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Original Investigation
April 14, 2020

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial

Author Affiliations
  • 1University of Pittsburgh, Pittsburgh, Pennsylvania
  • 2VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
  • 3University of California Los Angeles Medical Center, Los Angeles
  • 4Mayo Clinic, Rochester, Minnesota
  • 5Emory University, Atlanta, Georgia
  • 6University of Pittsburgh, Pittsburgh, Pennsylvania
  • 7Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 8University of Washington, Seattle
JAMA. 2020;323(14):1378-1387. doi:10.1001/jama.2020.3138
Visual Abstract. Effect of Preemptive Therapy vs Antiviral Prophylaxis on CMV Disease in Seronegative Liver Transplant Recipients With Seropositive Donors
Effect of Preemptive Therapy vs Antiviral Prophylaxis on CMV Disease in Seronegative Liver Transplant Recipients With Seropositive Donors
Key Points

Question  Is preemptive therapy (based on the initiation of antiviral therapy for early asymptomatic cytomegalovirus [CMV] viremia detected by surveillance testing) more effective than antiviral prophylaxis (administered to all patients for 100 days) for the prevention of CMV disease in CMV-seronegative liver transplant recipients with seropositive donors?

Findings  In this randomized clinical trial that included 205 CMV-seronegative liver transplant recipients with seropositive donors, the use of antiviral preemptive therapy with valganciclovir, 900 mg twice daily, compared with antiviral prophylaxis with valganciclovir, 900 mg once daily, resulted in CMV disease incidence over 12 months of 9% vs 19%, a difference that was statistically significant.

Meaning  The use of preemptive therapy, compared with antiviral prophylaxis, reduced the 12-month incidence of CMV disease.

Abstract

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 Measures  The 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.

Trial Registration  ClinicalTrials.gov Identifier: NCT01552369

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