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Annual Review of Medicine

Volume 74, 2023

Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and Treatment in Transplant Recipients

Abstract

Cytomegalovirus (CMV) is a common viral pathogen in the transplant population and is associated with significant morbidity and mortality. CMV prevention is paramount; however, selecting the best preventive strategy depends on many factors including donor–recipient CMV serostatus, transplant-specific risks, antiviral toxicities and cost. Novel CMV therapeutics such as letermovir (LTV) are desperately needed to optimize CMV management. Uniquely among CMV antiviral therapies, LTV inhibits the viral terminase complex in the CMV DNA synthesis pathway and disrupts viral genome packaging. Further, it lacks side effects frequently associated with other CMV antiviral therapies and evades common mechanisms of resistance. LTV is approved by the US Food and Drug Administration for CMV prevention in adult CMV-seropositive hematopoietic cell transplant recipients but is increasingly applied off-label for prophylaxis and treatment. This review summarizes important concepts of CMV management in transplantation, with a specific focus on LTV pharmacology and clinical experience to date alongside future prospects for its application.

Keyword(s): antiviral therapy, cytomegalovirus, hematopoietic cell transplant, letermovir, solid organ transplant
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2023-01-27
2024-05-04
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Literature Cited

  1. 1.
    Meesing A, Razonable RR. 2018. New developments in the management of cytomegalovirus infection after transplantation. Drugs 78:1085–103
     [Google Scholar]
  2. 2.
    Razonable RR, Humar A. 2019. Cytomegalovirus in solid organ transplant recipients—guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transplant. 33:e13512
     [Google Scholar]
  3. 3.
    Hakki M, Aitken SL, Danziger-Isakov L et al. 2021. American Society for Transplantation and Cellular Therapy Series: #3—Prevention of cytomegalovirus infection and disease after hematopoietic cell transplantation. Transplant. Cell Ther. 27:707–19
     [Google Scholar]
  4. 4.
    Ljungman P, Boeckh M, Hirsch HH et al. 2017. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin. Infect. Dis. 64:87–91
     [Google Scholar]
  5. 5.
    Singh N. 2005. Late-onset cytomegalovirus disease as a significant complication in solid organ transplant recipients receiving antiviral prophylaxis: a call to heed the mounting evidence. Clin. Infect. Dis. 40:704–8
     [Google Scholar]
  6. 6.
    Legendre C, Pascual M. 2008. Improving outcomes for solid-organ transplant recipients at risk from cytomegalovirus infection: late-onset disease and indirect consequences. Clin. Infect. Dis. 46:732–40
     [Google Scholar]
  7. 7.
    Marty FM, Ljungman P, Chemaly RF et al. 2017. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N. Engl. J. Med. 377:2433–44
     [Google Scholar]
  8. 8.
    Hill JA, Zamora D, Xie H et al. 2021. Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients. Blood Adv 5:3113–19
     [Google Scholar]
  9. 9.
    Rubin RH. 1989. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA 261:3607–9
     [Google Scholar]
  10. 10.
    Valantine HA. 1999. Role of CMV in transplant coronary artery disease and survival after heart transplantation. Transpl. Infect. Dis. 1:Suppl. 125–30
     [Google Scholar]
  11. 11.
    Linares L, Sanclemente G, Cervera C et al. 2011. Influence of cytomegalovirus disease in outcome of solid organ transplant patients. Transpl. Proc. 43:2145–48
     [Google Scholar]
  12. 12.
    Roman A, Manito N, Campistol JM et al. 2014. The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients. Transplant. Rev. 28:84–91
     [Google Scholar]
  13. 13.
    Teira P, Battiwalla M, Ramanathan M et al. 2016. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood 127:2427–38
     [Google Scholar]
  14. 14.
    Green ML, Leisenring W, Xie H et al. 2016. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 3:e119–27
     [Google Scholar]
  15. 15.
    Ljungman P, Schmitt M, Marty FM et al. 2020. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic cell transplantation. Clin. Infect. Dis. 70:1525–33
     [Google Scholar]
  16. 16.
    Chemaly RF, Chou S, Einsele H et al. 2019. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin. Infect. Dis. 68:1420–26
     [Google Scholar]
  17. 17.
    Griffiths P. 2020. The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination. Antivir. Res. 176:104732
     [Google Scholar]
  18. 18.
    Scalzo AA, Corbett AJ, Rawlinson WD et al. 2007. The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. Immunol. Cell Biol. 85:46–54
     [Google Scholar]
  19. 19.
    Singh N, Winston DJ, Razonable RR et al. 2020. Effect of preemptive therapy versus antiviral prophylaxis on cytomegalovirus disease in seronegative liver transplant recipients with seropositive donors: a randomized clinical trial. JAMA 323:1378–87
     [Google Scholar]
  20. 20.
    Haidar G, Boeckh M, Singh N. 2020. Cytomegalovirus infection in solid organ and hematopoietic cell transplantation: state of the evidence. J. Infect. Dis. 221:S23–31
     [Google Scholar]
  21. 21.
    Avery RK, Alain S, Alexander BD et al. 2022. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin. Infect. Dis. 75:690–701
     [Google Scholar]
  22. 22.
    Prevymis (letermovir) [package insert]. Whitehouse Station, NJ: Merck and Company Inc.; 2017.
  23. 23.
    Chou S. 2020. Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance. Antivir. Res. 176:104711
     [Google Scholar]
  24. 24.
    Dickter JK, Ross JA, Zain JM et al. 2022. Letermovir and maribavir for pan-resistant cytomegalovirus infection in a patient with haematologic malignancy: consideration for combination therapy. J. Clin. Pharmacy Therapeut. 47:699–702
     [Google Scholar]
  25. 25.
    Griffiths PD, Emery VC. 2014. Taming the transplantation troll by targeting terminase. N. Engl. J. Med. 370:1844–46
     [Google Scholar]
  26. 26.
    Verghese PS, Schleiss MR. 2013. Letermovir treatment of human cytomegalovirus infection antiinfective agent. Drugs Future 38:291–98
     [Google Scholar]
  27. 27.
    Gentry BG, Bogner E, Drach JC. 2019. Targeting the terminase: an important step forward in the treatment and prophylaxis of human cytomegalovirus infections. Antivir. Res. 161:116–24
     [Google Scholar]
  28. 28.
    Kropeit D, Scheuenpflug J, Erb-Zohar K et al. 2017. Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Br. J. Clin. Pharmacol. 83:1944–53
     [Google Scholar]
  29. 29.
    Kaul DR, Stoelben S, Cober E et al. 2011. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am. J. Transplant. 11:1079–84
     [Google Scholar]
  30. 30.
    Isberner N, Van Daele R, Klinker H et al. 2021. Letermovir exposure in transplant patients with end-stage renal disease on renal replacement therapy. J. Antimicrob. Chemother. 76:3322–25
     [Google Scholar]
  31. 31.
    Vanstraelen K, Prattes J, Maertens J et al. 2016. Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients. Eur. J. Clin. Pharmacol. 72:953–63
     [Google Scholar]
  32. 32.
    Prohn M, Viberg A, Zhang D et al. 2021. Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients. CPT Pharmacometr. Syst. Pharmacol. 10:255–67
     [Google Scholar]
  33. 33.
    Veit T, Munker D, Kauke T et al. 2020. Letermovir for difficult to treat cytomegalovirus infection in lung transplant recipients. Transplantation 104:410–14
     [Google Scholar]
  34. 34.
    Linder KA, Kovacs C, Mullane KM et al. 2021. Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. Transpl. Infect. Dis. 23:e13687
     [Google Scholar]
  35. 35.
    Saullo JL, Baker AW, Snyder LD et al. 2021. Cytomegalovirus prevention in thoracic organ transplantation: a single-center evaluation of letermovir prophylaxis. J. Heart Lung Transplant. 41:508–15
     [Google Scholar]
  36. 36.
    Aryal S, Katugaha SB, Cochrane A et al. 2019. Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients. Transpl. Infect. Dis. 21:e13166
     [Google Scholar]
  37. 37.
    Derigs P, Radujkovic A, Schubert ML et al. 2021. Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann. Hematol. 100:2087–93
     [Google Scholar]
  38. 38.
    Chemaly RF, Ullmann AJ, Stoelben S et al. 2014. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N. Engl. J. Med. 370:1781–89
     [Google Scholar]
  39. 39.
    Menzel K, Kothare P, McCrea JB et al. 2021. Absorption, metabolism, distribution, and excretion of letermovir. Curr. Drug Metab. 22:784–94
     [Google Scholar]
  40. 40.
    Marshall WL, McCrea JB, Macha S et al. 2018. Pharmacokinetics and tolerability of letermovir coadministered with azole antifungals (posaconazole or voriconazole) in healthy subjects. J. Clin. Pharmacol. 58:897–904
     [Google Scholar]
  41. 41.
    McCrea JB, Macha S, Adedoyin A et al. 2019. Pharmacokinetic drug-drug interactions between letermovir and the immunosuppressants cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil. J. Clin. Pharmacol. 59:1331–39
     [Google Scholar]
  42. 42.
    Winstead RJ, Kumar D, Brown A et al. 2021. Letermovir prophylaxis in solid organ transplant—assessing CMV breakthrough and tacrolimus drug interaction. Transpl. Infect. Dis. 23:e13570
     [Google Scholar]
  43. 43.
    Hedvat J, Choe JY, Salerno DM et al. 2021. Managing the significant drug-drug interaction between tacrolimus and letermovir in solid organ transplant recipients. Clin. Transplant. 35:e14213
     [Google Scholar]
  44. 44.
    Maples KT, Maloy M, Devlin S et al. 2020. Lack of a significant pharmacokinetic interaction between letermovir and calcineurin inhibitors in allogeneic HCT recipients. Bone Marrow Transplant. 55:1687–89
     [Google Scholar]
  45. 45.
    Terrier J, Zanella MC, Masouridi-Levrat S et al. 2021. Clinical and pharmacological considerations for concomitant administration of posaconazole and isavuconazole with letermovir. Antimicrob. Agents Chemother. 65:e00274–21
     [Google Scholar]
  46. 46.
    Chou S. 2015. Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance. Antimicrob. Agents Chemother. 59:6588–93
     [Google Scholar]
  47. 47.
    Goldner T, Hempel C, Ruebsamen-Schaeff H et al. 2014. Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure. Antimicrob. Agents Chemother. 58:610–13
     [Google Scholar]
  48. 48.
    Chou S. 2017. Comparison of cytomegalovirus terminase gene mutations selected after exposure to three distinct inhibitor compounds. Antimicrob. Agents Chemother. 61:e01325–17
     [Google Scholar]
  49. 49.
    Chou S. 2017. A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance. Antivir. Res. 148:1–4
     [Google Scholar]
  50. 50.
    Chou S, Satterwhite LE, Ercolani RJ. 2018. New locus of drug resistance in the human cytomegalovirus UL56 gene revealed by in vitro exposure to letermovir and ganciclovir. Antimicrob. Agents Chemother. 62:e00922–18
     [Google Scholar]
  51. 51.
    Douglas CM, Barnard R, Holder D et al. 2020. Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients. J. Infect. Dis. 221:1117–26
     [Google Scholar]
  52. 52.
    Knoll BM, Seiter K, Phillips A, Soave R. 2019. Breakthrough cytomegalovirus pneumonia in hematopoietic stem cell transplant recipient on letermovir prophylaxis. Bone Marrow Transplant. 54:911–12
     [Google Scholar]
  53. 53.
    Turner N, Strand A, Grewal DS et al. 2019. Use of letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis. Antimicrob. Agents Chemother. 63:e02337–18
     [Google Scholar]
  54. 54.
    Singha A, Burcham PK, Logan A et al. 2021. Letermovir for cytomegalovirus prophylaxis in lung transplant patients with valganciclovir-induced leukopenia. Transplantology 2:129–39
     [Google Scholar]
  55. 55.
    Robin C, Thiebaut A, Alain S et al. 2020. Letermovir for secondary prophylaxis of cytomegalovirus infection and disease after allogeneic hematopoietic cell transplantation: results from the French compassionate program. Biol. Blood Marrow Transplant. 26:978–84
     [Google Scholar]
  56. 56.
    Frietsch JJ, Michel D, Stamminger T et al. 2019. In vivo emergence of UL56 C325Y cytomegalovirus resistance to letermovir in a patient with acute myeloid leukemia after hematopoietic cell transplantation. Mediterr. J. Hematol. Infect. Dis. 11:e2019001
     [Google Scholar]
  57. 57.
    Alain S, Feghoul L, Girault S et al. 2020. Letermovir breakthroughs during the French Named Patient Programme: interest of monitoring blood concentration in clinical practice. J. Antimicrob. Chemother. 75:2253–57
     [Google Scholar]
  58. 58.
    Jung S, Michel M, Stamminger T, Michel D. 2019. Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. BMC Infect. Dis. 19:388
     [Google Scholar]
  59. 59.
    Cherrier L, Nasar A, Goodlet KJ et al. 2018. Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection. Am. J. Transplant. 18:3060–64
     [Google Scholar]
  60. 60.
    Hofmann E, Sidler D, Dahdal S et al. 2021. Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: a case series and review of the literature. Transpl. Infect. Dis. 23:e13515
     [Google Scholar]
  61. 61.
    Paolucci S, Campanini G, Cassaniti I et al. 2021. Emergence of letermovir-resistant HCMV UL56 mutant during rescue treatment in a liver transplant recipient with ganciclovir-resistant infection HCMV: a case report. BMC Infect. Dis. 21:994
     [Google Scholar]
  62. 62.
    Marty FM, Ljungman PT, Chemaly RF et al. 2020. Outcomes of patients with detectable CMV DNA at randomization in the phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation. Am. J. Transplant. 20:1703–11
     [Google Scholar]
  63. 63.
    Anderson A, Raja M, Vazquez N et al. 2020. Clinical “real-world” experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin. Transplant. 34:e13866
     [Google Scholar]
  64. 64.
    Martino M, Pitino A, Gori M et al. 2021. Letermovir prophylaxis for cytomegalovirus infection in allogeneic stem cell transplantation: a real-world experience. Front. Oncol. 11:740079
     [Google Scholar]
  65. 65.
    Royston L, Royston E, Masouridi-Levrat S et al. 2021. Letermovir primary prophylaxis in high-risk hematopoietic cell transplant recipients: a matched cohort study. Vaccines 9:372
     [Google Scholar]
  66. 66.
    Lin A, Flynn J, DeRespiris L et al. 2021. Letermovir for prevention of cytomegalovirus reactivation in haploidentical and mismatched adult donor allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. Transplant. Cell Ther. 27:85.e1–6
     [Google Scholar]
  67. 67.
    Lin A, Maloy M, Su Y et al. 2019. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl. Infect. Dis. 21:e13187
     [Google Scholar]
  68. 68.
    Mori Y, Jinnouchi F, Takenaka K et al. 2021. Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data. Bone Marrow Transplant. 56:853–62
     [Google Scholar]
  69. 69.
    Johnsrud JJ, Nguyen IT, Domingo W et al. 2020. Letermovir prophylaxis decreases burden of cytomegalovirus (CMV) in patients at high risk for CMV disease following hematopoietic cell transplant. Biol. Blood Marrow Transplant. 26:1963–70
     [Google Scholar]
  70. 70.
    Sassine J, Khawaja F, Shigle TL et al. 2021. Refractory and resistant cytomegalovirus after hematopoietic cell transplant in the letermovir primary prophylaxis era. Clin. Infect. Dis. 73:1346–54
     [Google Scholar]
  71. 71.
    Li CR, Greenberg PD, Gilbert MJ et al. 1994. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 83:1971–79
     [Google Scholar]
  72. 72.
    Zamora D, Duke ER, Xie H et al. 2021. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood 138:34–43
     [Google Scholar]
  73. 73.
    Gabanti E, Borsani O, Colombo AA et al. 2022. Human cytomegalovirus-specific T-cell reconstitution and late-onset cytomegalovirus infection in hematopoietic stem cell transplantation recipients following letermovir prophylaxis. Transplant. Cell Ther. 28:211.e1–9
     [Google Scholar]
  74. 74.
    Styczyński J, Tridello G, Xhaard A et al. 2021. Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study. Bone Marrow Transplant. 56:1171–79
     [Google Scholar]
  75. 75.
    Chong PP, Teiber D, Prokesch BC et al. 2018. Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). Transpl. Infect. Dis. 20:e12965
     [Google Scholar]
  76. 76.
    Koepf US, Klehr HU, Eis-Huebinger AM et al. 2020. Suppression of CMV infection with letermovir in a kidney transplant patient. Eur. J. Case Rep. Intern. Med. 7:001622
     [Google Scholar]
  77. 77.
    Ortiz F, Lempinen M, Aaltonen S et al. 2022. Letermovir treatment for CMV infection in kidney and pancreas transplantation: a valuable option for complicated cases. Clin. Transplant. 36:e14537
     [Google Scholar]
  78. 78.
    Jorgenson MR, Descourouez JL, Garg N et al. 2021. The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients. Transpl. Infect. Dis. 23:e13693
     [Google Scholar]
  79. 79.
    Pearston AP, Ingemi AI, Ripley K et al. 2021. Successful treatment of UL97 mutation ganciclovir-resistant cytomegalovirus viremia in a renal transplant recipient with letermovir and adjunct hyperimmune cytomegalovirus immunoglobulin: a case report. Transplant. Proc. 53:1284–87
     [Google Scholar]
  80. 80.
    Phoompoung P, Ferreira VH, Tikkanen J et al. 2020. Letermovir as salvage therapy for cytomegalovirus infection in transplant recipients. Transplantation 104:404–9
     [Google Scholar]
  81. 81.
    Veit T, Munker D, Barton J et al. 2021. Letermovir in lung transplant recipients with cytomegalovirus infection: a retrospective observational study. Am. J. Transplant. 21:3449–55
     [Google Scholar]
  82. 82.
    Deleted in proof
  83. 83.
    Kachur E, Roshdy D, Hamadeh I et al. 2021. Single-center experience with use of letermovir for treatment of CMV infection in stem cell transplant recipients. Transpl. Infect. Dis. 23:e13502
     [Google Scholar]
  84. 84.
    Chiereghin A, Belotti T, Borgatti EC et al. 2021. Off-label use of letermovir as preemptive anti-cytomegalovirus therapy in a pediatric allogeneic peripheral blood stem cell transplant. Infect. Drug Resist. 14:1185–90
     [Google Scholar]
  85. 85.
    Kilgore JT, Becken B, Varga MG et al. 2020. Use of letermovir for salvage therapy for resistant cytomegalovirus in a pediatric hematopoietic stem cell transplant recipient. J. Pediatr. Infect. Dis. Soc. 9:486–89
     [Google Scholar]
  86. 86.
    Restelli U, Croce D, Pacelli V et al. 2019. Cost-effectiveness analysis of the use of letermovir for the prophylaxis of cytomegalovirus in adult cytomegalovirus seropositive recipients undergoing allogenic hematopoietic stem cell transplantation in Italy. Infect. Drug Resist. 12:1127–38
     [Google Scholar]
  87. 87.
    Golan Y, Tang Y, Mt-Isa S et al. 2021. Impact of letermovir use for cytomegalovirus prophylaxis on re-hospitalization following allogeneic hematopoietic stem cell transplantation: an analysis of a phase III randomized clinical trial. Pharmacoecon. Open 5:469–73
     [Google Scholar]
/content/journals/10.1146/annurev-med-042921-124739
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Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and Treatment in Transplant Recipients
Annual Review of Medicine 74, 89 (2023); https://doi.org/10.1146/annurev-med-042921-124739
/content/journals/10.1146/annurev-med-042921-124739
/content/journals/10.1146/annurev-med-042921-124739
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