Use of Combination Cytomegalovirus Immune Globulin Plus Ganciclovir for Prophylaxis in CMV-Seronegative Liver Transplant Recipients of a CMV-Seropositive Donor Organ: A Multicenter, Open-Label Study D.R. Snydman, M.E. Falagas, R. Avery, C. Perlino, R. Ruthazer, R. Freeman, R. Rohrer, R. Fairchild, E. O’Rourke, P. Hibberd, and B.G. Werner T HE ORIGINAL PROPHYLACTIC studies of cyto- megalovirus immune globulin for the prevention of cytomegalovirus (CMV) disease in orthotopic liver trans- plantation failed to reduce the rate of CMV disease in patients at highest risk, namely the CMV-seronegative recipient of the CMV-seropositive donor organ. 1 These patients are associated with poorer survival 2 than other liver transplant recipients and remain at highest risk for both the direct and indirect effects of CMV. 2–4 A number of CMV prophylactic strategies have been studied in OLT recipients to decrease the CMV-related morbidity and mortality. 1,5–14 Antiviral agents have had varying degrees of success in the prevention of primary CMV disease in liver transplantation. 8 –11 Antiviral prophy- laxis with oral or intravenous ganciclovir for the first 100 or more days posttransplant reduces the incidence of CMV disease. 9,12 However, the use of IV ganciclovir or oral ganciclovir for 100 days is costly, may be potentially toxic, and may result in the development of ganciclovir-resistant mutants. 15 Furthermore, it has been generally recognized that the CMV D+/R- patients are most likely to fail prophylaxis. 1,9,10 Recent observations provide the basis for the use of a combination approach using an antiviral with CMV im- mune globulin. In animal models the use of combination CMVIG plus ganciclovir may have a synergistic effect against CMV-associated mortality, 16 and immune globulin and CMV immune globulin plus intravenous ganciclovir are effective in the therapy of CMV-associated interstitial pneu- monitis in bone marrow transplantation. 17 We report the results of a prospective, multicenter, open-label trial of CMV immune globulin plus intravenous ganciclovir in the prevention of CMV disease in liver transplant recipients at risk for primary CMV disease. METHODS Study Population Eligible patients included children and adults who underwent liver transplantation at the participating centers: New England Medical Center, Children’s Hospital, and Massachusetts General Hospital, Boston, Massachusetts; Cleveland Clinic Foundation, Cleveland, Ohio; and Emory University Hospital, Atlanta, Georgia. The study protocol was approved by the human investigation review commit- tee of each institution. Microbiologic and serologic studies, follow-up, and case defini- tions of infection-associated outcomes were based on study proto- cols used in our previous trials of CMV prophylaxis in OLT recipients. 1,2,4 After enrollment, patients were followed weekly for the first 8 weeks after transplantation, monthly for the next 6 months, and at 1 year. Clinical care was individualized by the transplantation team at each institution. Laboratory studies were performed at enrollment, weekly for 2 months, when special problems arose, and at scheduled follow-up visits. Standard medi- cations during the induction phase of immunosuppression included cyclosporine or tacrolimus, azathioprine, and steroid. Acute rejec- tion was treated with intravenous bolus infusions of methylpred- nisolone; steroid-refractory rejection was treated with OKT3. Study Drugs The CMVIG (CytoGam) was supplied by MedImmune (Gaithers- burg, Md., USA) and produced by the Massachusetts Public Health Biologic Laboratories. 1 CMVIG was given at a dose of 150 mg per kg of body weight within 72 hours of transplantation, then at 2, 4, 6, and 8 weeks after transplantation and at a dose of 100 mg per kg of body weight at 12 and 16 weeks after transplantation. Ganciclo- vir was given for 2 weeks after transplantation at a dose of 5 mg/kg intravenously twice a day (dose was adjusted in cases of renal dysfunction). Additional prophylactic ganciclovir was given for each rejection episode if that episode was treated with antilympho- cyte therapy 12,18 at a dose of 5 mg/kg IV qd during each day of treatment for rejection. Peripheral blood leukocytes were obtained for viral isolation From the New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts; Cleveland Clinic Foundation, Cleveland, Ohio; Emory University, Atlanta, Geor- gia; Children’s Hospital of Boston, Massachusetts General Hos- pital, and Harvard Medical School,Boston, Massachusetts; and Massachusetts State Laboratory Institute, Boston, Massachu- setts. Address reprint requests to David R. Snydman, MD, New England Medical Center, 750 Washington Street, Box 238, Boston, MA 02111. © 2001 by Elsevier Science Inc. 0041-1345/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(01)02101-7 Transplantation Proceedings, 33, 2571–2575 (2001) 2571