The FDA has approved the antiviral letermovir for cytomegalovirus (CMV) prophylaxis in adult recipients of a CMV-seropositive kidney transplant. The new indication is based on results of a phase 3 clinical trial presented at the 2023 American Transplant Congress in San Diego, California, and concurrently published in JAMA.

In the placebo-controlled trial, investigators randomly assigned 601 CMV-seronegative kidney transplant recipients (84% White) to oral letermovir (480 mg daily) with acyclovir or standard of care oral valganciclovir (900 mg daily), adjusted for kidney function, for up to 200 days after transplantation. Patients receiving lymphocyte-depleting induction immunosuppression were equally distributed between groups.

Letermovir was noninferior to valganciclovir for prevention of CMV disease through 52 weeks, with 10.4% vs 11.8% developing CMV disease, respectively, Ajit P. Limaye, MD, of UW Medicine in Seattle, Washington, and colleagues reported. Time to onset of CMV disease was comparable between the groups.

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At 28 weeks, CMV disease had developed in 1.7% of the valganciclovir group but not in any patient in the letermovir group. CMV DNAemia developed in 2.1% of the letermovir group compared with 8.8% of valganciclovir recipients. According to the investigators, these secondary results highlight the limitations of universal 6 months CMV prophylaxis.

Leukopenia (11.3% vs 37.0%) and neutropenia (2.7% vs 16.5%) occurred in significantly lower proportions of the letermovir than valganciclovir group. Prophylaxis discontinuation due to an adverse event occurred in 4.1% vs 13.5%, respectively, and drug-related adverse events in 2.7% vs 8.8%. Antiviral resistance was not observed in the letermovir group but affected 12.1% of the valganciclovir group who were evaluated for suspected CMV disease/CMV DNAemia.

“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,” Dr Limaye’s team explained. “However, unlike valganciclovir, letermovir has potential drug interactions (moderate cytochrome P3450 3A inhibitor, substrate for organic anion transporting polypeptide 1B1/3) and does not have activity against herpes simplex virus (HSV) or varicella zoster virus (VZV).”

In an accompanying editorial, Zoe Raglow, MD, and Daniel R. Kaul, MD, of the Division of Infectious Disease, University of Michigan Medical School in Ann Arbor, Michigan, lauded the study.

“Strategies for posttransplant CMV prevention continue to evolve, with many promising alternatives on the horizon. This trial by Limaye and colleagues is a major step forward in demonstrating that letermovir is an equally effective and better tolerated antiviral option when used as universal prophylaxis in high-risk kidney transplant recipients.”

The editorialists pointed out that the average daily cost of letermovir is approximately $250 per day – far higher than the cost of generic valganciclovir. They suggested that letermovir may be most cost-effective when used among patients with leukopenia before or during valganciclovir treatment.

Future studies need to determine whether prophylaxis with letermovir vs valganciclovir decreases opportunistic infections and allograft rejection. The safety of letermovir in adults with end-stage renal disease, including patients on dialysis, is unknown. It is not recommended in children.

Disclosure: This research was supported by Merck Sharp & Dohme LLC. Please see the original reference for a full list of disclosures.


Limaye AP, Budde K, Humar A, et al. Letermovir vs valganciclovir for prophylaxis of cytomegalovirus in high-risk kidney transplant recipients: a randomized clinical trial. JAMA. Published online June 6, 2023. doi:10.1001/jama.2023.9106

Raglow Z and Kaul DR. A new antiviral option for cytomegalovirus prevention after kidney transplant. JAMA. Published online June 6, 2023.

US FDA approves new indication for Merck’s PREVYMIS® (letermovir) for prevention of cytomegalovirus (CMV) disease in high-risk adult kidney transplant recipients. News release. Merck; June 6, 2023.