Cytomegalovirus Risk in Seropositive Kidney Transplant Recipients Stratified by Quantiferon-CMV

• Conditions: CMV; Kidney Transplant Infection; Cytomegalovirus Infections

• Registration Number: NCT03858907
• Lead Sponsor: University of Sao Paulo General Hospital

Brief Summary

To evaluate the Quantiferon-CMV test ability to predict occurrence of cytomegalovirus (CMV) disease o treated infection after kidney transplantation. Patients studied are those already infected by CMV before transplantation ("seropositive"). Patients given thymoglobulin as induction therapy receive CMV prophylaxis with valganciclovir, while those given basiliximab undergo weekly monitoring for CMV viremia with preemptive treatment as needed.

Detailed Description

This study evaluates Quantiferon-CMV assay ability for CMV (cytomegalovirus) risk prediction in kidney transplant recipients. Quantiferon-Monitor ability to predict infection or graft rejection will be evaluated as an exploratory objective.

It is a prospective cohort study. The assumption is that CMV disease or preemptively treated viremia (dependent variable) may be predicted by Quantiferon-CMV result (independent variable). Quantiferon-CMV results will be masked for the assistant physician.

Patients are evaluated for eligibility on their hospital admission for kidney transplantation. Type of induction therapy follows current local protocol: thymoglobulin is given to sensitized patients against HLA - human leukocyte antigen (that is, PRA \> 0%), and basiliximab to unsensitized patients (PRA = 0%). Initial maintenance immunosuppression includes prednisone, tacrolimus and mycophenolate sodium to all patients. If a patient is enrolled in the study, blood is drawn before transplantation for pre-transplant Quantiferon assays (CMV and Monitor).

For CMV disease prevention, transplant recipients undergo until day 90 post-transplant: either weekly CMV monitoring (qPCR - quantitative polymerase chain reaction - and pp65 antigenemia) and preemptive treatment if given basiliximab or antiviral prophylaxis if given thymoglobulin for induction. Cutoff values for preemptive treatment are 4,000 IU/ml of plasma for Abbott Real Time PCR or ≥ 4 cells/300.000 neutrophils for pp65 Antigenemia. After day 90 post-transplant, all participants undergo biweekly CMV monitoring until day 180 with preemptive treatment as needed.

Quantiferon-CMV results from 2 or 3 different moments (pre-transplant, day 30 and for patients given thymoglobulin also day 90) will be analyzed with subsequent occurrence of CMV disease/treated viremia. Analysis will be stratified by type of induction therapy. A high negative predictive value of pre-transplant or day 30 Quantiferon-CMV could indicate unneeded monitoring for preemptive treatment. On the other hand, a high positive predictive value for CMV occurrence could indicate the necessity of antiviral prophylaxis implementation.

Patients given thymoglobulin will undergo a third Quantiferon-CMV on day 90, at the end of their antiviral prophylaxis. This third Quantiferon-CMV may predict occurrence of late disease, together with clinical variables (low kidney graft function / glomerular filtration rate, lymphopenia or type of donor). A high positive predictive value for CMV disease/treated viremia could indicate the need for antiviral extension beyond 3 months.

Clinical and laboratory parameters evaluated also include: demographic and pre-transplant clinical data, monthly creatinine and blood cell counts, complement 3 fraction, total IgG, blood BK and EBV virus qPCR, CD4/CD8 cells counts, CMV serology, acute rejection and type of treatment, opportunistic and bacterial infections, post-transplant diabetes, maintenance immunosuppression, diabetes, delayed graft-function.

Multivariable logistic regression models will be tested for their performance to predict CMV disease/treated infection.

For the cost-effectiveness analysis, current strategy without QF-CMV will be compared with a simulated strategy with a QF-CMV-oriented CMV prevention. For this analysis, costs will be in the perspective of Hospital das Clinicas de Sao Paulo with values obtained part from micro-costing and part from secondary data.

Study Timeline

• Study Start: 2018-08-05
• Status Verified: 2019-02
• Study First Submitted: 2019-02-21
• Study First Submitted QC: 2019-02-26
• Last Update Submitted: 2019-02-26
• Study First Posted: 2019-03-01
• Last Update Posted: 2019-03-01
• Primary Completion: 2020-08-05
• Study Completion: 2020-11-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

• CMV IgG seropositivity before kidney transplant
• to provide signed Informed Consent

Exclusion Criteria

• death or graft failure before day 19 post-transplant
• allergy to valganciclovir ou ganciclovir

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
CMV disease/treated infection occurrence according to Quantiferon-CMV result	365 days	To evaluate if QF-CMV (either pre or post-transplant) predicts occurrence of CMV disease or treated infection in CMV seropositive kidney recipients, stratified by type of induction therapy

Secondary Outcome Measures

Name	Time	Method
Association of CMV and total IgG levels	365 days	To evaluate the association of CMV infection with serum IgG (immunoglobulin G) levels at 0, 1, 3, and 6 months post-transplant
Association of CMV with clinical events	365 days	To evaluate the association of CMV infection with occurrence: acute rejection, bacterial or opportunistic infection and neutropenia
QF-CMV cutoff values	365 days	To define cut-off values of IFN-gamma production by Quantiferon-CMV that best predict CMV (disease or treated viremia) occurrence
CMV risk prediction index	365 days	To define the best predictive model for the occurrence of CMV, which includes QF-CMV and clinical/laboratory variables (donor type, kidney function and lymphocyte counts).
Association of CMV and lymphocytes counts	365 days	To evaluate the association of CMV infection with blood CD4 and CD8 lymphocytes counts at 0, 1, 3, and 6 months post-transplant
Association of CMV and graft function	365 days	To evaluate the association of CMV infection with estimated glomerular filtration rate by Modification of Diet in Renal Disease formula (creatinine based) at 0, 1, 3, and 6 months post-transplant
Association of CMV and patient and graft survivals	365 days	To analyze patient and graft survival stratified by CMV infection (Kaplan-Meier method)

Trial Locations

Locations (1)

Hospital das Clinicas, University of Sao Paulo School of MedicinE; 🇧🇷 Sao Paulo, SP, Brazil