Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36 days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21 days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.
Introduction: Maribavir is a potent and orally bioavailable antiviral with a novel mechanism of action against cytomegalovirus (CMV). The efficacy and safety of maribavir for treatment of CMV infections are being evaluated in ongoing Phase 3 trials. Characterization of drugÀdrug interaction (DDI) properties of maribavir is necessary in informing potential DDIs with co-medications. Objective: To evaluate the potential cytochrome p450 and p-glycoproteinÀmediated drugÀdrug interaction by maribavir. Methods: Cytochrome P450 (CYP) reversible inhibition: Probe substrates of CYPs were incubated with human liver microsomes (HLM) and maribavir. Percent remaining CYP activity was plotted against maribavir concentrations for IC 50 determination. Time-dependent inhibition (TDI) for CYPs: After pre-incubation with maribavir for varying durations, percent remaining CYP activity in HLM was measured. The concentration at half-maximal inactivation (K I ) and maximum inactivation rate constant (k inact ) were calculated. CYP induction: After treating human hepatocytes with maribavir for three days, CYP mRNA expression was plotted against maribavir concentrations to determine half-maximal induction concentration (EC 50 ) and maximal fold induction (E max ). Pglycroprotein (P-gp) inhibition: Bi-directional transport of digoxin in Caco-2 cells with maribavir was measured and IC 50 calculated by plotting percent transporter activity against maribavir concentration. Results: Maribavir is not a reversible inhibitor of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, or CYP3A4 and is a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19 (IC 50 40, 18, and 35 mM). Maribavir is not a TDI of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 but a weak TDI for CYP3A (K I 41.2 mM, k in-
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