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Background: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known., Methods: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment., Results: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir., Conclusions: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains., Methods: Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs)., Results: From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses., Conclusions: Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified., Clinical Trials Registration: NCT01611974., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both ''direct'' and ''indirect'' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established., Methods: A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients., Results: Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation., Conclusions: Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.

Background: The optimal regimen for prophylaxis of cytomegalovirus (CMV) disease after kidney and/or pancreas transplantation remains unclear. We compared the effectiveness of three months of oral ganciclovir (3 g/day) versus low-dose valganciclovir (450 mg/day) for CMV prophylaxis., Methods: We performed a retrospective cohort study of patients at our center who received kidney and/or pancreas transplants between January 2000 and April 2003. We used a Cox proportional hazards model to examine the relationship between baseline covariates, including type of CMV prophylaxis, and time to development of CMV disease., Results: Of the 500 patients (295 ganciclovir, 205 valganciclovir), 22 patients (4.4%) developed CMV disease (mean time to CMV disease, 163+/-85 days). Sixteen of the ganciclovir patients (5.4%) and six of the valganciclovir patients (2.9%) developed CMV disease (P=0.18). By CMV serostatus, the incidence of CMV disease during the first posttransplant year was 8.5% among donor-seropositive, recipient-seronegative (D+/R-) patients, 8.6% among D+/R+ patients, 2.9% among D-/R+ patients, 1.0% among D-/R- patients, and 0.9% among patients for whom documentation of CMV serostatus was incomplete. In the unadjusted Cox proportional hazards analysis, race/ethnicity, type of transplant, type of antiviral prophylaxis, CMV serostatus, and use of mycophenolate mofetil were each associated with risk of developing CMV disease. In the adjusted, multivariable model, only CMV serostatus was associated with development of CMV disease., Conclusions: Three months of low-dose valganciclovir (450 mg/day) was as effective as ganciclovir (3 g/day) for prophylaxis of CMV disease after kidney and/or pancreas transplantation.

Purpose: A historical perspective and the epidemiology, pathogenesis, and typical patient presentation of cytomegalovirus (CMV) disease in transplant patients; the implications of clinical trials of prophylactic antiviral drug therapy; and unanswered questions about the optimal duration of prophylaxis and the risk of antiviral drug resistance are discussed., Summary: CMV infection and disease are common in transplant patients. They often are the result of transplantation from a CMV-seropositive donor to a CMV-seronegative recipient or reactivation of latent virus in a CMV-seropositive recipient. Reactivation in transplant recipients may be the result of a blunted cytotoxic T-lymphocyte response and an imbalance in the release of pro-inflammatory and anti-inflammatory cytokines. CMV disease develops in many infected patients and frequently involves the graft. Antiviral drug therapies reduce the risk of and delay the onset of CMV disease in transplant recipients. They also reduce the risk of graft injury., Conclusion: The optimal duration of antiviral drug prophylaxis in transplant patients remains to be determined; however, it is clear that antiviral prophylaxis can prevent CMV disease as well as many of the complications associated with CMV disease.