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CMV Antiviral — Viral Terminase Inhibitor (Prophylaxis in HSCT) Pregnancy: Avoid — insufficient human data; animal studies suggest foetal toxicity. CMV management in pregnancy with HSCT requires specialist ID and maternal-foetal medicine input.

Letermovir

Brand names: Prevymis

Adult dose

Dose: 480 mg once daily (without ciclosporin). 240 mg once daily (with ciclosporin — CYP3A4 interaction)
Route: Oral or Intravenous (bioavailability ~94% — oral and IV doses identical)
Frequency: Once daily (start within 28 days of HSCT; continue for 100 days post-transplant)
Max: 480 mg/day
CMV prophylaxis in CMV-seropositive adult haematopoietic stem cell transplant (HSCT) recipients. Start within 28 days post-transplant, continue through day 100. If on ciclosporin: reduce to 240 mg/day (CYP3A4 interaction increases letermovir AUC). NOT active against other herpesviruses. NOT for treatment — prophylaxis only. Source: BNF 90; NICE TA568; MHRA SPC Prevymis.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg
Route: N/A
Frequency: N/A
Max: N/A
Not licensed in paediatric HSCT. Off-label use under specialist ID/microbiology guidance.

Dose adjustments

Renal

No dose adjustment required for renal impairment. Oral formulation preferred in renal impairment (IV cyclodextrin vehicle accumulates below eGFR 50 mL/min).

Hepatic

Severe hepatic impairment (Child-Pugh C): not recommended — significantly increased letermovir exposure. Mild-moderate: no adjustment.

Paediatric weight-based calculator

Not licensed in paediatric HSCT. Off-label use under specialist ID/microbiology guidance.

Clinical pearls

  • NEJM 2018 landmark trial: letermovir prophylaxis for 14 weeks post-HSCT reduced clinically significant CMV infection by 38% vs placebo (19% vs 44% at week 24, HR 0.30). Significantly reduced all-cause mortality at week 48 — the first CMV antiviral to show survival benefit in HSCT. NICE TA568 recommended for CMV-seropositive adult HSCT recipients.
  • Completely new mechanism — viral terminase inhibitor: letermovir inhibits the CMV DNA terminase complex (pUL89, pUL51, pUL56), which is essential for packaging viral DNA into capsids. No cross-resistance with ganciclovir (DNA polymerase inhibitor) or maribavir (UL97 kinase inhibitor). Completely novel target — active against ganciclovir-resistant CMV.
  • No myelosuppression — transformative advantage: ganciclovir and valganciclovir cause significant neutropenia (40–60% incidence), often limiting CMV prophylaxis in HSCT patients who are already profoundly neutropenic post-transplant. Letermovir has no bone marrow toxicity — a paradigm shift in CMV prophylaxis.
  • Ciclosporin dose interaction — must monitor: letermovir + ciclosporin leads to doubled letermovir levels (use 240 mg) AND reduced ciclosporin by 15–25% (need to increase ciclosporin and check trough levels weekly for 4 weeks after starting letermovir). This dual interaction requires proactive management and close pharmaceutical review in transplant units.
  • Prophylaxis only — not treatment: letermovir is licensed only for CMV prophylaxis, not treatment of active CMV disease (insufficient efficacy data for established CMV infection). If CMV viraemia detected while on letermovir — switch to treatment-dose ganciclovir/valganciclovir + confirm ganciclovir resistance testing if refractory. Source: BNF 90; Marty et al. NEJM 2017; NICE TA568; MHRA SPC Prevymis.

Contraindications

  • Concomitant pimozide or ergot alkaloids (CYP3A4 substrate NTI — letermovir is CYP3A4 inducer; increases pimozide/ergot levels)
  • Active CMV disease (prophylaxis indication only — not for treatment)
  • Severe hepatic impairment

Side effects

  • Nausea, diarrhoea, vomiting (most common — 25–30%; generally mild)
  • Peripheral oedema
  • Elevated liver transaminases (monitor LFTs)
  • Tachycardia
  • No myelosuppression (key advantage over ganciclovir/valganciclovir — no bone marrow toxicity)

Interactions

  • Ciclosporin: inhibits letermovir hepatic uptake (OATP1B1/3 inhibition) → doubles letermovir AUC → reduce letermovir to 240 mg/day. Conversely, letermovir moderately induces CYP3A4 → reduces ciclosporin levels by 15–25%: monitor ciclosporin trough levels and increase dose if needed
  • Tacrolimus: letermovir moderately induces CYP3A4 → reduces tacrolimus levels: increase tacrolimus dose and monitor trough levels more frequently during and after letermovir
  • Sirolimus: CYP3A4 induction — reduce with monitoring
  • Statins (atorvastatin, rosuvastatin): OATP1B1/3 inhibition → increased statin levels — dose reduction or statin pause during prophylaxis period
  • Pimozide, ergot alkaloids: contraindicated — increased plasma levels

Monitoring

  • CMV PCR (blood) weekly during prophylaxis — detect breakthrough CMV if viraemia develops
  • LFTs every 4 weeks
  • Ciclosporin/tacrolimus trough levels weekly for first 4 weeks (drug interaction — increase doses as needed)
  • FBC (less critical than with ganciclovir — letermovir does not cause myelosuppression, but monitor engraftment)
  • Clinical symptoms (fever, malaise — break-through CMV)

Reference: BNFc; BNF 90; Marty et al. NEJM 2017 (HSCT letermovir trial); NICE TA568; MHRA SPC Prevymis. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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