HORUS-Cytomegalovirus Open Proof-of-concept Exploratory Trial

Cytomegalovirus (CMV) remains a significant cause of morbidity and mortality following organ transplantation.

Cell-mediated immunity plays a crucial role in controlling CMV replication after transplantation. Immune monitoring involves the use of immune biomarkers-primarily those assessing cell-mediated immunity-to dynamically estimate the risk of CMV replication. This approach allows for the individualization of preventive and therapeutic strategies, improving patient outcomes.

The HORUS consortium is a comprehensive European research initiative aimed at providing an in-depth assessment of immune signatures associated with CMV immune control in SOT recipients. One of the ultimate goals of the HORUS project is to leverage these immune signatures to design and implement a clinical trial evaluating their feasibility and impact in routine clinical practice.

As part of this initiative, we introduce the HORUS-COPE trial, designed to assess the effect of immune modulation on CMV replication kinetics and to explore the performance of a selected immune signature during antiviral therapy for CMV infection to stratify patients based on their risk of not responding to immune modulation.

Specifically, immune modulation consists of either:

• a 50% dose reduction of an antimetabolite agent- mycophenolate mofetil [MMF, Cellcept®] or enteric-coated mycophenolate sodium [EC-MPS, Myfortic®]; hereafter referred to as mycophenolic acid [MPA])
• a switch from MPA to a mammalian target of rapamycin inhibitor (mTORi) everolimus, together with an adapted dose of tacrolimus.

Inclusion criteria

• Clinically stable adult patients (aged 18 years or older) who have received a solid organ transplant (e.g., kidney, liver, heart, lung, pancreas) and developed clinically significant CMV infection as determined by positive CMV PCR.
• On maintenance therapy of tacrolimus, MPA, +/- steroids.
• Informed consent signed.

Exclusion criteria

• Active acute graft rejection or significant graft dysfunction requiring modification of the current immunosuppressive regimen, in the opinion of the investigator.
• Receipt of more than 72 hours of antiviral therapy for CMV infection prior to enrolment, before randomization, including valganciclovir and/or IV ganciclovir therapy
• Known intolerance or hypersensitivity to mTOR inhibitors or to any component of the everolimus formulation.
• Any medical condition that constitutes a contraindication to everolimus use, as judged by the investigator.
• Additional exclusion criteria for French sites:

• Patient not affiliated to the French social security system
• Patient under legal protection (guardianship, curatorship).