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Letermovir (Prevymis) proved noninferior to valganciclovir (Valcyte), the standard of care, in a clinical trial of cytomegalovirus (CMV) prophylaxis in high-risk kidney transplant patients, researchers reported.

In a of 589 patients randomized 1:1 to receive either drug for up to 200 days post-transplant, the prevalence of CMV disease at 1 year was not significantly different in the letermovir group versus the valganciclovir group (10.4% vs 11.8%, adjusted difference -1.4%, 95% CI -6.5% to 3.8%), reported Ajit Limaye, MD, of the University of Washington Medicine in Seattle, and colleagues.

The rate of myelosuppression (leukopenia or neutropenia) at 28 weeks was significantly lower with letermovir compared with valganciclovir (26% vs 64%, P<0.001), the researchers reported in .

Furthermore, fewer participants in the letermovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%) compared with the valganciclovir group, the researchers said.

"Cytomegalovirus disease is a major cause of morbidity and mortality among kidney transplant recipients," Limaye and colleagues wrote. "The incidence is highest in the subgroup of CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, who comprise approximately 20% of all kidney transplant recipients."

The standard prophylaxis, valganciclovir, has important limitations, however, the investigators noted. It requires dose adjustments, and patients have been known to develop resistance. Furthermore, valganciclovir commonly causes myelosuppression, especially leukopenia and neutropenia, which can lead to discontinuation or necessitate dose reductions of immunosuppressants.

"Letermovir is an antiviral active against CMV without associated myelotoxicity, does not require dose adjustment for kidney impairment, has a unique mechanism of action as an inhibitor of the CMV DNA terminase complex, and is not associated with cross-resistance to other anti-CMV agents," the study authors said.

Letermovir has limitations of its own, however, Limaye and colleagues noted. Unlike valganciclovir, it does not have activity against herpes simplex virus (HSV) or varicella zoster virus (VZV). And as a moderate cytochrome P3450 3A inhibitor, it has the potential to interact with other drugs.

Letermovir was approved by the FDA in 2017 for CMV prophylaxis in CMV-seropositive adult hematopoietic cell transplant recipients, and has been widely adopted in this population. The drug's manufacturer, Merck, that the FDA also approved letermovir for CMV prophylaxis in adult kidney transplant recipients at high risk, based on results of the current study.

In an accompanying the study, Zoe Raglow, MD, and Daniel R. Kaul, MD, both of the University of Michigan Medical School in Ann Arbor, said another limitation of letermovir is its cost. "Cost will certainly be a factor, because the average daily cost of letermovir (approximately $250 per day) is more than 20 times that of generic valganciclovir, making it one of the most expensive routine post-transplant medications," they wrote.

Nevertheless, Raglow and Kaul said the results presented by Limaye's group were "practice changing," and clinicians will need to weigh the limitations and advantages of letermovir in considering the patients mostly likely to benefit. "Letermovir may be most cost-effective when used among patients with baseline leukopenia or who develop leukopenia during valganciclovir treatment," the editorialists suggested.

The double-blind, double-dummy phase III trial included the highest-risk adult patients: CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor. The majority were white (84%) and male (71%).

The letermovir group received 480 mg of letermovir orally daily, 400 mg of acyclovir twice daily (as HSV and VZV prophylaxis), and a valganciclovir placebo. The valganciclovir group received 900 mg of valganciclovir orally daily with placebos for letermovir and acyclovir. Acyclovir does not have activity against CMV, the researchers noted.

The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through post-transplant week 52, with a prespecified noninferiority difference of 10%. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.

Secondary outcomes included CMV disease through week 28 and time to onset of CMV disease. No participants in the letermovir group developed CMV disease through week 28 versus five participants who received valganciclovir. The time to onset of CMV disease was comparable between the groups (HR 0.90, 95% CI 0.56-1.47).

Study limitations, the team said, included that myelotoxicity was evaluated as leukopenia or neutropenia, but valganciclovir may also cause anemia and thrombocytopenia. There was also no cost analysis, despite cost being an important consideration with letermovir.

In addition, the study lacked diversity, the authors said, although CMV disease risk has not been linked to gender, race, or ethnicity. Finally, long-term outcomes of CMV disease were not formally assessed. "However, because CMV disease was comparable between groups, there is no reason to anticipate differences in long-term outcomes with letermovir versus valganciclovir," the researchers said.

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