Correspondence
Valacyclovir to Prevent Cytomegalovirus Disease after Renal Transplantation
N Engl J Med 1999; 341:921September 16, 1999
- Article
To the Editor:
In their placebo-controlled study, Lowance et al. (May 13 issue)1 found that treatment with valacyclovir markedly reduced the incidence of cytomegalovirus (CMV) disease after renal transplantation. The reduction in CMV disease among CMV-seronegative recipients was accompanied by a 50 percent reduction in the rate of acute graft rejection. Of concern, however, is the fact that this study was performed with a placebo control. The authors state that this approach was acceptable because “there was no accepted standard regimen of prophylaxis at the inception of the study.” At the time the study began — July 7, 1992 — there were prophylactic regimens with demonstrated efficacy against CMV in renal-transplant recipients. In fact, the use of both CMV immune globulin2,3 and acyclovir4 had been reported in the Journal and elsewhere to reduce the incidence of CMV disease significantly after renal transplantation. Thus, the use of a placebo control in seronegative recipients of kidneys from CMV-seropositive donors subjected these patients to an unnecessary and unacceptable risk. It would have been more appropriate to use acyclovir prophylaxis as the control treatment, as was recently done in a controlled trial of oral ganciclovir.5
5 ReferencesMichael E. Shapiro, M.D.
Joan M. Abrams, R.N.
Hackensack University Medical Center, Hackensack, NJ 076011
Lowance D ,Neumayer H-H ,Legendre CM , et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med 1999;340:1462-1470
Full Text | Web of Science | Medline2
Snydman DR ,Werner BG ,Heinze-Lacey B , et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med 1987;317:1049-1054
Full Text | Web of Science | Medline3
Snydman DR ,Werner BG ,Tilney NL , et al. Final analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus-immune globulin: comparison of the randomized and open-label trials. Transplant Proc 1991;23:1357-1360
Web of Science | Medline4
Balfour HH Jr ,Chace BA ,Stapleton JT ,Simmons RL ,Fryd DS . A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989;320:1381-1387
Full Text | Web of Science | Medline5
Flechner SM ,Avery RK ,Fisher R , et al. A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998;66:1682-1688
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We appreciate the concern of Shapiro and Abrams, and we are well aware of the studies they cited. Although many renal-transplant physicians now consider high-dose oral acyclovir to be the gold standard for CMV prophylaxis after kidney transplantation, this was not uniformly the case when our study was designed.
The study by Balfour et al.1 was small and has been criticized by many because of its size and the unusually high rate of disease (100 percent) reported in the CMV-negative group receiving placebo. In the absence of a confirmatory study with sufficient numbers of patients, many transplant physicians were reluctant to consider acyclovir therapy as a routine CMV prophylactic strategy. CMV hyperimmune globulin has been shown to be effective, but it must be administered intravenously, is very costly, and still has not gained wide acceptance in the transplantation community.
At the time our study was designed, we thought that it was imperative to answer the question regarding the efficacy of valacyclovir as a preventive treatment and at the same time to avoid exposing any of our patients to undue risk. The protocol stipulated that the investigator at each center was allowed to stop the study drug if CMV infection was suspected and to intervene with the most appropriate therapy. The centers that participated in the study did not use prophylaxis as the routine strategy for the prevention of CMV; most relied on the preemptive approach.2 The protocol was approved at all the study centers by institutional review boards or ethics committees. The question of the efficacy of valacyclovir was answered and the safety of the study validated by the outcomes. We do not agree that the study design entailed unacceptable risks to the patients.
2 ReferencesDavid Lowance, M.D.
Piedmont Hospital, Atlanta, GA 30367Michael R. Keating, M.D.
St. Mary's Hospital, Rochester, MN 559021
Balfour HH Jr ,Chace BA ,Stapleton JT ,Simmons RL ,Fryd DS . A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989;320:1381-1387
Full Text | Web of Science | Medline2
Rubin RH . Preemptive therapy in immunocompromised hosts. N Engl J Med 1991;324:1057-1059
Full Text | Web of Science | Medline
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Sanae Numata, Yoshiro Koda, Kenji Ihara, Tomo Sawada, Yoshiyuki Okano, Toshinobu Matsuura, Fumio Endo, Han-Wook Yoo, Jose A Arranz, Vicente Rubio, Bendicht Wermuth, Nicholas Ah Mew, Mendel Tuchman, Jason R Pinner, Edwin P Kirk, Makoto Yoshino. (2010) Mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients have recurrently arisen and have been retained in some populations. Journal of Human Genetics 55:1, 18-22
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E Ploechl, W Ploechl, S Stoeckler-Ipsiroglu, H Pokorny, B Wermuth. (2001) Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon. Clinical Genetics 59:2, 111-114
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