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Preemptive Ganciclovir Therapy To Prevent Cytomegalovirus Disease in Cytomegalovirus Antibody-Positive Renal Transplant Recipients: A Randomized Controlled Trial

Patricia L. Hibberd, MD, PhD; Nina E. Tolkoff-Rubin, MD; David Conti, MD; Frank Stuart, MD; J. Richard Thistlethwaite, MD; John F. Neylan, MD; David R. Snydman, MD; Richard Freeman, MD; Marc I. Lorber, MD; and Robert H. Rubin, MD
[+] Article and Author Information

From Massachusetts General Hospital and New England Medical Center, Boston, Massachusetts. Yale University School of Medicine, New Haven, Connecticut. Albany Medical College, Albany, New York. Northwestern Memorial Hospital and University of Chicago Medical Center, Chicago, Illinois. Emory University Medical School, Atlanta, Georgia. For author affiliations and current author addresses, see end of text. Requests for Reprints: Patricia L. Hibberd, MD, PhD, Infectious Disease Unit, Massachusetts General Hospital, Fruit Street, GRJ-504, Boston, MA 02114. Acknowledgments: The authors thank Maureen Doran, RN, MPH, and Angela DelVecchio, RN, for collecting the data from the six study sites, ensuring its completeness and accuracy, and doing the data entry. The authors also thank Drs. A. Benedict Cosimi and Nesli O. Basgoz for their assistance with this study. Grant Support: In part by a grant from Ortho Pharmaceutical Corporation. Ganciclovir was provided by Syntex Laboratories, Inc.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(1):18-26. doi:10.7326/0003-4819-123-1-199507010-00002
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Objective: To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody.

Design: Randomized, controlled, multicenter trial.

Setting: 6 university-affiliated transplantation centers.

Patients: 113 renal transplant recipients who were positive for cytomegalovirus antibody.

Intervention: Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy.

Measurements: Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia.

Results: Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional-hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration.

Conclusions: Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.

*For a listing of the members of the Task Force on Principles for Economic Analysis, see Appendix B.

Figures

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Figure 1.
Renal transplant recipients in six transplantation centers.
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Figure 2.
Kaplan-Meier product-limit estimates of the probability of remaining free of cytomegalovirus disease during the 6 months after antilymphocyte antibody therapy and during the 9 months after transplantation.PP

The probability that cytomegalovirus disease will develop after antilymphocyte antibody therapy was different in the two groups ( = 0.008 by the log-rank test). The probability that cytomegalovirus disease will develop after transplantation differed significantly between the two groups ( = 0.007 by the log-rank test). Patients received preemptive ganciclovir therapy during each course of antilymphocyte antibody therapy, whereas controls received no specific anticytomegalovirus therapy during any course of antilymphocyte antibody therapy.

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Figure 3.
Cumulative frequency and timing of cytomegalovirus disease and viremia in the two study groups.

In the preemptive ganciclovir group, cytomegalovirus disease was diagnosed in nine patients a median of 46 days after they received antilymphocyte antibodies. In the control group, cytomegalovirus disease was diagnosed in 16 patients a median of 31 days after they received antilymphocyte antibodies. Patients received preemptive ganciclovir during each course of antilymphocyte antibody therapy, whereas controls received no specific anticytomegalovirus therapy during any course of antilymphocyte antibody therapy.

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