Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients

Abstract

ImportanceValganciclovir 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.ObjectiveTo 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 ParticipantsRandomized, 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).InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30

A new direction for cytomegalovirus prophylaxis among transplant recipients: Benefits and nonviral outcomes of letermovir use as primary CMV prophylaxis

“…As demonstrated by Limaye et al letermovir was well tolerated for up to 200 days in KT recipients and similar long-term tolerability was observed in a recently completed, placebo-controlled trial among HSCT recipients (NCT03930615) [12 ▪▪ ,21 ▪▪ ]. Given prior evidence that demonstrates increased risk of clinically significant-CMV infection occurrence following discontinuation of primary prophylaxis, the ability to extend letermovir durations out to 200 days following transplant may allow for enhanced protection during periods of more intense immunosuppression [12 ▪▪ ,22,23].…”

“…Notable adverse effects associated with letermovir included diarrhea (31.5%) and peripheral edema (13.4%), although these were not reported at significantly higher rates compared to VGCV. These data demonstrating improved safety and tolerability led to better letermovir adherence compared to VGCV (≥90% daily adherence reported: 98.6% of LTV patients vs. 77.5% of VGCV patients), which may have significant clinical implications in real-world settings [12 ▪▪ ].…”

“…This associated myelotoxicity often leads to earlier dose reduction or discontinuation of essential posttransplant immunosuppressive agents which could contribute to increased risk of graft rejection [20 ▪ ]. Head-to-head comparisons in randomized, clinical trials demonstrated significantly lower rates of myelosuppression with letermovir use (leukopenia: 11.3% vs. 37.0%, Dif -25.7, 95% CI -32.3, -19.1) compared to VGCV among kidney transplant recipients and similar rates (leukopenia: 2.9% vs. 3.6%, 95% CI -4.6, 2.2) to placebo when used in HSCT recipients [10,12 ▪▪ ].…”

“…1) [13,14]. Given its favorable safety profile as demonstrated in observational studies and clinical trials, letermovir offers a notable benefit over other antivirals used for CMV primary prophylaxis (PP), namely, less myelosuppression and rare need for renal dose adjustment, as seen with historical standard of care (SOC) agents [10,11,12 ▪▪ ,15,16 ▪▪ ,17]. Use of such traditional antivirals, including valganciclovir (VGCV) and ganciclovir (GCV), as prophylaxis has been primarily limited by bone marrow suppression [15,18,19].…”

“…In August 2023, the prescribing information was updated to consider extension of primary prophylaxis for up to 200 days among HSCT recipients at risk for delayed CMV infection [9]. Its expanded approval provides a promising approach to antiviral prophylaxis for CMV due to noninferior clinical efficacy and limited toxicity risk compared to traditional therapies [10,11,12 ▪▪ ]. This review will discuss the role of letermovir as prophylaxis against CMV in transplant recipients, with a particular focus on its nonviral related outcomes…”