Ganciclovir-resistant cytomegalovirus disease in heart transplant recipients: the dilemma of donor-positive/recipient-negative serostatus.

In the early days of heart transplantation, cytomegalovirus (CMV) disease was frequent and often severe. The development of strategies to prevent CMV disease has had a major beneficial effect [1, 2], but problems still remain. Traditionally, patients with donor-seropositive (D+)/recip-ient-seronegative (RϪ) status have had the highest risk of high viral loads, tissue-invasive disease, and ganciclovir resistance [3, 4]. These patients have also been the least likely to reap the benefits of CMV-prevention strategies. For example, in 1992, Merigan et al. [5] conducted a ran-domized trial of a 4-week regimen of intravenous ganciclovir regimen that showed a reduction in the incidence of symptomatic CMV disease from 46% to 9% in the recipient-seropositive (R+) group, whereas the D+/RϪ group experienced little, if any, reduction. However, because many organ donors are CMV se-ropositive, it has not been practical to match donors and recipients on the basis of CMV serostatus. Instead, intensified efforts have been applied to patients with D+/RϪ serostatus, including randomized trials devoted solely to such patients [6, 7]. In the current issue of Clinical Infectious Diseases, Li et al. [8] provide a significant contribution to the literature with their careful analysis of 274 patients who received heart transplants over a 10-year period , in which one cohort () re-n p 40 ceived prophylaxis with a 4-week course of intravenous ganciclovir, followed by oral acyclovir, and another, more recent cohort () received oral ganciclovir n p 191 for 3 months. Although it was not a ran-domized trial, the study yields information of considerable interest to the clinician. Limaye et al. [4] (from the same research group), in a landmark article in The Lancet from 2000, had already described ganci-clovir-resistant CMV disease in kidney, liver, and pancreas transplant recipients who had received 3 months of oral gan-ciclovir prophylaxis. It is notable that, in the present study, the 4-week regimen of intravenous ganciclovir was associated with more cases of symptomatic CMV disease but with fewer cases of ganciclovir-resistant CMV disease. Although, at first, this may seem counterintuitive, it makes sense, because the 3-month oral ganciclo-vir regimen involves prolonged exposure to lower levels of drug. Because patients with D+/RϪ serostatus can develop high viral loads with rapid doubling times, exposure to subtherapeutic levels of the drug at those times of rapid viral replication can predispose to ganciclovir resistance [9]. In addition to demonstrating that gan-ciclovir resistance is still with us, the present study reminds us …