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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Singh reported receiving funding from the National Institutes of Health (NIH). Dr Winston reported receiving grants from Merk, Chimerix, Shire, Gilead, and Oxford Immunotech during the conduct of the study. Dr Razonable reported receiving grants from Roche and personal fees from Novartis and Merck outside the submitted work. Dr Lyon reported receiving grants from Takeda Pharmaceutical Company outside the submitted work. Dr Silveira reported receiving grants from the NIH during the conduct of the study and grants from Shire and Qiagen outside the submitted work. Ms Wagener reported receiving grants from the NIH during the conduct of the study. Mr Stevens-Ayers reported receiving grants from the NIH during the conduct of the study. Mr Edmison reported receiving grants from the NIH during the conduct of the study. Dr Boeckh reported receiving grants from the NIH during the conduct of the study and grants and personal fees from Merck, Astellas, Chimerix, Vir Bio, Gilead, and GlaxoSmithKline; personal fees from Allovir, Oxford Immunotec, Helocyte, Moderna, and Artemis Therapeutics; and grants from Lophius Biosciences outside the submitted work. Dr Limaye reported receiving grants from the NIH during the conduct of the study, as well as grants and personal fees from Merck and personal fees from Helocyte and AlloVir and serving as a site investigator for Astellas and Oxford Immunotech. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-up

aCytomegalovirus (CMV)-seronegative liver transplant candidates awaiting liver transplant could be screened and consented. Ultimately, 207 of 538 eligible patients either did not receive CMV-seropositive donor allograft or did not undergo transplant. bDefined as creatinine clearance less than 10 mL/min or kidney replacement therapy; an amendment (after 19 patients had been enrolled) eliminated kidney dysfunction as an exclusion. cLong-term follow-up was a median of 3.2 years (range, 1-5.2 years).

Figure 2.. Cumulative Incidence of Cytomegalovirus (CMV) Disease With Death as a Competing Risk

Cumulative incidence curves of CMV disease show that the antiviral prophylaxis group had more postprophylaxis (delayed-onset) CMV disease than the preemptive therapy group (P = .048); the curves begin to separate about 4 to 6 weeks after the study drug administration period. Death prior to CMV disease was considered a competing risk. The number at risk is patients alive without CMV disease. The median follow-up for patients was 1152 days (interquartile range, 541 to 1537 days) in the preemptive therapy group and 1020 days (interquartile range, 588 to 1450 days) in the antiviral prophylaxis group.

Figure 3.. Cytomegalovirus (CMV)-Specific T-Cell Responses and Lymphocyte Subsets

CMV pp65-specific T-cell responses were stronger following preemptive therapy than with antiviral prophylaxis in both CD4+ (A) or CD8+ (B) T cells expressing interferon-γ (IFN-γ) without regard for other markers (IFN-γ; left side of x-axis; CD4+, P = .009; CD8+, P < .001) or IFN-γ and at least 1 other marker (IFN-γ polyfunctional; right side of x-axis; CD4+, P = .02; CD8+, P < .001). C, Staphylococcal enterotoxin B (SEB)–responsive T cells expressing any marker, a measure of global immune function, were only different for CD8+ T cells between preemptive therapy and antiviral prophylaxis groups (P = .01). D, Lymphocyte subset counts were greater following preemptive therapy (total lymphocyte count; P = .006), with significantly more CD8+ T cells after preemptive therapy than antiviral prophylaxis (P < .001). The higher number of SEB-responsive CD8+ T cells following preemptive therapy may relate to greater clonal expansion of CMV-specific CD8+ T cells. Box edges represent the third (upper) and first (lower) quartiles, and the central line denotes the median. The dots indicate actual data points for the data depicted along the y-axis. For all comparisons, there were 73 patients in the preemptive therapy group and 79 in the antiviral prophylaxis group.