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

Atabani, Sowsan; Smith, Colette; Atkinson, Claire; Aldridge, Robert W; Rodríguez‐Perálvarez, Manuel; Rolando, Nancy; Harber, Mark; Jones, Gareth; O'Riordan, Aisling; Burroughs, Andrew K.; Thorburn, Douglas; O’Beirne, James; Milne, Richard S. B.; Emery, Vincent C.; Griffiths, Paul

doi:10.1111/j.1600-6143.2012.04087.x

Cited by 169 publications

(236 citation statements)

References 25 publications

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“…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%.…”

Section: Discussionmentioning

confidence: 43%

“…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).…”

Section: Impact Of CMV Preventionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Manuel

Kralidis

Mueller

et al. 2013

American Journal of Transplantation

100

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We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients.Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (Dþ/RÀ vs. Rþ, hazard ratio [HR] 5.36 [95% CI 3.14-9.14], p < 0.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63-2.17], p ¼ 0.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64-2.53], p ¼ 0.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01-2.64], p ¼ 0.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

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Section: Discussionmentioning

confidence: 43%

Section: Impact Of CMV Preventionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Manuel

Kralidis

Mueller

et al. 2013

American Journal of Transplantation

100

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Shabir

Kaul

Pachnio

et al. 2013

Journal of the American Society of Nephrology

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Cytomegalovirus (CMV) infection increases the risk of complications after renal transplantation, but the mechanisms controlling donor-derived infection are not adequately characterized. Here, we assessed the risk of clinically significant CMV disease in donor-seropositive, recipient-seropositive (D+R+) renal transplantation and examined recipients' CMV antigen-specific cellular immune responses primed directly by donor cells. In a retrospective cohort of 569 patients administered standardized basiliximab-tacrolimus-mycophenolate-corticosteroid immunosuppressive therapy, CMV disease rates increased in D+R+ serostatus pairings compared with D2R+ pairings (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.36 to 5.01; P=0.004) and associated with increased donor-recipient HLA mismatch in the D+R+ group (HR [per class 1 mismatch], 1.43; 95% CI, 1.12 to 1.82]; P=0.02). D+R+ and D+R2 transplants in which the donor and recipient differentially expressed at least one HLA class I allele were followed prospectively from the time of transplantation. During the first year after transplantation, four of eight seropositive recipients and one of three seronegative recipients displayed peripheral blood CD8+ T cell responses to CMV presented by recipient-specific HLA. Notably, no recipients mounted responses to CMV presented by donorspecific HLA, despite the detection of CMV antigen expression in all seropositive donor organs examined (n=10), suggesting that the allograft of Class I HLA-mismatched seropositive donors is inaccessible to CD8+ T cell responses. Finally, pretransplant assays of anti-CMV cellular immunity predicted post-transplant CMV replication less accurately in D+R+ pairings than in D2R+ pairings, possibly reflecting in vitro assay specificity for recipient, rather than donor, HLA. These findings are relevant to the clinical management and immunologic understanding of donortransmitted viral infection.

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Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors

Singh

Winston

Razonable

et al. 2020

JAMA

128

149

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IMPORTANCE Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients.OBJECTIVE To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018.INTERVENTIONS Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). MAIN OUTCOMES AND MEASURESThe primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. RESULTS Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, −9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, −14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, −4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, −5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, −14% to 6%]; P = .46).CONCLUSIONS AND RELEVANCE Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes.

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

Cited by 169 publications

References 25 publications

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

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

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

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors

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