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

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 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.

Cytomegalovirus infection and allograft rejection among pediatric heart transplant recipients in the era of valganciclovir prophylaxis

“…To account for the difference in time to infection following VGC prophylaxis among CMV risk cohorts, we considered a number of possibilities, including the role of CMV‐specific CMI in preventing CMV infection and disease following SOT 20‐22 . In a study of 95 CMV HR (D+R−) SOT recipients, evidence of CMV CMI following VGC prophylaxis was associated with protection from subsequent CMV infection in 92%‐100% of cases.…”

“…6,7 To account for the difference in time to infection following VGC prophylaxis among CMV risk cohorts, we considered a number of possibilities, including the role of CMV-specific CMI in preventing CMV infection and disease following SOT. [20][21][22] In a study of 95…”

Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers

“…Although there is no study comparing different intervals of CMV testing, studies evaluating preemptive approaches with frequent testing have shown non-inferiority to prophylaxis even in high-risk patients (D+/R−) [34][35][36]. (b) In patients with prophylaxis, testing can be reduced to monthly, followed by every 3 months (or in case of symptoms) for the first year.…”

“…International practice guidelines for liver transplantation are only precise in the high-risk scenario (D+/R−), recommending pharmacological CMV prophylaxis for at least 3 months [5,25,37]. However, a recent study showed that an adequate monitoring and low threshold for treatment initiation, i.e., immediately upon detection of viremia, allows the application of a preemptive therapy approach also for high-risk patients [36]. The efficacy of preemptive therapy strongly correlates with a high frequency of DNA testing in order to detect the dynamics of DNA quantification before the patient becomes symptomatic.…”

“…Extension of the treatment duration to 6 months relates to a study in kidney transplant recipients, where 200 days in high-risk patients reduced the risk of CMV disease over 100 days of prophylaxis [56]. Alternatively, preemptive management seemed to be equally efficacious [36].…”