A 2024 review provides a comprehensive analysis of the roles of letermovir in the management of cytomegalovirus (CMV) infection among solid organ transplant (SOT) recipients. Letermovir is CMV-specific and does not affect other herpesviruses like herpes simplex or varicella-zoster, necessitating the concurrent use of antiviral agents, such as valacyclovir. As a prophylactic agent, letermovir has been used off-label for secondary prophylaxis in SOT recipients who are at high risk of CMV relapse after treatment for CMV infection. In these instances, letermovir has been shown to reduce the frequency of CMV recurrence when viral loads were adequately suppressed, although treatment-resistant mutations, particularly in the UL56 gene, have emerged in some patients. Additionally, letermovir’s oral availability has provided a more convenient option for outpatient care, substantially reducing hospitalization durations when transitioned from intravenous foscarnet therapy. However, breakthrough infections and drug resistance remain concerns in certain cases, especially when letermovir is used as secondary prophylaxis or initiated at high viral loads, highlighting the importance of careful patient monitoring and viral load assessments. [1]
Initially approved in 2017 for CMV-seropositive hematopoietic stem cell transplant (HSCT) recipients, letermovir subsequently gained FDA approval in 2023 for CMV prophylaxis in high-risk CMV D+/R− kidney transplant recipients. In a pivotal Phase 3 randomized clinical trial involving 601 CMV D+/R− kidney recipients (Table 1), letermovir demonstrated comparable efficacy to valganciclovir in preventing CMV disease (10.4% vs. 11.8%, respectively) and was associated with significantly lower incidences of neutropenia or leukopenia (25% vs. 64%). Additionally, fewer patients on letermovir discontinued treatment due to adverse events (4.1% vs.13.5% for valganciclovir). Despite some reports of breakthrough CMV DNAemia, letermovir did not show as high rates of resistance-associated mutations as valganciclovir, which highlighted its safety and efficacy for CMV prophylaxis in this population. Letermovir has also shown promise in off-label applications, including its use in non-kidney SOT recipients who developed myelosuppression during valganciclovir prophylaxis. Though breakthrough CMV DNAemia was occasionally reported in this setting, it was often asymptomatic and did not necessitate additional treatment. [1]
Another 2024 review also discusses the use of letermovir in transplant recipients. Real-world studies suggest letermovir is effective as prophylaxis against CMV across transplant settings. Smaller studies suggest potential for preemptive or resistant/refractory CMV treatment, alone or combined with other agents, achieving viral control in around 76% of cases. For kidney transplant recipients, letermovir was non-inferior to valganciclovir prophylaxis and had fewer side effects like leukopenia, leading to FDA approval for this use in 2023. Letermovir has high oral bioavailability and is well-tolerated, though drug interactions such as those with cyclosporine require dose adjustments. Its novel mechanism avoids cross-resistance with other antivirals. While resistance can emerge, rates remain low during prophylactic use but higher with treatment of active CMV. Data for SOT patients also appears more limited. [2]
A final 2024 article discusses the role of emerging antiviral agents for use in pediatric transplant patients. For letermovir, data appears limited to pediatric hematopoietic stem cell (HCT) patients and comprises a handful of case reports. Within the case reports, the outcomes were reported to be favorable, but letermovir’s effectiveness as primary prophylaxis remains unknown. While pediatric dosing has not yet been established, one study suggests adult dosing may be appropriate. The favorable safety profile is also limited to adult HCT and kidney transplants with a similar rate of acute kidney injury and hematological toxicities between treatment and placebo recipients. [3], [4], [5], [6]