What is Prevymis (letermovir) and how is it used for cytomegalovirus prophylaxis in adult allogeneic hematopoietic stem‑cell transplant recipients?

What is Prevymis (Letermovir)?

Prevymis (letermovir) is a novel antiviral medication that inhibits the CMV terminase complex and is FDA-approved for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and in high-risk kidney transplant recipients. 1

Mechanism of Action

• Letermovir works through a unique mechanism by inhibiting the CMV terminase complex, which is distinct from traditional polymerase inhibitors like ganciclovir. 2
• This novel mechanism provides no cross-resistance with existing anti-CMV agents. 3

FDA-Approved Indications

• HSCT recipients: Prophylaxis of CMV infection and disease in adult and pediatric patients ≥6 months of age and weighing ≥6 kg who are CMV-seropositive recipients of allogeneic HSCT. 1
• Kidney transplant recipients: Prophylaxis of CMV disease in adult and pediatric patients ≥12 years of age and weighing ≥40 kg who are at high risk (D+/R- serostatus). 1

Standard Dosing in HSCT Recipients

Adults and Pediatric Patients ≥12 Years

• Without cyclosporine: 480 mg once daily (oral or IV). 2, 1
• With cyclosporine: 240 mg once daily due to significant drug-drug interactions that increase letermovir exposure. 2, 1

Timing and Duration

• Start letermovir between Day 0 and Day 28 post-transplant. 2, 1
• Continue through Day 100 (week 14) post-transplant as standard duration. 2, 1
• Consider extending prophylaxis through Day 200 (week 28) in high-risk patients with ongoing immunosuppression or graft-versus-host disease (GVHD). 2

Clinical Efficacy

• In the pivotal phase III randomized trial, letermovir reduced clinically significant CMV infection from 60.6% with placebo to 37.5% (P<0.001). 2
• This represents a reduction from 61% to 38% in the incidence of CMV infection in CMV-seropositive HSCT recipients. 2

Superior Safety Profile

• No nephrotoxicity: Unlike foscarnet and cidofovir, letermovir causes no kidney damage. 2
• No myelosuppression: Unlike ganciclovir/valganciclovir, letermovir does not cause neutropenia or thrombocytopenia. 2
• This favorable toxicity profile makes letermovir particularly valuable in the post-transplant setting where patients are already at risk for cytopenias and renal dysfunction. 3

Critical Clinical Caveats

Lack of HSV/VZV Activity

• Letermovir has NO activity against herpes simplex virus (HSV) or varicella-zoster virus (VZV). 2
• Concurrent acyclovir or valacyclovir prophylaxis must be continued throughout the entire letermovir treatment period. 2

Resistance Concerns

• Rapid emergence of resistant mutants can occur if letermovir is interrupted, underdosed, or in patients with additional risk factors. 2
• The most common resistance mutation is UL56 C325Y or C325W, which confers high-level letermovir resistance. 4, 5
• De novo resistance remains rare (approximately 1-2% of cases), but breakthrough CMV reactivation at subclinical levels occurs more frequently. 5

Breakthrough CMV Reactivation

• Breakthrough CMV reactivation occurs in approximately 42% of patients at any detectable level, though clinically significant infection (≥500 IU/mL) occurs in only 7%. 5
• Cumulative steroid exposure is the strongest risk factor for breakthrough CMV reactivation. 5
• Post-transplant cyclophosphamide or calcineurin inhibitor plus mycophenolate GVHD prophylaxis increases risk of breakthrough reactivation. 5

Formulations and Administration

• Oral tablets: 120 mg, 240 mg, and 480 mg tablets; swallow whole with or without food. 1
• Oral pellets: Available for patients unable to swallow tablets; do not crush or chew. 1
• Intravenous: Must be diluted and administered over 1 hour through a 0.2 or 0.22 micron PES in-line filter; should not exceed 4 weeks of use due to hydroxypropyl betadex content. 1

Post-Prophylaxis Monitoring

• Following completion of letermovir prophylaxis, monitoring for CMV reactivation is recommended, as late CMV reactivation can occur after discontinuation. 1
• This is particularly important given that 50-60% of CMV-seropositive HSCT recipients experience CMV reactivation despite routine surveillance. 2

Secondary Prophylaxis Use

• Letermovir can be used as secondary prophylaxis after at least one CMV episode (infection or disease) post-HCT. 4
• In a French compassionate use program, only 5.5% of patients developed breakthrough CMV infection or disease when letermovir was used as secondary prophylaxis. 4
• This provides a bridge between pre-emptive/therapeutic treatment and CMV-specific immune reconstitution while tapering immunosuppressants. 4