Kidney transplant Preemptive therapy or Prophylaxis (KPoP) for CMV Preventionin D+R- Recipients

In kidney transplant recipients (KTR), cytomegalovirus (CMV) increases short- and long-term morbidity, mortality, and allograft failure, mainly due to limitations in current preventive strategies. ~90% of CMV disease occurs in the ~20% of recipients who are CMV seronegative (R-) and receive of an organ from a CMV

seropositive donor (D+) [D+R-], and results from immune-suppression-impaired development of protective CMV-specific immune responses. The strategies for CMV prevention in D+R- KTR are Antiviral Prophylaxis [AP] (suppressive antiviral drug [valganciclovir [VALGAN] or letermovir [LET] given for 200d), and Preemptive

Therapy [PET] (CMV DNAemia is monitored by sensitive quantitative PCR (qPCR) for 100d and VALGAN is given only to those with CMV DNAemia. AP is used by >90% of centers due to a smaller evidence base for PET (especially with ATG use) and uncertainty about other long-term outcomes with PET vs AP. In CMV D+R-

liver txp, a randomized clinical trial (RCT) showed that PET was feasible (>90% adherence), reduced antiviral drug days by ~40% (62d vs. 100d), increased protective CMV-specific immunity (multifunctional CD4/CD8 T- cells, NK cells, and neutralizing antibody [nAb]) and decreased CMV disease by >50% vs. AP. These results

cannot be directly extrapolated to KTR due to important differences between liver and kidney txp, including the intensity of immunosuppression and different established/approved prophylaxis regimens. As a result, despite potential advantages, use of PET in D+R- KTR remains minimal. The long-term goals are to reduce the

negative impact of CMV in D+R- SOT by harnessing CMV-specific immunity, to define CMV immune correlates for future immune-based preventive strategies, and to provide high-quality evidence to change clinical practice. The central hypothesis is that PET, compared to AP, through permissive viral replication and

associated antigen exposure-mediated immune priming, leads to increased CMV-specific humoral and cellular immune responses that result in lower CMV disease incidence in high-risk D+R- KTR. The Specific Aims are 1) To compare PET and AP in D+R- KTR for the prevention of Endpoint Committee confirmed CMV disease by

1-year post-txp (primary endpoint) and longer-term outcomes (graft and patient survival, biopsy-proven acute allograft rejection, and eGFR by end of follow-up (secondary endpoints), and 2) To characterize longitudinal CMV-specific humoral (nAb) and cellular (T-cell, NK cell) immune responses and their association with

prevention strategy, CMV infection (DNAemia) in the PET arm, and Endpoint Committee confirmed CMV disease. The Aims will be accomplished with a 5-center trial of 360 adult CMV D+R- KTR who will be randomized 1:1 to a standardized PET protocol for 100d (described above) or to AP (200d of VALGAN or letermovir). CMV-specific immunity assessments at 3, 6, 12, 24, and 36 months will include nAb, NK cells, and

multifunctional T-cells with multi-color flow cytometry that incorporates a novel computational approach (COMbinatorial Polyfunctionality analysis of Antigen-Specific T cell Subsets [COMPASS]).