Current and Future Strategies for the Prevention and Treatment of Cytomegalovirus Infections in Transplantation

Abstract

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ transplantation (SOT) and allogeneic hematopoietic cell transplantation (HCT). Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T cells. Observational studies and interventional trials of commercially available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

Keywords: antivirals; cytomegalovirus (CMV); preemptive therapy; transplantation; virus-specific T-cells.

Figure 1.

Strategies for the prevention of CMV disease in adult solid organ and allogeneic hematopoietic cell transplant recipients. For prevention strategies, circles represent CMV PCR tests. Open circles represent negative CMV PCRs, while shaded circles represent positive CMV PCRs. Curved arrows represent a course of antiviral treatment. Thick black lines represent a period of prophylaxis, and the dashed black arrow represents variation in duration of prophylaxis. Common uses include guideline-recommended approaches. All citations refer to references in Supplementary Material 2. Abbreviations: AP, antiviral prophylaxis; CMV, cytomegalovirus; D, donor CMV serostatus; HCT, hematopoietic cell transplant; Ht, Heart; In, Intestine; Li, Liver; Lu, Lung; Ki, Kidney; PET, preemptive therapy; RCT, randomized controlled trial; R, recipient CMV serostatus; SOT, solid organ transplant.^aCMV surveillance during letermovir prophylaxis is recommend for HCT recipients. CMV surveillance during antiviral prophylaxis is not recommended in SOT recipients.^bCMV surveillance from day +100 to +180 is recommended for HCT recipients who receive letermovir prophylaxis through day 100.

Figure 2.

Advantages and disadvantages of antiviral prophylaxis and preemptive therapy in CMV D + R− and CMV R + solid organ transplant recipients. Abbreviations: AP, antiviral prophylaxis; CMV, cytomegalovirus; PET, preemptive therapy; SOT, solid organ transplant; SOTr, solid organ transplant recipients. ^aRepresents the concept of PET in D + R− SOTr, although robust head-to-head clinical trial evidence comparing PET and AP exists only for D + R− liver transplant recipients. Liver and kidney transplant recipients are the only groups of SOTr for whom PET is a guideline recommended strategy.

Figure 3.

Advantages and disadvantages of antiviral prophylaxis with letermovir and preemptive therapy in CMV R + and CMV D + R− allogeneic hematopoietic cell transplant recipients. Abbreviations: AP, antiviral prophylaxis; CMV, cytomegalovirus; csCMVi, clinically significant cytomegalovirus infection; HCT, hematopoietic cell transplant; HCTr, hematopoietic cell transplant recipients; LET, letermovir; PET, preemptive therapy.

Figure 4.

Cumulative incidence of CMV disease in CMV seronegative liver transplant recipients with CMV seropositive donors randomized to 3 months of preemptive therapy or prophylaxis. Adapted from Singh N, Winston DJ, Razonable RR, et al. JAMA 2020; 323:1378–87. doi:10.1001/jama.2020.3138. Abbreviation: CMV, cytomegalovirus.

Figure 5.

Probability of neutropenia or leukopenia (A) and endpoint committee-adjudicated CMV disease (B) in CMV seronegative kidney transplant recipients with CMV seropositive donors randomized to valganciclovir or letermovir as CMV prophylaxis. Adapted from Limaye AP, Budde K, Humar A, et al. JAMA 2023. doi:10.1001/jama.2023.9106. Abbreviation: CMV, cytomegalovirus.

Figure 6.

Clinical applications of cytomegalovirus cell-mediated immune monitoring (CMV-CMI) in completed or planned interventional trials^31,52–55. Triangles represent time points for CMV-CMI measurement and interpretation. Solid lines represent time on antiviral therapy and/or active CMV surveillance. Dashed lines represent time off of antiviral therapy and/or without active CMV surveillance. All numeric citations refer to references in Supplementary Material 2. Abbreviations: CMI, cell-mediated immunity; CMV, cytomegalovirus; D, donor CMV serostatus; EOT, end of treatment; HCT, hematopoietic cell transplant; R, recipient CMV serostatus; SOT, solid organ transplant.