Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review

Figures & data

Table 1 CMV risk factors for solid organ transplant recipients

Serostatus	Mild risk	Moderate risk	High risk
D+/R–			XX
D+/R+		XX
D–/R+		X
D–/R–	X (from primary infection acquired in the community)
Transplanted organ
Lung			XX
Pancreas			XX
Intestinal			XX
Heart		X
Kidney		X
Liver		X
Induction immunotherapy
Alemtuzumab			XX
ATG			XX
Basiliximab		X
Maintenance immunosuppression
Calcineurin inhibitors/antimetabolites		X
Steroids			X
mTOR inhibitors	X
Mycophenolate mophetil		X (standard dose of =<2 g/day)	X (high dose of ≥3 g/day)

Notes: XX is higher risk than X for the same risk category

Risk factors for CMV in allogeneic hematopoietic stem cell transplant recipients are listed in the text.

Abbreviations: CMV cytomegalovirus; ATG, anti-thymocyte globulin, mTOR, mammalian target of rapamycin.

Table 2 Comparison of current CMV prevention strategies

Strategy	Prophylaxis	Preemptive Therapy
Principle	Antivirals administered to all at-risk patients for a defined period of time following transplantation	CMV DNA test (at least once weekly) Antiviral therapy started when viral load exceeds a certain threshold
Advantages	Effectively prevents early CMV reactivation	Reduced medication cost Lower risk of drug toxicity Allows immune reconstitution
Disadvantages	High rates of medication side effects Increased drug cost Risk for delayed-onset CMV disease	Does not prevent early CMV reactivation Escape CMV infections (not detected by weekly CMV NAT) Burden, logistics and cost of weekly surveillance labs

Abbreviations: CMV, Cytomegalovirus; NAT, Nucleic Amplification Test.

Table 3 Characteristics of antiviral drugs approved for cytomegalovirus

Drug Name	Ganciclovir and valganciclovir	Foscarnet	Cidofovir	Letermovir
Mechanism of action	2ʹ-deoxyguanosine analogue Competitive binding to UL54 DNA polymerase Needs phosphorylation by CMV (UL97 encoded) and host kinases Virostatic agent	Pyrophosphate analogue Noncompetitive inhibitor of many RNA and DNA polymerases (UL54 DNA polymerase in CMV) Virostatic agent	Acyclic monophosphate deoxycytidine analogue Competitive substrate of UL54 DNA polymerase leads to inhibition of viral DNA synthesis through incorporation into growing viral DNA chain Virostatic agent	Inhibits viral terminase complex, encoded by genes UL56, UL51 and UL89 Virostatic agent
Indications/uses	CMV retinitis CMV prophylaxis SOT Non-FDA uses: CMV disease CMV preemptive strategy CMV prophylaxis in HSCT	CMV retinitis Non-FDA uses: second line for GCV resistant CMV disease therapy, prophylaxis or preemptive therapy	CMV retinitis Non-FDA uses: 2nd line for GCV resistant CMV disease therapy, prophylaxis or preemptive therapy	CMV prophylaxis in CMV-seropositive HSCT recipients
Formulations	GCV IV only VGCV oral	IV only	IV only Lipid conjugate not yet approved (brincidofovir)	IV and PO
Adverse effects	Pancytopenia and myelosuppression (leukopenia/neutropenia++) Renal injury Diarrhea Less common: pruritus, nausea, fever, torsade de pointe	Renal injury Electrolytes wasting Neutropenia Less common: headache, diarrhea, fever, QTc prolongation	Renal injury Proteinuria Neutropenia Ocular toxicity (iritis, uveitis, amblyopia) Less common: headaches, shivering, rash, alopecia, dyspnea	Uncommon, mainly GI (gastritis, nausea), dyspnea, hepatitis
Resistance mechanism	Mutations in UL97 gene prevent activation of drug Mutations in UL54 gene prevent binding to DNA polymerase (may confer cross-resistance with all DNA-polymerase active antivirals)	Mutations in UL54 gene prevent binding to DNA polymerase (may confer cross-resistance with all DNA-polymerase active antivirals)	Mutations in UL54 gene prevent binding to DNA polymerase (may confer cross-resistance with all DNA-polymerase active antivirals)	Mutations in UL56 gene Less commonly, mutations in UL51 or UL89 genes

Abbreviations: CMV, cytomegalovirus; GVC, Ganciclovir; HSCT, hematopoietic stem cell transplant; IV, intravenous; PO, oral; GI, gastrointestinal; VGCV, Valganciclovir.

Table 4 Letermovir key characteristics

Molecule	3,4-dihydro-quinazoline-4-yl-acetic acid derivative
Mechanism of action	Inhibits terminase complex subunit pUL56
Spectrum of activity	Only active against CMV (no activity against HSV)
Bioavailability	94% healthy individuals 35% in HSCT (increased to 85% with cyclosporine)
Excretion	93% in feces, mostly as unchanged drug
Dosing	480 mg daily (240 mg if administered with cyclosporine) for prophylaxis in HSCT No dose adjustment for renal dysfunction
Side effects	Uncommon, mainly GI (gastritis, nausea), dyspnea, hepatitis
Drug interactions	Reduces exposure to voriconazole Increases exposure to tacrolimus, cyclosporine, midazolam Letermovir exposure increased with cyclosporine
Current FDA approved indication	CMV prophylaxis in CMV-seropositive HSCT recipients
Ongoing trials	Use of letermovir for CMV prophylaxis in CMV-seronegative kidney transplant recipients clinicaltrials.gov NCT3443869

Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; HSCT, hematopoietic stell cell transplant; GI, gastrointestinal.