What is the recommended use and dosage of Letermovir (Letermovir) for preventing cytomegalovirus (CMV) infection in high-risk patients?

Letermovir for CMV Prophylaxis in High-Risk Patients

Letermovir should be administered at 480 mg once daily (oral or IV) starting between day 0-28 post-allogeneic hematopoietic cell transplant (HCT) and continued through day 100 in CMV-seropositive recipients, with dose reduction to 240 mg daily when co-administered with cyclosporine. 1

Target Population

Primary prophylaxis with letermovir is specifically indicated for:

• CMV-seropositive recipients undergoing allogeneic HCT 1, 2
• Patients at highest risk include those with CMV-seropositive status pre-transplant, where reactivation rates reach 50-60% despite standard prophylaxis 1
• The drug is approved for adults ≥18 years of age 3

Dosing and Administration

Standard dosing regimen:

• 480 mg once daily (oral or IV) when used alone 1, 4
• 240 mg once daily when co-administered with cyclosporine due to drug-drug interactions 1, 4
• Initiate between day 0 through day 28 post-transplant 1, 3
• Continue through day 100 post-HCT as standard duration 1, 3

Extended duration considerations:

• Some centers extend prophylaxis to day 200 in patients at particularly high risk for CMV reactivation 1, 2
• High-risk features warranting extended prophylaxis include severe chronic GVHD, intensive glucocorticoid therapy, or T-cell depletion 2

Renal and Hepatic Adjustments

• No renal dose adjustment needed until creatinine clearance <10 mL/min, but monitor serum creatinine when CrCl <50 mL/min 3
• Not recommended in severe hepatic impairment (Child-Pugh class C) 3

Critical Limitations and Concurrent Prophylaxis

Letermovir lacks activity against HSV and VZV, requiring continuation of separate HSV/VZV prophylaxis with acyclovir, valacyclovir, or famciclovir throughout the treatment period. 1, 2 This is a common pitfall—providers must not discontinue HSV/VZV prophylaxis when initiating letermovir.

Surveillance Strategy During and After Prophylaxis

Weekly quantitative CMV viral load monitoring by PCR should continue throughout the prophylaxis period and for at least 3-6 months post-transplant. 1, 5, 2 The NCCN guidelines favor a surveillance-based preemptive therapy approach over universal long-term prophylaxis in allogeneic HCT recipients 1

After discontinuation of letermovir:

• CMV surveillance must continue, as reactivation can occur post-prophylaxis 6
• In one study, CMV reactivation occurred at a median of 28 days after stopping secondary prophylaxis 6
• Surveillance should extend through periods of chronic GVHD requiring immunosuppressive therapy 1

Efficacy Data

The pivotal phase III trial demonstrated significant reduction in clinically significant CMV infection:

• 37.5% in letermovir group versus 60.6% in placebo group by week 24 (P<0.001) 1, 4
• All-cause mortality at week 48 was 20.9% with letermovir versus 25.5% with placebo 4

Safety Profile and Tolerability

Letermovir demonstrates superior tolerability compared to ganciclovir/valganciclovir:

• No hematologic toxicity or nephrotoxicity in clinical trials 1
• Most common adverse events: vomiting (18.5%), edema (14.5%), atrial fibrillation/flutter (4.6%) 4
• In real-world use, only 2-5% of patients discontinue due to adverse effects 7, 6

This contrasts sharply with ganciclovir/valganciclovir, which cause bone marrow suppression, and foscarnet, which causes nephrotoxicity and electrolyte abnormalities 1, 2

Resistance Concerns

Rapid emergence of resistant mutants can occur with letermovir if treatment is interrupted, underdosed, or in patients with other risk factors. 1 Resistance mutations in the CMV UL56 gene (C325Y or W) confer high-level letermovir resistance 7. Consider testing for drug resistance if clinically significant breakthrough infection occurs 1

Secondary Prophylaxis Use

While not FDA-approved for this indication, letermovir shows promise as secondary prophylaxis after treated CMV episodes:

• Initiated at median 47-170 days post-HCT in high-risk patients 7, 6
• Administered for median duration 77-118 days 7, 6
• Breakthrough infection rates of 5-5.5% during secondary prophylaxis 7, 6
• Well-tolerated with 77% completing planned duration 6

Preemptive Therapy Alternative

If letermovir prophylaxis is not used, initiate preemptive therapy with valganciclovir (oral) or ganciclovir (IV) upon detection of CMV viremia, continuing for at least 2 weeks and until CMV is no longer detected. 1, 2 Foscarnet serves as second-line for ganciclovir intolerance or resistance 1