Letermovir

Letermovir is an antiviral medicine belonging to the cytomegalovirus (CMV) terminase complex inhibitor class. It is used to prevent CMV infection, reactivation, and disease in selected patients who have undergone stem cell or kidney transplantation and are at increased risk of complications. CMV is a common virus that can remain dormant in the body and reactivate when the immune system is weakened, particularly after transplantation and immunosuppressive treatment. Letermovir works by inhibiting the viral terminase complex, which is essential for processing and packaging CMV DNA into new virus particles. This mechanism prevents the virus from reproducing effectively and differs from that of several older antiviral medicines. Letermovir is available as oral tablets and as an intravenous formulation for patients who cannot take oral medication or when intravenous administration is clinically appropriate. Its use is preventive rather than a substitute for treatment of established CMV disease. In high-risk transplant recipients, prophylaxis can reduce clinically significant CMV infection and the need for additional antiviral treatment. Letermovir does not provide protection against every viral infection and is not active against herpes simplex virus or varicella-zoster virus. Treatment selection, duration, and monitoring depend on the type of transplant, CMV risk status, concurrent medicines, and the patient's clinical condition.

Letermovir was developed as a targeted antiviral agent that inhibits the CMV terminase complex, a viral mechanism required for DNA processing and packaging. The US Food and Drug Administration (FDA) first approved letermovir in November 2017 for preventing CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. The European Medicines Agency (EMA) granted marketing authorisation for Prevymis in January 2018. Subsequent regulatory expansions extended its use to high-risk kidney transplant recipients and eligible paediatric transplant populations. In the United States, approval for high-risk kidney transplant recipients followed in June 2023, and additional paediatric indications were approved in August 2024. The pivotal phase 3 stem cell transplantation trial demonstrated a reduction in clinically significant CMV infection compared with placebo. A separate phase 3 kidney transplantation trial established its role in CMV prophylaxis compared with valganciclovir. Regulatory indications and eligible patient groups vary by jurisdiction; local prescribing information should be consulted for current approval status and requirements.

Letermovir is indicated for the prevention of CMV infection and disease in CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation and for the prevention of CMV disease in selected high-risk kidney transplant recipients who receive a kidney from a CMV-seropositive donor while being CMV-seronegative themselves. Depending on the country's approved prescribing information, eligible paediatric patients may also receive prophylaxis. Letermovir may be used as a single antiviral prophylactic medicine, although additional medicines may be required to prevent other infections, such as herpes simplex virus or varicella-zoster virus. It is not indicated as routine treatment for established CMV disease, and suspected breakthrough infection requires appropriate diagnostic evaluation and a suitable antiviral treatment strategy. The choice of prophylaxis depends on transplant type, donor and recipient CMV status, immune suppression, and the applicable clinical guidelines.

Letermovir is administered orally or by intravenous infusion, according to the patient's condition and the prescribed formulation. For eligible adult allogeneic stem cell transplant recipients, the standard dose is generally 480 mg once daily, with prophylaxis commonly continued through day 100 after transplantation. In selected patients at increased risk of late CMV infection, treatment may be extended through day 200 under the applicable prescribing recommendations. For eligible high-risk adult kidney transplant recipients, the usual regimen is 480 mg once daily, generally continued through day 200 after transplantation. When letermovir is given with cyclosporine, the dose is reduced to 240 mg once daily because cyclosporine increases letermovir exposure. Paediatric doses depend on age, body weight, transplant indication, and formulation. Intravenous administration requires appropriate infusion procedures and product-specific preparation. Treatment duration and any dose adjustment must be determined by the transplant specialist, with consideration of tolerability, concomitant medicines, and local prescribing guidance.

Commonly reported side effects of letermovir include nausea, diarrhoea, vomiting, abdominal discomfort, swelling caused by fluid retention, cough, headache, and fatigue. The frequency and severity of these effects can vary depending on the patient's overall condition, transplant recovery, and other medicines being taken. Some symptoms may overlap with complications of transplantation or other treatments, so they should not automatically be attributed to letermovir. Patients should report persistent gastrointestinal symptoms, worsening swelling, or any new or unusual symptoms to their healthcare team. Supportive care or a change in management may be appropriate when side effects interfere with treatment. Patients should not stop or modify prophylaxis without consulting their prescribing clinician.

Important safety considerations include clinically significant drug interactions, hypersensitivity reactions, and reported cardiac rhythm disturbances such as atrial fibrillation or atrial flutter. The risk of cardiac events should be assessed in the context of the patient's medical history and concurrent therapies. Letermovir is contraindicated with certain medicines, including pimozide and ergot alkaloids, because interactions may cause serious harm. Pitavastatin and simvastatin are contraindicated with letermovir when co-administered with cyclosporine because of increased risk of statin-related toxicity. Breakthrough CMV infection can occur despite prophylaxis, so new clinical findings or evidence of viral replication require prompt assessment. Letermovir should not be relied upon as the sole treatment for established CMV disease. Clinicians may need to interrupt or discontinue treatment when serious adverse reactions occur or when an alternative antiviral strategy is required.

Before starting letermovir, clinicians should review the patient's CMV serostatus, transplant history, renal and hepatic function where clinically relevant, medication list, and risk of drug interactions. Although letermovir generally does not require dose adjustment solely because of renal impairment, the intravenous formulation contains excipients that require particular consideration in patients with impaired renal function. Severe hepatic impairment and combined hepatic and renal impairment warrant careful review of prescribing recommendations. Letermovir can affect drug transporters and metabolic pathways, potentially altering concentrations of immunosuppressants, statins, and other medicines. Particular attention is required when it is used with cyclosporine, tacrolimus, sirolimus, or other narrow-therapeutic-index drugs, with drug-level monitoring and dose adjustments when indicated. Letermovir does not protect against herpes simplex virus or varicella-zoster virus, so additional prophylaxis may be necessary. Vaccination planning should follow transplant-specific guidance, and live vaccines should be avoided when contraindicated by the patient's immune status or treatment plan.

Prescribers should confirm the transplant indication, CMV serostatus, and intended prophylaxis duration before initiating letermovir. Review the complete medication list at baseline and whenever medicines are added, discontinued, or adjusted, particularly cyclosporine, tacrolimus, sirolimus, and interacting statins. Confirm the appropriate dose when cyclosporine is co-administered and ensure that any paediatric regimen follows current weight-based prescribing guidance. Monitor for breakthrough CMV infection according to the transplant centre's protocol, including CMV nucleic acid testing when indicated, and evaluate suspected infection promptly rather than assuming that prophylaxis excludes CMV disease. Pharmacists should verify formulation, dose, infusion compatibility, preparation requirements, and the prescribed duration. Reinforce adherence to once-daily dosing and advise patients to consult their transplant team before stopping treatment or taking new medicines. Coordinate care among transplant specialists, infectious disease clinicians, and pharmacists to support appropriate prophylaxis, manage interactions, and ensure timely review of adverse effects.