Everolimus and Valganciclovir Prophylaxis: How to Chase Cmv but Not the Patient: Insights from Protect Randomized Study

PurposeCytomegalovirus (CMV) infection may influence the development of Cardiac Allograft Vasculopathy (CAV). In this prospective randomized study we aimed to analyze the interplay of immunosuppressive, anti-CMV strategies and CMV immunity on the risk for CMV infection and CAV during the first year after transplant.MethodsBy a 2x2 randomization process, CMV seropositive heart transplant (HT) recipients were randomized to receive 3 months of valganciclovir prophylaxis (PRO) or a pre-emptive based approach (PRE), and to receive mycophenolate (MMF) or everolimus (EVE) on top of a cyclosporine-based immunosuppressive therapy. All were monitored for CMV infection by whole blood PCR and CMV-immunity reconstitution by elispot assay. At month 1 and 12 after transplant eligible patients underwent intravascular ultrasound (IVUS). Occurrence of CMV infection and change in maximal intimal thickness (MIT) >0.5mm were study endpoints.ResultsForty-six patients were randomized: 22 to PRE vs. 24 to PRO, and 24 to EVE vs. 22 to MMF. Six (25%) patients discontinued EVE and 13 (54%) did not completed the 3-months period of PRO for adverse events (mainly effusions in EVE and leucopenia in PRO). Only 23 patients underwent IVUS both at month 1 and month 12. After adjusting for donor serology, PRO and EVE were associated with reduced risk of 70 and 54% respectively for CMV infection in the intention to treat (ITT) analysis (P<0.05). However, EVE discontinuation and lack of PRO completion were associated with increased risk for CMV infection. Only 4 (17%) patients developed the MIT endpoint, not allowing any conclusion about treatments efficacy. Nevertheless 100% of the patients who discontinued EVE developed the MIT endpoint. Recovery of CMV immunity at month 1 by Elispot analysis allowed stratifying the risk for CMV infection: patients with lack of immunity were at higher risk of infection, and most likely to benefit from PRO or EVE (P<0.01).ConclusionEVE and PRO are protective from CMV infection, but a significant percentage of patients discontinued the treatments for intolerance and appear to be exposed to higher risk of events. Analysis of CMV immunity recovery may provide guidance in customizing therapeutic strategies, by identifying patients in whom aggressive anti-CMV strategies may have a favorable risk/benefit ratio. PurposeCytomegalovirus (CMV) infection may influence the development of Cardiac Allograft Vasculopathy (CAV). In this prospective randomized study we aimed to analyze the interplay of immunosuppressive, anti-CMV strategies and CMV immunity on the risk for CMV infection and CAV during the first year after transplant. Cytomegalovirus (CMV) infection may influence the development of Cardiac Allograft Vasculopathy (CAV). In this prospective randomized study we aimed to analyze the interplay of immunosuppressive, anti-CMV strategies and CMV immunity on the risk for CMV infection and CAV during the first year after transplant. MethodsBy a 2x2 randomization process, CMV seropositive heart transplant (HT) recipients were randomized to receive 3 months of valganciclovir prophylaxis (PRO) or a pre-emptive based approach (PRE), and to receive mycophenolate (MMF) or everolimus (EVE) on top of a cyclosporine-based immunosuppressive therapy. All were monitored for CMV infection by whole blood PCR and CMV-immunity reconstitution by elispot assay. At month 1 and 12 after transplant eligible patients underwent intravascular ultrasound (IVUS). Occurrence of CMV infection and change in maximal intimal thickness (MIT) >0.5mm were study endpoints. By a 2x2 randomization process, CMV seropositive heart transplant (HT) recipients were randomized to receive 3 months of valganciclovir prophylaxis (PRO) or a pre-emptive based approach (PRE), and to receive mycophenolate (MMF) or everolimus (EVE) on top of a cyclosporine-based immunosuppressive therapy. All were monitored for CMV infection by whole blood PCR and CMV-immunity reconstitution by elispot assay. At month 1 and 12 after transplant eligible patients underwent intravascular ultrasound (IVUS). Occurrence of CMV infection and change in maximal intimal thickness (MIT) >0.5mm were study endpoints. ResultsForty-six patients were randomized: 22 to PRE vs. 24 to PRO, and 24 to EVE vs. 22 to MMF. Six (25%) patients discontinued EVE and 13 (54%) did not completed the 3-months period of PRO for adverse events (mainly effusions in EVE and leucopenia in PRO). Only 23 patients underwent IVUS both at month 1 and month 12. After adjusting for donor serology, PRO and EVE were associated with reduced risk of 70 and 54% respectively for CMV infection in the intention to treat (ITT) analysis (P<0.05). However, EVE discontinuation and lack of PRO completion were associated with increased risk for CMV infection. Only 4 (17%) patients developed the MIT endpoint, not allowing any conclusion about treatments efficacy. Nevertheless 100% of the patients who discontinued EVE developed the MIT endpoint. Recovery of CMV immunity at month 1 by Elispot analysis allowed stratifying the risk for CMV infection: patients with lack of immunity were at higher risk of infection, and most likely to benefit from PRO or EVE (P<0.01). Forty-six patients were randomized: 22 to PRE vs. 24 to PRO, and 24 to EVE vs. 22 to MMF. Six (25%) patients discontinued EVE and 13 (54%) did not completed the 3-months period of PRO for adverse events (mainly effusions in EVE and leucopenia in PRO). Only 23 patients underwent IVUS both at month 1 and month 12. After adjusting for donor serology, PRO and EVE were associated with reduced risk of 70 and 54% respectively for CMV infection in the intention to treat (ITT) analysis (P<0.05). However, EVE discontinuation and lack of PRO completion were associated with increased risk for CMV infection. Only 4 (17%) patients developed the MIT endpoint, not allowing any conclusion about treatments efficacy. Nevertheless 100% of the patients who discontinued EVE developed the MIT endpoint. Recovery of CMV immunity at month 1 by Elispot analysis allowed stratifying the risk for CMV infection: patients with lack of immunity were at higher risk of infection, and most likely to benefit from PRO or EVE (P<0.01). ConclusionEVE and PRO are protective from CMV infection, but a significant percentage of patients discontinued the treatments for intolerance and appear to be exposed to higher risk of events. Analysis of CMV immunity recovery may provide guidance in customizing therapeutic strategies, by identifying patients in whom aggressive anti-CMV strategies may have a favorable risk/benefit ratio. EVE and PRO are protective from CMV infection, but a significant percentage of patients discontinued the treatments for intolerance and appear to be exposed to higher risk of events. Analysis of CMV immunity recovery may provide guidance in customizing therapeutic strategies, by identifying patients in whom aggressive anti-CMV strategies may have a favorable risk/benefit ratio.