Articles Introduction Cytomegalovirus infection is common in recipients of solid-organ transplants; more than 50% of recipients have laboratory evidence of primary or reactivated cytomegalovirus infection in the first year after transplantation. 1 Clinical sequelae of cytomegalovirus infection have been divided into the direct effects of viral replication (fever, leucopenia, and thrombocytopenia with or without specific organ dysfunction) and indirect effects resulting from the influence of the virus on the host’s immune response. The indirect effects include acute rejection of the transplanted organ, 2 reduced long- term graft function, 3,4 and increased risk of other opportunistic infections. 5 Before prophylaxis was widely used, cytomegalovirus disease occurred in 7–32% of recipients of solid-organ transplants; the risk was lowest in kidney recipients and highest in heart-lung recipients. 6 After the initial infection, cytomegalovirus persists throughout life in the host, with periodic reactivation. In general, primary infection is associated with the highest risk of disease. De-novo infection with a new cytomegalovirus strain can also occur in a cytomegalo- virus-positive individual. Cytomegalovirus-negative recipients of organs from donors positive for the virus 2,4,7 and recipients being treated with antibodies to lymphocyte antigens are at higher risk of developing symptomatic cytomegalovirus disease. 8 The high risk of sequelae from cytomegalovirus infection in recipients of solid-organ transplants has resulted in the widespread use of antiviral prophylaxis or pre-emptive therapy to prevent cytomegalovirus disease, but many questions remain unanswered. Does cytomegalovirus prophylaxis reduce mortality or the indirect effects of cytomegalovirus infection? What is the best regimen to prevent cytomegalovirus disease? Which recipients should be given prophylaxis? In this systematic review we aimed to answer these questions. Methods Design We included randomised controlled trials comparing antiviral medications with placebo or no treatment, comparing different combinations of antiviral medica- tions, or comparing different dosing regimens of the same antiviral medication to prevent cytomegalovirus disease in recipients of solid-organ transplants. Other interventions were excluded from this study because they are less commonly used (cytomegalovirus immuno- globulin), are experimental only (cytomegalovirus vaccines and interferon), or warrant a separate systematic Lancet 2005; 365: 2105–15 Published online May 31, 2005 DOI:10.1016/S0140-6736(05) 66553-1 National Health and Medical Research Council Centre for Clinical Research Excellence, Centre for Kidney Research (E M Hodson MB, A C Webster MB, G F M Strippoli MD, D Vimalachandra MPH, J C Craig PhD) and Herpesvirus Research Unit (C A Jones PhD), The Children’s Hospital at Westmead, Sydney, Australia; Departments of Pharmacy (P G Barclay BPharm) and Renal Medicine (K Kable MN), Westmead Hospital, Sydney, Australia; School of Public Health (E M Hodson, A C Webster, J C Craig) and Discipline of Paediatrics and Child Health (C A Jones), University of Sydney, Sydney, Australia; and Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari, Italy (G F M Strippoli) Correspondence to: Dr Elisabeth Hodson, Centre for Kidney Research, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia Elisah@chw.edu.au www.thelancet.com Vol 365 June 18, 2005 2105 Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials Elisabeth M Hodson, Cheryl A Jones, Angela C Webster, Giovanni F M Strippoli, Peter G Barclay, Kathy Kable, Dushyanthi Vimalachandra, Jonathan C Craig Summary Background Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. Methods Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid- organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. Findings Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0·42 [95% CI 0·34–0·52]), cytomegalovirus infection (17 trials, 1786 patients; 0·61 [0·48–0·77]), and all-cause mortality (17 trials, 1838 patients; 0·63 [0·43–0·92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0·26 [0·08–0·78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. Interpretation Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus- positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.