Cytomegalovirus (CMV), the most common viral infection after solid organ transplant (SOT) (1), causes significant morbidity and mortality. It can result in CMV pneumonitis, hepatitis, encephalitis and gastrointestinal disease, as well as many less serious but clinically problematic events such as fever and neutropenia (2). Furthermore, CMV has been shown to be associated with a number of indirect effects in SOT recipients including reduced long-term patient survival, increased risks of opportunistic infections, allograft dysfunction, acute and chronic graft rejection, and increased total costs (3,4). Without prophylaxis, most CMV disease occurs during the first 3 months post-transplant, when patients are receiving intensive immunosuppressive agents for prevention of graft rejection (5,6). SOT patients at highest risk are seronegative recipients of organs from seropositive donors (CMV D+/R-) (2,7,8), and those on highly immunosuppressive regimens.
Antiviral agents have proved successful for prevention of CMV infection and disease in SOT recipients (9). While originally intravenous (i.v.) ganciclovir was the mainstay, effective for both CMV prevention and treatment (10–12), more recently an oral ganciclovir formulation has been used. While this has proved effective in preventing CMV disease in SOT transplant recipients, including high-risk D+/R- patients (13–15), it has a low bioavailability (about 6–10%), and a total of 3 g, administered as 12 capsules/day in a three times a day (t.i.d.) regimen, is needed to deliver plasma ganciclovir exposures 40–50% of that achieved with the standard 5 mg/kg dose of i.v. ganciclovir (16,17). This low bioavailability limits the degree of viral suppression that can be achieved (18), and thus may predispose to emergence of resistance (19).
Valganciclovir, a valine ester pro-drug of ganciclovir, was developed to overcome the limitations of oral and i.v. ganciclovir, with a single once-daily 900 mg oral dose providing comparable plasma ganciclovir exposures to those achieved with 5 mg/kg i.v. ganciclovir (16). At 60%, its bioavailability is up to 10-fold higher than that of oral ganciclovir (16). There is already extensive clinical experience with valganciclovir in AIDS patients, where it has proved as effective as i.v. ganciclovir in treating newly diagnosed CMV retinitis (20). We therefore conducted a prospective, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of valganciclovir compared with oral ganciclovir for prevention of CMV disease in high-risk (CMV D+/R-) SOT recipients.