Practice point www.nature.com/clinicalpractice/neph Utility of oral valganciclovir for the treatment of cytomegalovirus disease after renal transplantation

Original article Asberg A et al. (2007) Oral valganciclovir is OUTCOME MEASURES noninferior to intravenous ganciclovir for the treatment of The primary end point was eradication of CMV cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 7: 2106–2113 viremia, defined as <600 virus copies per ml plasma, after 21 days. Secondary end points SYNOPSIS included the rate of clinical resolution of CMV keywords cytomegalovirus, ganciclovir, disease and the rate of adverse events. renal transplantation, treatment, valganciclovir RESULTS BACKGROUND A total of 333 patients were screened Standard therapy for cytomegalovirus (CMV) between April 2004 and June 2006. Of the disease in recipients of solid organ transplants 321 patients who comprised the intention- comprises intravenous ganciclovir, which is to-treat population, 164 (122 kidney transplant costly and inconvenient to administer. recipients) had been randomized to receive valganciclovir and 157 (115 kidney transplant OBJECTIVE recipients) to receive ganciclovir. Clinical To compare the efficacy and safety of intravenous presentation of CMV disease, incidence of ganciclovir with that of its orally administered previous anti-CMV therapy, and baseline CMV prodrug, valganciclovir, for the treatment of serostatus were similar in the two groups. By CMV disease after solid organ transplantation. day 21, CMV viremia had been eradicated in 45.1% (74) of the valganciclovir-treated DESIGN patients and in 48.4% (76) of the ganciclovir- This open-label, noninferiority trial (‘VICTOR’) treated patients (95% CI for difference –14% enrolled adult solid organ transplant recipients to 8%); therefore, valganciclovir met the from five continents who had CMV in their blood noninferiority criterion of achieving 50% eradi­ and symptoms consistent with CMV disease. cation, within a range of –15%. Rates of viral Life-threatening CMV disease, resistance to eradication remained comparable for valgan- ganciclovir, and Cockcroft–Gault-estimated ciclovir and ganciclovir at study end (67.1% creatinine clearance <10 ml/min were among [110 patients] and 70.1% [110 patients], the exclusion criteria. respectively). Rates of clinical resolution were similar in the two groups at 21 days INTERVENTION (77.4% [127 patients] for valganciclovir; Participants were randomized to receive induc- 80.3% [126 patients] for ganciclovir) and at tion treatment with either oral valganciclovir 49 days (85.4% [140 patients] and 84.1% [132 900 mg twice daily or intravenous ganciclovir patients], respectively). The kinetics of viral 5 mg/kg twice daily, for 21 days. After 21 days, eradication were also similar in the two groups, patients in both groups underwent maintenance according to the per-protocol analysis. There treatment with valganciclovir 900 mg/day for were no differences in the rates of treatment 28 days. Doses of both drugs were adjusted discontinuation or adverse events between according to Cockcroft–Gault-estimated creati- the groups. nine clearance. Use of other antiviral agents (such as aciclovir), interferons and CMV hyperimmune CONCLUSION globulin was prohibited. CMV load was meas- Oral valganciclovir is not inferior to intravenous ured with a polymerase chain reaction assay at ganciclovir for the treatment of CMV disease baseline, on days 3, 7, 10, 14, 17 and 21, and in renal transplant recipients and has a similar weekly thereafter until study end (49 days). adverse event profile.

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COMMENTARY were, however, longer than that reported in Acknowledgments a recent observational study of pre-emptive The synopsis was written 6 by Chloë Harman, David A Pegues valganciclovir therapy. These findings empha- Associate Editor, size the need for at least weekly monitoring of Nature Clinical Practice. Over 75% of solid organ transplant recipients are blood viral load in patients receiving treatment at risk of the direct and indirect effects of CMV for CMV disease, and the fact that suppression Competing interests The author declared no disease, which include viremia, tissue invasion, of viremia rather than arbitrary cutoff points competing interests. secondary bacterial and fungal infection, graft (e.g. 14 or 21 days) should be used to guide the rejection and loss, and death.1 The prevention and duration of therapy. Correspondence David Geffen School of treatment of CMV disease in this setting has been The results of the VICTOR trial provide Medicine at UCLA recently reviewed.2,3 Valganciclovir, the oral valine important information for clinicians, but Division of Infectious Diseases prodrug of ganciclovir, is effective for the primary questions remain to be answered. Pediatric 37-121 CHS prevention of CMV disease after solid organ patients and those with severe CMV disease 10833 Le Conte Avenue transplantation.4 Intravenous ganciclovir remains were excluded, and the impact on virologic Los Angeles CA 90095-1688 the standard treatment for CMV disease in solid response of reducing immunosuppression was USA organ transplant patients despite its need for not compared between the two groups. A formal [email protected] long-term intravenous access, the inconvenience economic analysis that included the administra- Received 23 August 2007 of administration, and the substantial cost of tive costs of the two therapies and the cost of Accepted 17 September 2007 hospitalization. Although there are only limited medical care would have been useful, as the phar- Published online data from small, nonrandomized trials, out­ macy acquisition price of intravenous ganciclovir 23 October 2007 www.nature.com/clinicalpractice patient administration of oral valganciclovir has in the US (US$47.50 per 10 ml vial of 500 mg) is doi:10.1038/ncpneph0642 recently emerged as an alternative to intravenous less than that of valganciclovir ($61.50 for two ganciclovir for the management of CMV disease 450 mg capsules). Until further information after solid organ transplantation, particularly for is available, kidney transplant recipients with patients with low-level viremia (<10,000 copies/ml) high CMV viral loads (e.g. >500,000 copies/ml) or mild disease. or severe tissue-invasive disease, and those who The results of the VICTOR study support fail to achieve a reduction in viral load after 7 the efficacy of oral valganciclovir and repre- or more days of oral valganciclovir treatment, sent an important advance in the treatment of should probably be treated with intravenous CMV disease after solid organ transplantation. ganciclovir. Other patients should receive In this large, randomized, multicenter trial, valganciclovir until viremia is eradicated. oral valganciclovir was found to have safety References and efficacy comparable to that of intravenous 1 Fishman JA et al. (2007) Cytomegalovirus in ganciclovir for clearing CMV viremia and transplantation—challenging the status quo. Clin Transplant 21: 149–158 resolving clinical disease. Of those patients with 2 [No authors listed] (2004) Cytomegalovirus. known CMV serostatus, 24% were seronegative Am J Transplant 4 (Suppl 10): S51–S58 and had a seropositive donor; furthermore, a 3 Preiksaitis JK et al. (2005) Canadian society of transplantation consensus workshop on substantial proportion (46%) of patients had cytomegalovirus management in solid organ tissue-invasive infection. Both of these groups transplantation final report. Am J Transplant 5: are at increased risk of severe complications, 218–227 4 Paya C et al. (2004) Efficacy and safety of and typically receive intravenous ganciclovir valganciclovir vs. oral ganciclovir for prevention for CMV disease.1 Despite the inclusion of such of cytomegalovirus disease in solid organ transplant patients in the study, baseline viral load was the recipients. Am J Transplant 4: 611–620 PRACTICE POINT 5 Humar A et al. (2005) A prospective assessment of Renal transplant only predictor of viral suppression. The primary valganciclovir for the treatment of cytomegalovirus recipients with outcome—suppression of CMV viremia after infection and disease in transplant recipients. J Infect CMV disease 3 weeks of induction therapy—was achieved in Dis 192: 1154–1157 should be given oral 6 Mattes FM et al. (2005) Kinetics of cytomegalovirus valganciclovir until only 45–48% of patients, a response rate similar load decrease in solid-organ transplant recipients after viremia is eradicated, to that (46.9–50%) in a recent historically preemptive therapy with valganciclovir. J Infect Dis unless they have controlled trial that compared oral valganciclovir 191: 89–92 a high viral load or severe tissue-invasive with intravenous ganciclovir in solid organ DA Pegues is a Professor of Clinical Medicine disease, or their viral transplant patients.5 The median viral load and Hospital Epidemiologist at the David Geffen load fails to decrease half-lives in the VICTOR trial (11.5 days for School of Medicine at UCLA, Los Angeles, after ≥7 days of treatment valganciclovir and 10.4 days for ganciclovir) CA, USA.

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