After day 100 post-transplant, patients who are considered at risk for late CMV were recommended to continue weekly CMV PCR testing and to start preemptive therapy if the viral load was ≥250 IU/ml. 6 Patients considered high-risk, such as those receiving ≥1mg/kg body weight of prednisone, or cord blood transplant recipients, were started at any positive viral load. Preemptive antiviral therapy was initiated once the viral load reached 125 IU/ml for most patients as previously described.
The conversion factor to the WHO standard is 4 copies = 1 IU. 12 The lower limit of detection for this assay (95% reproducibility limit) is 20 IU/ml. Since 2007, allogeneic HCT recipients undergo weekly CMV testing by quantitative PCR measured in blood plasma at least until day 100 post-transplant (using BioRad master mix and Roche MP96 instrument for extraction).
Patients receiving their first allogeneic HCT at the Fred Hutchinson Cancer Research Center (Fred Hutch) between 01 January 2007 and 28 February 2012 who were CMV seropositive (R+) or had a seropositive donor (D+) were included in this study. Participants and Routine Clinical Care Setting Mortality was chosen for the endpoint not only because of the now relatively rare incidence of CMV disease, but also to account for the indirect effects of CMV infection and its treatment, such as neutropenia, and death from fungal infection and gram negative bacteremia. 10 The purpose of this study was to estimate the association of CMV viral load, using the new international standard, with non-relapse mortality and overall mortality during the first year after HCT. 7– 9 Furthermore, the development of a standard method of quantitation (WHO standard IU/ml) has reduced the heterogeneity in the performance of different assays, making comparison of viral load values between different laboratories feasible. 4– 6 Several studies have described the early kinetics of viral replication in bone marrow transplant recipients and the association of viral load with CMV disease, but few of these patients received preemptive therapy. While CMV DNA viral load testing by quantitative PCR is increasingly used to guide preemptive therapy, data linking specific viral load thresholds with clinical outcomes are lacking. Clinicians caring for immunocompromised patients are in need of better preventative agents however without an accepted virologic endpoint, clinical trials powered to prevent CMV end organ disease are likely too costly and time consuming. 1– 3 Yet these therapies have important toxicities, viral resistance does occur, and CMV pneumonia remains a deadly disease. Current prevention strategies that utilize antiviral agents such as ganciclovir or foscarnet at the onset of viremia (preemptive therapy), have successfully limited the incidence of CMV end organ disease to 3–6% in the first three months after HCT. Cytomegalovirus (CMV) is a highly prevalent herpesvirus that is an important cause of morbidity and mortality in immunocompromised patients such as those receiving hematopoietic cell transplantation (HCT).
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