administered via an intravenous central lineover 6 weeks to newborn infants symptomatically infectedwith cytomegalovirus (CMV), has been shown to preventprogressive disease, as gauged by less hearing deteriora-tion, in a randomized phase III trial [2]. However, almosttwo-thirds of treated infants have significant neutropeniaduring therapy, and some get infections related to indwell-ing intravenous catheters [2, 3]. The valine ester ofganciclovir, valganciclovir, is an orally applicable prodrugsuccessfully used in transplant recipients and humanimmunodeficiency virus (HIV) patients. Bioavailabilityof ganciclovir from oral valganciclovir has been reported tobe about 60% in adults and 43% in a 6-year-old child [1]while it has been difficult to attain stable ganciclovir serumlevels with oral valganciclovir in a newborn infant as wasrecently published [4].We report on a term newborn girl with symptomaticCMV infection presenting with hepatosplenomegaly,“blueberry muffin” rash, thrombocytopenia, elevated liverenzymes, lenticulostriate vasculopathy, periventricularcalcifications, partial polymicrogyria, and severe hearingimpairment (hearing thresholds 100 and 120 dB). Shetested positive for anti-CMV IgG and IgM, and CMV wasdetected in urine and blood by culture and polymerasechain reaction (PCR).On day 4 of life, ganciclovir was started via central venousaccess as described [2]. While the rash and hepatospleno-megaly resolved completely, there was progressive anemia(nadir of hemoglobin 7.8 g/dl) treated with oral iron. Plateletcounts dropped to 26,000/μl immediately prior to start ofganciclovir but recovered quickly thereafter, remainingabove 200,000/μl. However, intravenous ganciclovir wasreduced and eventually discontinued when her absoluteneutrophil counts (ANC) dropped <500/μl (Table 1). Thecentral line was removed, and after informed parentalconsent and notification of the Swiss federal healthcareauthority, oral treatment with valganciclovir (Valcyte,Roche, Switzerland) was commenced as soon as ANCrose to 540 cells/μl at 20 days of life. Oral valganciclovir wasincrementally increased up to 56 mg/kg per day as long asganciclovir serum trough levels were <1 mg/l and ANC>1,000/μl. This regimen did not result in relapse ofneutropenia, while CMV viral load fell below the detectionlimit of 600 copies/ml (Table 1). Valganciclovir wasdiscontinued after a total of 6 weeks on medication [2]. Nofurther side effects were noted. For the last 4 weeks, she wasseen as an outpatient. When last examined at 9 months ofage, she was well, equipped with hearing aids, and beingevaluated for cochlear implants.Thus, substituting oral valganciclovir for intravenousganciclovir in term newborn infants is feasible, resulting inganciclovir serum concentrations in the range associatedwith CMV control [6], eventual suppression of CMVviremia, and significant cost savings, as much of thetherapy can be done on an outpatient basis. In addition, itallows for studies aiming at extending the time ofadministration beyond 6 weeks [4] and also including notovertly symptomatic infants with congenital CMV infec-tion [5]. However, the complex relationship betweenvalganciclovir dose and serum levels in this and the onlyother report so far [4] points to the need for priorpharmacokinetic studies.S. Schulzke . C. Bührer (*)Department of Neonatology,Universitäts-Kinderspital beider Basel,4005 Basel, Switzerlande-mail: christoph.buehrer@ukbb.chTel.: +41-61-2659565Fax: +41-61-2659568References1. Burri M, Wiltshire H, Kahlert C, Wouters G, Rudin C (2004)Oral valganciclovir in children: single dose pharmacokinetics ina six-year-old girl. Pediatr Infect Dis J 23:263–2662. Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W,Shelton M, Jacobs RF, Vaudry W, Pass RF, Kiell JM, Soong SJ,Whitley RJ, National Institute of Allergy and InfectiousDiseases Collaborative Antiviral Study Group (2003) Effectof ganciclovir therapy on hearing in symptomatic congenitalcytomegalovirus disease involving the central nervous system:a randomized, controlled trial. J Pediatr 143:16–253. Michaels MG, Greenberg DP, Sabo DL, Wald ER (2003)Treatment of children with congenital cytomegalovirus infec-tion with ganciclovir. Pediatr Infect Dis J 22:504–5094. Meine Jansen CF, Toet MC, Rademaker CM, Ververs TF,Gerards LJ, van Loon AM (2005) Treatment of symptomaticcongenital cytomegalovirus infection with valganciclovir. JPerinat Med 33:364–3665. Modlin JF, Grant PE, Makar RS, Roberts DJ, KrishnamoorthyKS (2003) Case records of the Massachusetts General Hospital.Weekly clinicopathological exercises. Case 25-2003. A new-born boy with petechiae and thrombocytopenia. N Engl J Med349:691–7006. Piketty C, Bardin C, Gilquin J, Gairard A, Kazatchkine MD,Chast F (2000) Monitoring plasma levels of ganciclovir inAIDS patients receiving oral ganciclovir as maintenancetherapy for CMV retinitis. Clin Microbiol Infect 6:117–120Table 1 Absolute neutrophilcounts (ANC), ganciclovirplasma trough levels (kindlymeasured by Dr. M. Oellerich,Göttingen, Germany) andCMV plasma loads (kindly de-termined by Dr. K. Hamprecht,Tübingen, Germany) in thenewborn infant with symptom-atic congenital CMV infectionsequentially treated withintravenous ganciclovir andoral valganciclovirAged(days)ANCcells/μlGanciclovir dose(mg/kg per day)Valganciclovir dosemg (mg/kg per day)Ganciclovir plasmatrough level (mgl/l)CMV plasmaload (copies/ml)1 3,1954 880 2×12 (9.2)7 825 2×12 (9.7) 0.2615 517 2×6 (4.5) 0.64 1,71518 442 – –20 540 2×18 (12.8)24 528 2×18 (12.4) 1.33 67129 998 2×18 (12.0) 0.4131 1596 2×38 (24.9)38 1541 2×80 (49.4)43 956 2×100 (58.9) 0.97 <60050 1400 2×100 (56.0) 0.80 <600576

Valganciclovir for treatment of congenital cytomegalovirus infection

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Valganciclovir for treatment of congenital cytomegalovirus infection

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