Cytomegalovirus Replication Kinetics in Solid Organ Transplant Recipients Managed by Preemptive Therapy

Abstract

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Impact of Antiviral Preventive Strategies on the Incidence and Outcomes of Cytomegalovirus Disease in Solid Organ Transplant Recipients

“…CMV disease incidence was 16.9% in high-risk patients (CMV Dþ/RÀ) and 4.4% in the intermediate-risk patients (CMV Rþ). These numbers are similar to or lower than those observed in the most recent published prospective cohort studies (9,26) or randomized controlled trials (15,16,27), reflecting the improved management on the prevention of CMV disease over the last years. Some patients took sequentially more than one drug, so the addition of numbers may result in >100%.…”

“…However, Dþ/RÀ patients were not included (14) or represented only a minority of all patients included in these trials (10,11). Some studies showed a marked benefit of the preemptive approach in Dþ/RÀ patients (28,29), although recent studies have shown a similar or even higher incidence of CMV diseases compared to the use of antiviral prophylaxis (9,30). In a French study, 80 Dþ/RÀ kidney transplant recipients followed preemptively were compared to a historical cohort of 32 Dþ/RÀ patients who received antiviral prophylaxis (30).…”

“…The preemptive approach consists in monitoring the CMV viral load and administering an antiviral drug in case of CMV detection in the blood, before the development of symptoms. Both strategies have greatly reduced CMV-associated morbidity and mortality (7,8), although the efficacy of the preemptive approach has been less well-established (9). Current guidelines recommend both approaches, although antiviral prophylaxis is generally preferred for high-risk patients (1,2).…”

Impaired Direct Priming of CD8 T Cells by Donor-Derived Cytomegalovirus Following Kidney Transplantation

“…This observation represents a real-world scenario, dealing specifically with patients experiencing clinically manifest CMV disease, thereby extending data from previous clinical trials addressing asymptomatic CMV infection/replication. 5,7 Although "strain-specific" mismatch is cited as an underlying mechanism for this phenomenon, 9 substantial data exist that question this hypothesis (discussed further below). We therefore investigated whether donor-recipient HLA mismatch impaired development of cognate cellular immunity to CMV within transplanted donor tissue.…”

“…However, historical evidence suggests that D+R+ transplantation is associated with increased disease rates compared with D2R+ transplantation. 4 Also, two recent trials 5,6 and a single-center study 7 showed higher infection rates in D+R+ than in D2R+ transplantation. Because these latter studies focused on (often asymptomatic) CMV infection, rather than symptomatic disease, and because all used antiviral prophylaxis or pre-emptive therapy for CMV infection, it remains unclear whether disease rates differ between D+R+ and D2R+ transplantation, particularly under contemporary immunosuppression without antiviral prophylaxis.…”