Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial

Abstract

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.

Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.

Design, setting, and participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).

Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.

Main outcomes and measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.

Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).

Conclusion and relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.

Trial registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Figure 1.. Participant Flow in a Study of Letermovir vs Valganciclovir for Cytomegalovirus (CMV) Prophylaxis in Kidney Transplant Recipients

CrCI indicates creatinine clearance. ^aParticipants could have ≥1 reason for exclusion. The inclusion and exclusion criteria are listed in Supplement 1. ^bStratified by receipt of lymphocyte-depleting induction immunosuppression. ^cOne participant developed glomerulonephritis (reported as an adverse event) that began the day after transplant and prior to initiating letermovir prophylaxis. One participant discontinued valganciclovir prophylaxis due to an adverse event (hallucinations) and died prior to week 28. ^dParticipants were encouraged to complete all remaining scheduled visits through week 52 after confirmation of CMV disease and/or early discontinuation of prophylaxis. ^eOne death due to COVID-19 was not reported as an adverse event.

Figure 2.. Primary Outcome of Cytomegalovirus (CMV) Disease With Letermovir vs Valganciclovir Prophylaxis Through Week 52 in the Full Analysis Set

^aAll participants in the letermovir group received acyclovir for prophylaxis of herpes simplex and varicella-zoster virus. ^bThe 95% CIs for the differences in proportions of participants were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per group for each stratum (use/nonuse of lymphocyte-depleting induction immunosuppression). The upper bound of the 2-sided 95% CI for the primary outcome had to be no higher than 10% to conclude noninferiority. Participants who did not complete the study through week 52 or a had missing result for CMV DNAemia in the week-52 visit window were not considered failures (observed failure approach). ^cCMV disease confirmed by the independent masked adjudication committee (CMV end-organ disease or CMV syndrome). ^dPrespecified sensitivity analysis for investigator-reported CMV disease (included CMV syndrome and/or CMV end-organ disease). ^eData were not available for 2 participants in the letermovir group and 1 participant in the valganciclovir group.

Figure 3.. Leukopenia or Neutropenia Events and Time to Onset Through Week 28 in the Safety Population

^aAll participants in the letermovir group received acyclovir for prophylaxis of herpes simplex and varicella zoster virus. ^bParticipants were only counted once for the composite safety outcome of ≥1 leukopenia or neutropenia event. P < .001. P value and 95% CI based on the Miettinen and Nurminen method. ^cNumber of events is shown by time period: day 1 to week 14, week 14 to week 28, and week 28 to 14 days after prophylaxis was completed. Data were censored at the time of last assessment.