Researchers have found that Letermovir, sold under the brand name Prevymis, is just as effective as the standard prophylaxis, Valganciclovir, in preventing cytomegalovirus (CMV) disease in high-risk kidney transplant patients. CMV disease is a major cause of morbidity and mortality in kidney transplant recipients, especially in those who receive an organ from a CMV-seropositive donor. The study included 589 patients randomized to receive either drug for up to 200 days post-transplant. After one year, the prevalence of CMV disease was not significantly different between the two groups. However, the rate of myelosuppression, which can lead to discontinuation or necessitate dose reductions of immunosuppressants, was significantly lower with Letermovir than with Valganciclovir. Fewer participants in the Letermovir group also discontinued prophylaxis due to adverse events or drug-related adverse events compared to the Valganciclovir group.
Valganciclovir, the standard prophylaxis, requires dose adjustments, and patients have been known to develop resistance. Furthermore, myelosuppression, especially leukopenia and neutropenia, is a common side effect of Valganciclovir. Letermovir, on the other hand, 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. However, Letermovir does not have activity against herpes simplex virus or varicella zoster virus, 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 FDA has just approved Letermovir for CMV prophylaxis in adult kidney transplant recipients at high risk based on results of the current study.
In an editorial accompanying the study, the authors noted that another limitation of Letermovir is its cost, which is more than 20 times that of generic Valganciclovir, making it one of the most expensive routine post-transplant medications. Nevertheless, the results presented by the researchers were described as “practice changing,” and clinicians will need to weigh the limitations and advantages of Letermovir in considering the patients most likely to benefit. Letermovir may be most cost-effective when used among patients with baseline leukopenia or who develop leukopenia during Valganciclovir treatment.
The study 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 herpes simplex virus and varicella zoster virus prophylaxis), and a Valganciclovir placebo. The Valganciclovir group received 900 mg of Valganciclovir orally daily with placebos for Letermovir and Acyclovir. 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 study had several limitations, including 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, 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.
Letermovir has shown promise as an effective prophylaxis against CMV disease in high-risk kidney transplant patients. While more expensive than the standard prophylaxis, Valganciclovir, Letermovir may be most cost-effective when used among patients with baseline leukopenia or who develop leukopenia during Valganciclovir treatment. Clinicians will need to weigh the limitations and advantages of Letermovir in considering the patients most likely to benefit.