Letermovir Dosing for CMV Prophylaxis in Kidney Transplant Recipients
Letermovir is not currently the standard of care for kidney transplant recipients, but when used, the dose is 480 mg orally once daily (or 240 mg once daily if co-administered with cyclosporine), with no dose adjustment required for renal impairment.
Standard Dosing Regimen
Administer letermovir 480 mg orally once daily starting within 7 days post-transplant and continuing through 28 weeks (approximately 200 days) after transplantation 1, 2.
Reduce the dose to 240 mg once daily when co-administered with cyclosporine due to drug-drug interactions that increase letermovir exposure 3, 4, 1.
No renal dose adjustment is required even in patients with severe renal impairment (CrCl <10 mL/min), making letermovir particularly advantageous in kidney transplant recipients with impaired renal function 4.
Evidence Supporting Use in Kidney Transplantation
The most recent and highest quality evidence comes from a 2023 randomized phase 3 trial in JAMA demonstrating that letermovir was noninferior to valganciclovir for preventing CMV disease in high-risk (D+/R-) kidney transplant recipients through 52 weeks post-transplant 1. This trial showed:
- CMV disease occurred in 10.4% of letermovir recipients vs 11.8% of valganciclovir recipients (difference -1.4%, meeting noninferiority criteria) 1.
- Letermovir had significantly lower rates of leukopenia/neutropenia (26% vs 64%, P<0.001) compared to valganciclovir 1.
- Fewer patients discontinued letermovir due to adverse events (4.1% vs 13.5%) 1.
A 2024 Japanese phase 3 study confirmed these findings, showing letermovir 480 mg daily was well tolerated with no CMV disease or infection requiring intervention through week 28 in adult Japanese kidney transplant recipients 2.
Important Clinical Considerations
Advantages Over Valganciclovir in Renal Impairment
- Letermovir does not require dose adjustment for renal function, unlike valganciclovir which requires complex dosing adjustments based on creatinine clearance 4, 1.
- No nephrotoxicity or myelosuppression has been observed with letermovir, contrasting sharply with valganciclovir's bone marrow suppression risk 3, 4.
- Serum creatinine monitoring is recommended only when CrCl is <50 mL/min 4.
Hepatic Considerations
- Avoid letermovir in severe hepatic impairment (Child-Pugh class C) as it is metabolized primarily by hepatic OATP1B1/3 4.
- No dose adjustment needed for mild to moderate hepatic impairment 4.
Duration and Timing
- Initiate letermovir between day 0 through day 28 post-transplant and continue through day 100-200 post-transplant 3, 4, 1, 2.
- The JAMA trial used 200 days of prophylaxis, which is longer than the 100-day duration studied in hematopoietic cell transplant recipients 1, 5.
Critical Pitfalls to Avoid
Lack of HSV/VZV Coverage
- Letermovir lacks activity against HSV and VZV, so concurrent acyclovir or valacyclovir prophylaxis must be continued 3, 1.
- This is a critical distinction from valganciclovir, which provides coverage for HSV, VZV, and CMV 1.
Resistance Development
- Rapid emergence of resistant mutants (UL56 mutations C325Y or W) can occur if letermovir is interrupted, underdosed, or in high-risk patients 3, 6.
- Cross-resistance with DNA polymerase inhibitors (ganciclovir, foscarnet, cidofovir) has not been observed, making letermovir active against strains resistant to these agents 4.
Drug Interactions
- Always reduce dose to 240 mg daily with cyclosporine co-administration 3, 4, 1.
- Letermovir is a moderate CYP3A inducer and may interact with other immunosuppressants 4.
Context: Current Standard of Care
While letermovir shows promise, valganciclovir remains the standard of care for CMV prophylaxis in kidney transplant recipients, particularly high-risk D+/R- patients 7, 8, 1. The KDIGO guidelines recommend 6 weeks of CMV chemoprophylaxis with valganciclovir after T-cell-depleting antibody therapy for rejection treatment 7.
However, letermovir represents an important alternative when:
- Myelosuppression from valganciclovir is problematic or anticipated
- Renal function is severely impaired, making valganciclovir dosing complex
- Patient cannot tolerate valganciclovir side effects
The 2024 NCCN guidelines primarily discuss letermovir in the context of allogeneic hematopoietic cell transplantation rather than solid organ transplantation, reflecting its more established role in that population 3.