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High-Dose Acyclovir Compared with Short-Course Preemptive Ganciclovir Therapy To Prevent Cytomegalovirus Disease in Liver Transplant Recipients: A Randomized Trial

Nina Singh, MD; Victor L. Yu, MD; Luis Mieles, MD; Marilyn M. Wagener, MPH; Richard C. Miner, BA; and Timothy Gayowski, MD
[+] Article, Author, and Disclosure Information

From the Veterans Affairs Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mount Zion Medical Center of the University of San Francisco, San Francisco, California. Requests for Reprints: Victor L. Yu, MD, Infectious Disease Section, Veterans Affairs Medical Center, University Drive C, Pittsburgh, PA 15240. Acknowledgments: The authors thank Shirley Brinker and Linda Szalla for the preparation of this manuscript and Margaret Kraft, RN, Brenda Brown, RN, and Cheryl Wannstedt, RN, for collection of specimens for CMV cultures.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;120(5):375-381. doi:10.7326/0003-4819-120-5-199403010-00004
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Objective: To assess the efficacy of high-dose oral acyclovir therapy compared with preemptive, short-course ganciclovir therapy (administered only if cytomegalovirus [CMV] shedding occurred) to prevent CMV disease in liver transplant recipients.

Design: A randomized, controlled trial.

Setting: Liver transplant center at a university-affiliated Veterans Affairs Medical Center.

Patients: 47 consecutive patients having liver transplantation.

Intervention: Patients were stratified by their CMV antibody status and the CMV antibody status of the donor and were randomly assigned to one of two treatment groups. Surveillance cultures for CMV (buffy coat and urine) were done every 2 to 4 weeks for 24 weeks in all patients. One group received high-dose oral acyclovir (800 mg four times daily). The experimental group received no acyclovir, but if surveillance cultures were positive, ganciclovir (5 mg/kg intravenously twice daily) was administered for 7 days.

Measurements: Cytomegalovirus shedding and CMV disease were measured in the two groups.

Results: Cytomegalovirus shedding before the onset of CMV disease occurred in 25% (6 of 24) of patients in the acyclovir group compared with 22% (5 of 23) in the experimental group. Cytomegalovirus disease developed in 29% (7 of 24) of the acyclovir group and in 4% (1 of 23) of the experimental group (P < 0.05). No hematologic toxicity occurred with ganciclovir.

Conclusion: Oral acyclovir is ineffective prophylaxis against CMV in liver transplant recipients. Preemptive, short-course ganciclovir therapy in patients with CMV shedding was well tolerated and provided effective prophylaxis against subsequent CMV disease; this protocol targets the patients at risk for CMV disease and minimizes toxicity and expense.


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Figure 1.
Flow chart representing the study design.

Note that the experimental group did not receive acyclovir. Two approaches were used for the experimental group. First, antiviral prophylaxis was not used for patients who were not shedding virus. Second, preemptive ganciclovir therapy was used only if cytomegalovirus (CMV) shedding was observed. Buffy coat and urine cultures for CMV were done 2, 4, 6, 8, 12, 16, and 24 weeks after transplantation.

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Figure 2.
Cumulative probability (Kaplan-Meier curve) of a patient shedding cytomegalovirus where the end point is first viral isolation.nn

The probability of shedding cytomegalovirus was not statistically different between the acyclovir group ( = 24) and the experimental group ( = 23). Three patients died without viral shedding, one in the acyclovir group at about 5 weeks after transplantation and two in the experimental group, both at approximately 4 weeks after transplantation.

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Figure 3.
The frequency and timing of cytomegalovirus infection and disease in the two study groups.

CMV = cytomegalovirus.

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Figure 4.
The cumulative probability (Kaplan-Meier curves) of cytomegalovirus disease in the acyclovir (n = 24) and experimental groups (n = 23).P

The probability of disease differed between the two groups ( = 0.03). Four patients died without any evidence of cytomegalovirus disease before the end of study, one in the acyclovir group at about 5 weeks after transplantation and three in the experimental group at 4, 4, and 10 weeks after transplantation.

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