nach oben

Current Hematologic Malignancy Reports

Erschienen in:

24.01.2020 | Stem Cell Transplantation (R Maziarz, Section Editor)

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

verfasst von: Morgan Hakki

Erschienen in: Current Hematologic Malignancy Reports | Ausgabe 2/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.

Recent Findings

Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study.

Summary

No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.

Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711–9.PubMedPubMedCentralCrossRef

Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010;23(4):689–712.PubMedPubMedCentralCrossRef

Bogner E. Human cytomegalovirus terminase as a target for antiviral chemotherapy. Rev Med Virol. 2002;12(2):115–27.PubMedCrossRef

Neuber S, Wagner K, Goldner T, Lischka P, Steinbrueck L, Messerle M, et al. Mutual interplay between the human cytomegalovirus terminase subunits pUL51, pUL56, and pUL89 promotes terminase complex formation. J Virol. 2017;91(12).

Borst EM, Kleine-Albers J, Gabaev I, Babic M, Wagner K, Binz A, et al. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J Virol. 2013;87(3):1720–32.PubMedPubMedCentralCrossRef

Dunn W, Chou C, Li H, Hai R, Patterson D, Stolc V, et al. Functional profiling of a human cytomegalovirus genome. Proc Natl Acad Sci U S A. 2003;100(24):14223–8.PubMedPubMedCentralCrossRef

Underwood MR, Ferris RG, Selleseth DW, Davis MG, Drach JC, Townsend LB, et al. Mechanism of action of the ribopyranoside benzimidazole GW275175X against human cytomegalovirus. Antimicrob Agents Chemother. 2004;48(5):1647–51.PubMedPubMedCentralCrossRef

Buerger I, Reefschlaeger J, Bender W, Eckenberg P, Popp A, Weber O, et al. A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products. J Virol. 2001;75(19):9077–86.PubMedPubMedCentralCrossRef

Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother. 2010;54(3):1290–7.PubMedPubMedCentralCrossRef

10.

Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmermann H, Lischka P. The novel anticytomegalovirus compound AIC246 (letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011;85(20):10884–93.PubMedPubMedCentralCrossRef

11.

Marschall M, Stamminger T, Urban A, Wildum S, Ruebsamen-Schaeff H, Zimmermann H, et al. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob Agents Chemother. 2012;56(2):1135–7.PubMedPubMedCentralCrossRef

12.

Piret J, Boivin G. Clinical development of letermovir and maribavir: overview of human cytomegalovirus drug resistance. Antivir Res. 2019;163:91–105.PubMedCrossRef

13.

Kropeit D, von Richter O, Stobernack HP, Rubsamen-Schaeff H, Zimmermann H. Pharmacokinetics and safety of letermovir coadministered with cyclosporine A or tacrolimus in healthy subjects. Clin Pharmacol Drug Dev. 2018;7(1):9–21.PubMedCrossRef

14.

McCrea JB, Macha S, Adedoyin A, Marshall W, Menzel K, Cho CR, et al. Pharmacokinetic drug-drug interactions between letermovir and the immunosuppressants cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil. J Clin Pharmacol. 2019;59(10):1331–9.PubMedCrossRef

15.

Duong A, Sweet A, Jain R, Hill JA, Pergam SA, Boeckh M, et al. Clinically significant drug interaction: letermovir and voriconazole. J Antimicrob Chemother. 2019.

16.

Marshall WL, McCrea JB, Macha S, Menzel K, Liu F, van Schanke A, et al. Pharmacokinetics and tolerability of letermovir coadministered with azole antifungals (posaconazole or voriconazole) in healthy subjects. J Clin Pharmacol. 2018;58(7):897–904.PubMedCrossRef

17.

PREVYMIS: Package insert and label information [press release]. 2017.

18.

Kropeit D, McCormick D, Erb-Zohar K, Moiseev VS, Kobalava ZD, Stobernack HP, et al. Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment. Br J Clin Pharmacol. 2017;83(12):2678–86.PubMedPubMedCentralCrossRef

19.

Kropeit D, Scheuenpflug J, Erb-Zohar K, Halabi A, Stobernack HP, Hulskotte EGJ, et al. Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Br J Clin Pharmacol. 2017;83(9):1944–53.PubMedPubMedCentralCrossRef

20.

Erb-Zohar K, Kropeit D, Scheuenpflug J, Stobernack HP, Hulskotte E, van Schanke A, et al. Intravenous hydroxypropyl beta-cyclodextrin formulation of letermovir: a phase I, randomized, single-ascending, and multiple-dose trial. Clin Transl Sci. 2017;10(6):487–95.PubMedPubMedCentralCrossRef

21.

Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhauser M, Groth C, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014;370(19):1781–9.PubMedCrossRef

22.

•• Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433–44 Phase 3 study of letermovir that led to FDA approval for use as prophylaxis in CMV seropositive allogeneic HCT recipients. PubMedCrossRef

23.

• Ljungman P, Schmitt M, Marty FM, Maertens J, Chemaly RF, Kartsonis NA, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation. Clin Infect Dis. 2019; Analysis of mortality benefit observed in HCT recipients receiving prophylaxis as part of the phase 3 study.

24.

Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185(3):273–82.PubMedCrossRef

25.

Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood. 2013;122(19):3359–64.PubMedCrossRef

26.

Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427–38.PubMedPubMedCentralCrossRef

27.

Chou S. Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance. Antimicrob Agents Chemother. 2015;59(10):6588–93.PubMedPubMedCentralCrossRef

28.

Goldner T, Hempel C, Ruebsamen-Schaeff H, Zimmermann H, Lischka P. Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure. Antimicrob Agents Chemother. 2014;58(1):610–3.PubMedPubMedCentralCrossRef

29.

Chou S. A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance. Antivir Res. 2017;148:1–4.PubMedCrossRef

30.

Chou S. Comparison of cytomegalovirus terminase gene mutations selected after exposure to three distinct inhibitor compounds. Antimicrobial agents and chemotherapy. 2017;61(11).

31.

Lischka P, Michel D, Zimmermann H. Characterization of cytomegalovirus breakthrough events in a phase 2 prophylaxis trial of letermovir (AIC246, MK 8228). J Infect Dis. 2016;213(1):23–30.PubMedCrossRef

32.

• Douglas CM, Barnard R, Holder D, Leavitt R, Levitan D, Maguire M, et al. Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients. J Infect Dis. 2019; Analysis of letermovir resistance from the phase 3 prophylaxis study in HCT recipients.

33.

Kilgore JT, Becken B, Varga MG, Parikh S, Prasad V, Lugo D, et al. Use of letermovir for salvage therapy for resistant cytomegalovirus in a pediatric hematopoietic stem cell transplant recipient. J Pediatric Infect Dis Soc. 2019.

34.

Knoll BM, Seiter K, Phillips A, Soave R. Breakthrough cytomegalovirus pneumonia in hematopoietic stem cell transplant recipient on letermovir prophylaxis. Bone Marrow Transplant. 2019;54(6):911–2.PubMedCrossRef

35.

Popping S, Dalm V, Lubke N, Cristanziano VD, Kaiser R, Boucher CAB, et al. Emergence and persistence of letermovir-resistant cytomegalovirus in a patient with primary immunodeficiency. Open Forum Infect Dis. 2019;6(9):ofz375.PubMedPubMedCentralCrossRef

36.

Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10(5):1228–37.PubMedCrossRef

37.

Sharma P, Gakhar N, MacDonald J, Abidi MZ, Benamu E, Bajrovic V, et al. Letermovir prophylaxis through day 100 post transplant is safe and effective compared with alternative CMV prophylaxis strategies following adult cord blood and haploidentical cord blood transplantation. Bone Marrow Transplant. 2019.

38.

Lin A, Maloy M, Su Y, Bhatt V, DeRespiris L, Griffin M, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl Infect Dis. 2019:e13187.

39.

Marty FM, Ljungman PT, Chemaly RF, Wan H, Teal VL, Butterton JR, et al. 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. 2019.

40.

Frietsch JJ, Michel D, Stamminger T, Hunstig F, Birndt S, Schnetzke U, et al. 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. 2019;11(1):e2019001.PubMedPubMedCentralCrossRef

41.

Cherrier L, Nasar A, Goodlet KJ, Nailor MD, Tokman S, Chou S. Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection. Am J Transplant. 2018;18(12):3060–4.PubMedPubMedCentralCrossRef

42.

Jung S, Michel M, Stamminger T, Michel D. Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. BMC Infect Dis. 2019;19(1):388.PubMedPubMedCentralCrossRef

43.

Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW, et al. Use of letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis. Antimicrobial agents and chemotherapy. 2019;63(3).

44.

Wildum S, Zimmermann H, Lischka P. In vitro drug combination studies of letermovir (AIC246, MK-8228) with approved anti human cytomegalovirus (HCMV) and HIV compounds in inhibition of HCMV and HIV replication. Antimicrob Agents Chemother. 2015.

45.

O'Brien MS, Markovich KC, Selleseth D, DeVita AV, Sethna P, Gentry BG. In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus. Antivir Res. 2018;158:255–63.PubMedCrossRef

46.

Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA 3rd, Davis MG, et al. Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother. 2002;46(8):2365–72.PubMedPubMedCentralCrossRef

47.

Prichard MN. Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir. Rev Med Virol. 2009;19(4):215–29.PubMedPubMedCentralCrossRef

48.

Azzeh M, Honigman A, Taraboulos A, Rouvinski A, Wolf DG. Structural changes in human cytomegalovirus cytoplasmic assembly sites in the absence of UL97 kinase activity. Virology. 2006;354(1):69–79.PubMedCrossRef

49.

Prichard MN, Gao N, Jairath S, Mulamba G, Krosky P, Coen DM, et al. A recombinant human cytomegalovirus with a large deletion in UL97 has a severe replication deficiency. J Virol. 1999;73(7):5663–70.PubMedPubMedCentralCrossRef

50.

Webel R, Hakki M, Prichard MN, Rawlinson WD, Marschall M, Chou S. Differential properties of cytomegalovirus pUL97 kinase isoforms affect viral replication and maribavir susceptibility. J Virol. 2014;88(9):4776–85.PubMedPubMedCentralCrossRef

51.

Chou S, Ercolani RJ, Marousek G, Bowlin TL. Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance. Antimicrob Agents Chemother. 2013;57(7):3375–9.PubMedPubMedCentralCrossRef

52.

Hamirally S, Kamil JP, Ndassa-Colday YM, Lin AJ, Jahng WJ, Baek MC, et al. Viral mimicry of Cdc2/cyclin-dependent kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress. PLoS Pathog. 2009;5(1):e1000275.PubMedPubMedCentralCrossRef

53.

Chou S, Van Wechel LC, Marousek GI. Effect of cell culture conditions on the anticytomegalovirus activity of maribavir. Antimicrob Agents Chemother. 2006;50(7):2557–9.PubMedPubMedCentralCrossRef

54.

Drew WL, Miner RC, Marousek GI, Chou S. Maribavir sensitivity of cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. J Clin Virol. 2006;37(2):124–7.PubMedCrossRef

55.

Williams SL, Hartline CB, Kushner NL, Harden EA, Bidanset DJ, Drach JC, et al. In vitro activities of benzimidazole D- and L-ribonucleosides against herpesviruses. Antimicrob Agents Chemother. 2003;47(7):2186–92.PubMedPubMedCentralCrossRef

56.

Wang LH, Peck RW, Yin Y, Allanson J, Wiggs R, Wire MB. Phase I safety and pharmacokinetic trials of 1263W94, a novel oral anti-human cytomegalovirus agent, in healthy and human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. 2003;47(4):1334–42.PubMedPubMedCentralCrossRef

57.

Koszalka GW, Johnson NW, Good SS, Boyd L, Chamberlain SC, Townsend LB, et al. Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 2002;46(8):2373–80.PubMedPubMedCentralCrossRef

58.

Swan SK, Smith WB, Marbury TC, Schumacher M, Dougherty C, Mico BA, et al. Pharmacokinetics of maribavir, a novel oral anticytomegalovirus agent, in subjects with varying degrees of renal impairment. J Clin Pharmacol. 2007;47(2):209–17.PubMedCrossRef

59.

Song IH, Ilic K, Murphy J, Lasseter K, Martin P. Effects of maribavir on P-glycoprotein and CYP2D6 in healthy volunteers. J Clin Pharmacol. 2019.

60.

Pescovitz MD, Bloom R, Pirsch J, Johnson J, Gelone S, Villano SA. A randomized, double-blind, pharmacokinetic study of oral maribavir with tacrolimus in stable renal transplant recipients. Am J Transplant. 2009;9(10):2324–30.PubMedCrossRef

61.

• Papanicolaou GA, Silveira FP, Langston AA, Pereira MR, Avery RK, Uknis M, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis. 2019;68(8):1255–64 This study demonstrated that maribavir may be a viable option for the treatment of resistant/refractory CMV infection in HCT and SOT recipients. Results from the phase 3 study will be most informative. PubMedCrossRef

62.

Lalezari JP, Aberg JA, Wang LH, Wire MB, Miner R, Snowden W, et al. Phase I dose escalation trial evaluating the pharmacokinetics, anti-human cytomegalovirus (HCMV) activity, and safety of 1263W94 in human immunodeficiency virus-infected men with asymptomatic HCMV shedding. Antimicrob Agents Chemother. 2002;46(9):2969–76.PubMedPubMedCentralCrossRef

63.

Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem-cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood. 2008;111:5403–10.PubMedPubMedCentralCrossRef

64.

Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11(4):284–92.PubMedCrossRef

65.

Winston DJ, Saliba F, Blumberg E, Abouljoud M, Garcia-Diaz JB, Goss JA, et al. Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial. Am J Transplant. 2012;12(11):3021–30.PubMedCrossRef

66.

Marty FM, Boeckh M. Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? Current opinion in virology. 2011;1(6):555–62.PubMedCrossRef

67.

Snydman DR. Why did maribavir fail in stem-cell transplants? Lancet Infect Dis. 2011;11(4):255–7.PubMedCrossRef

68.

Avery RK, Marty FM, Strasfeld L, Lee I, Arrieta A, Chou S, et al. Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients. Transpl Infect Dis. 2010;12(6):489–96.PubMedCrossRef

69.

• Maertens J, Cordonnier C, Jaksch P, Poire X, Uknis M, Wu J, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med. 2019;381(12):1136–47 This study demonstrated the potential utility of maribavir as preemptive therapy in HCT and SOT recipients. A phase 3 study in HCT recipients is underway. PubMedCrossRef

70.

Chou S, Marousek GI. Accelerated evolution of maribavir resistance in a cytomegalovirus exonuclease domain II mutant. J Virol. 2008;82(1):246–53.PubMedCrossRef

71.

Chou S, Van Wechel LC, Marousek GI. Cytomegalovirus UL97 kinase mutations that confer maribavir resistance. J Infect Dis. 2007;196(1):91–4.PubMedCrossRef

72.

Strasfeld L, Lee I, Villano S, Chou S. Virologic characterization of multi-drug-resistant cytomegalovirus infection in two transplant recipients treated with maribavir. J Infect Dis. 2010;202(1):104–8.PubMedCrossRef

73.

Chou S. Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev Med Virol. 2008;18(4):233–46.PubMedCrossRef

74.

Chou S, Wu J, Song K, Bo T. Novel UL97 drug resistance mutations identified at baseline in a clinical trial of maribavir for resistant or refractory cytomegalovirus infection. Antivir Res. 2019;172:104616.PubMedCrossRef

75.

Chou S. Diverse cytomegalovirus UL27 mutations adapt to loss of viral UL97 kinase activity under maribavir. Antimicrob Agents Chemother. 2009;53(1):81–5.PubMedCrossRef

76.

Chou S, Marousek GI, Senters AE, Davis MG, Biron KK. Mutations in the human cytomegalovirus UL27 gene that confer resistance to maribavir. J Virol. 2004;78(13):7124–30.PubMedPubMedCentralCrossRef

77.

Komazin G, Ptak RG, Emmer BT, Townsend LB, Drach JC. Resistance of human cytomegalovirus to the benzimidazole L-ribonucleoside maribavir maps to UL27. J Virol. 2003;77(21):11499–506.PubMedPubMedCentralCrossRef

78.

Zhou S, Breitenbach JM, Borysko KZ, Drach JC, Kern ER, Gullen E, et al. Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines: second-generation methylenecyclopropane analogues of nucleosides. J Med Chem. 2004;47(3):566–75.PubMedCrossRef

79.

Gentry BG, Gentry SN, Jackson TL, Zemlicka J, Drach JC. Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase. Biochem Pharmacol. 2011;81(1):43–9.PubMedCrossRef

80.

Gentry BG, Kamil JP, Coen DM, Zemlicka J, Drach JC. Stereoselective phosphorylation of cyclopropavir by pUL97 and competitive inhibition by maribavir. Antimicrob Agents Chemother. 2010;54(8):3093–8.PubMedPubMedCentralCrossRef

81.

Kern ER, Kushner NL, Hartline CB, Williams-Aziz SL, Harden EA, Zhou S, et al. In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication. Antimicrob Agents Chemother. 2005;49(3):1039–45.PubMedPubMedCentralCrossRef

82.

Chen H, Li C, Zemlicka J, Gentry BG, Bowlin TL, Coen DM. Potency and stereoselectivity of cyclopropavir triphosphate action on human cytomegalovirus DNA polymerase. Antimicrob Agents Chemother. 2016;60(7):4176–82.PubMedPubMedCentralCrossRef

83.

Chou S, Bowlin TL. Cytomegalovirus UL97 mutations affecting cyclopropavir and ganciclovir susceptibility. Antimicrob Agents Chemother. 2011;55(1):382–4.PubMedCrossRef

84.

Chou S. Recombinant phenotyping of cytomegalovirus UL97 kinase sequence variants for ganciclovir resistance. Antimicrob Agents Chemother. 2010;54(6):2371–8.PubMedPubMedCentralCrossRef

85.

Chou S, Marousek G, Bowlin TL. Cyclopropavir susceptibility of cytomegalovirus DNA polymerase mutants selected after antiviral drug exposure. Antimicrob Agents Chemother. 2012;56(1):197–201.PubMedPubMedCentralCrossRef

86.

Gentry BG, Drach JC. Metabolism of cyclopropavir and ganciclovir in human cytomegalovirus-infected cells. Antimicrob Agents Chemother. 2014;58(4):2329–33.PubMedPubMedCentralCrossRef

87.

Kern ER, Bidanset DJ, Hartline CB, Yan Z, Zemlicka J, Quenelle DC. Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections. Antimicrob Agents Chemother. 2004;48(12):4745–53.PubMedPubMedCentralCrossRef

88.

Bowlin TL, Brooks J, Zemlicka J. Preclinical pharmacokinetic, Toxicokinetic and toxicology results for cyclopropavir, a promising new agent for the treatment of beta- and gamma-herpesviruses. Antivir Res. 2009;82(2):A46–A7.CrossRef

89.

Rouphael NG, Hurwitz SJ, Hart M, Beck A, Anderson EJ, Deye G, et al. Phase Ib trial to evaluate the safety and pharmacokinetics of multiple ascending doses of filociclovir (MBX-400, cyclopropavir) in healthy volunteers. Antimicrobial agents and chemotherapy. 2019;63(9).

90.

Wu Z, Drach JC, Prichard MN, Yanachkova M, Yanachkov I, Bowlin TL, et al. L-valine ester of cyclopropavir: a new antiviral prodrug. Antivir Chem Chemother. 2009;20(1):37–46.PubMedPubMedCentralCrossRef

91.

James SH, Hartline CB, Harden EA, Driebe EM, Schupp JM, Engelthaler DM, et al. Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. Antimicrob Agents Chemother. 2011;55(10):4682–91.PubMedPubMedCentralCrossRef

92.

Beadle JR, Hartline C, Aldern KA, Rodriguez N, Harden E, Kern ER, et al. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Chemother. 2002;46(8):2381–6.PubMedPubMedCentralCrossRef

93.

• Marty FM, Winston DJ, Chemaly RF, Mullane KM, Shore TB, Papanicolaou GA, et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019;25(2):369–81 This study reported the disappointing results using brincidofovir prophylaxis in HCT recipients. PubMedCrossRef

94.

Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013;369(13):1227–36.PubMedCrossRef

95.

Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis. 2004;39(2):233–9.PubMedCrossRef

96.

Diamond DJ, La Rosa C, Chiuppesi F, Contreras H, Dadwal S, Wussow F, et al. A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection. Expert review of vaccines. 2018;17(10):889–911.PubMedPubMedCentralCrossRef

97.

Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85.PubMedPubMedCentralCrossRef

98.

Vincenti F, Budde K, Merville P, Shihab F, Ram Peddi V, Shah M, et al. A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Am J Transplant. 2018;18(12):2945–54.PubMedCrossRef

99.

Plotkin SA, Boppana SB. Vaccination against the human cytomegalovirus. Vaccine. 2019;37(50):7437–42.PubMedPubMedCentralCrossRef

100.

Wang D, Freed DC, He X, Li F, Tang A, Cox KS, et al. A replication-defective human cytomegalovirus vaccine for prevention of congenital infection. Science translational medicine. 2016;8(362):362ra145.PubMedCrossRef

101.

Adler SP, Lewis N, Conlon A, Christiansen MP, Al-Ibrahim M, Rupp R, et al. Phase 1 clinical trial of a conditionally replication-defective human cytomegalovirus (CMV) vaccine in CMV-seronegative subjects. J Infect Dis. 2019;220(3):411–9.PubMedCrossRef

102.

Liu Y, Freed DC, Li L, Tang A, Li F, Murray EM, et al. A replication-defective human cytomegalovirus vaccine elicits humoral immune responses analogous to those with natural infection. J Virol. 2019;93(23).

103.

Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science (New York), NY. 1992;257(5067):238–241.

104.

Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333(16):1038–44.PubMedCrossRef

105.

Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood. 2010;116(20):4360–7.PubMedCrossRef

106.

Peggs KS, Thomson K, Samuel E, Dyer G, Armoogum J, Chakraverty R, et al. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis. 2011;52(1):49–57.PubMedCrossRef

107.

Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Loffler J, et al. Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood. 2002;99(11):3916–22.PubMedCrossRef

108.

Pei XY, Zhao XY, Chang YJ, Liu J, Xu LP, Wang Y, et al. Cytomegalovirus-specific T-cell transfer for refractory cytomegalovirus infection after Haploidentical stem cell transplantation: the quantitative and qualitative immune recovery for cytomegalovirus. J Infect Dis. 2017;216(8):945–56.PubMedCrossRef

109.

Blyth E, Clancy L, Simms R, Ma CK, Burgess J, Deo S, et al. Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. Blood. 2013;121(18):3745–58.PubMedCrossRef

110.

Ma JD, Nafziger AN, Villano SA, Gaedigk A, Bertino JS Jr. Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob Agents Chemother. 2006;50(4):1130–5.PubMedPubMedCentralCrossRef

111.

Mackinnon S, Thomson K, Verfuerth S, Peggs K, Lowdell M. Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol Dis. 2008;40(1):63–7.PubMedCrossRef

112.

Micklethwaite K, Hansen A, Foster A, Snape E, Antonenas V, Sartor M, et al. Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(6):707–14.PubMedCrossRef

113.

Micklethwaite KP, Clancy L, Sandher U, Hansen AM, Blyth E, Antonenas V, et al. Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation. Blood. 2008;112(10):3974–81.PubMedCrossRef

114.

Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362(9393):1375–7.PubMedCrossRef

115.

Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH, et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood. 2013;121(26):5113–23.PubMedPubMedCentralCrossRef

116.

• Tzannou I, Papadopoulou A, Naik S, Leung K, Martinez CA, Ramos CA, et al. Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2017;35(31):3547–57 Provides additional support for the safety of adoptive immunotherapy using third-party donor T cells. PubMedPubMedCentralCrossRef

117.

• Withers B, Blyth E, Clancy LE, Yong A, Fraser C, Burgess J, et al. Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells. Blood Adv. 2017;1(24):2193–205 Provides additional support for the safety of adoptive immunotherapy using third-party donor T cells. PubMedPubMedCentralCrossRef

118.

Boeckh M, Corey L. Adoptive immunotherapy of viral infections: should infectious disease embrace cellular immunotherapy? J Infect Dis. 2017;216(8):926–8.PubMedCrossRef

119.

Ljungman P, Cordonnier C, Einsele H, Bender-Gotze C, Bosi A, Dekker A, et al. Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT). Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 1998;21(5):473–6.PubMedCrossRef

120.

Alexander BT, Hladnik LM, Augustin KM, Casabar E, McKinnon PS, Reichley RM, et al. Use of cytomegalovirus intravenous immune globulin for the adjunctive treatment of cytomegalovirus in hematopoietic stem cell transplant recipients. Pharmacotherapy. 2010;30(6):554–61.PubMedPubMedCentralCrossRef

121.

Emanuel D, Cunningham I, Jules-Elysee K, Brochstein JA, Kernan NA, Laver J, et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med. 1988;109(10):777–82.PubMedCrossRef

122.

Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. 1988;109(10):783–8.PubMedCrossRef

123.

Erard V, Guthrie KA, Seo S, Smith J, Huang M, Chien J, et al. Reduced mortality of cytomegalovirus pneumonia after hematopoietic cell transplantation due to antiviral therapy and changes in transplantation practices. Clin Infect Dis. 2015;61(1):31–9.PubMedPubMedCentralCrossRef

124.

Bowden RA, Fisher LD, Rogers K, Cays M, Meyers JD. Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant [see comments]. J Infect Dis. 1991;164(3):483–7.PubMedCrossRef

125.

Bowden RA, Sayers M, Flournoy N, Newton B, Banaji M, Thomas ED, et al. Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation. N Engl J Med. 1986;314(16):1006–10.PubMedCrossRef

126.

Ruutu T, Ljungman P, Brinch L, Lenhoff S, Lonnqvist B, Ringden O, et al. No prevention of cytomegalovirus infection by anti-cytomegalovirus hyperimmune globulin in seronegative bone marrow transplant recipients. The Nordic BMT Group. Bone Marrow Transplant. 1997;19(3):233–6.PubMedCrossRef

127.

Bass E, Powe N, Goodman S, Graziano S, Griffiths R, Kickler T, et al. Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis. Bone Marrow Transplant. 1993;12:179–83.

128.

Messori A, Rampazzo R, Scroccaro G, Martini N. Efficacy of hyperimmune anti-cytomegalovirus immunoglobulins for the prevention of cytomegalovirus infection in recipients of allogeneic bone marrow transplantation: a meta analysis. Bone Marrow Transplant. 1994;13:163–8.PubMed

129.

Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in patients undergoing haematopoietic stem cell transplantation: systematic review and meta-analysis. Bone Marrow Transplantation. 2008:S46 (abstract O267).

130.

Sullivan KM, Kopecky KJ, Jocom J, Fisher L, Buckner CD, Meyers JD, et al. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med. 1990;323(11):705–12.PubMedCrossRef

131.

Winston DJ, Ho WG, Lin CH, Bartoni K, Budinger MD, Gale RP, et al. Intravenous immune globulin for prevention of cytomegalovirus infection and interstitial pneumonia after bone marrow transplantation. Ann Intern Med. 1987;106(1):12–8.PubMedCrossRef

132.

Zikos P, Van Lint MT, Lamparelli T, Gualandi F, Occhini D, Mordini N, et al. A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs. cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell transplants (HSCT). Haematologica. 1998;83(2):132–7.PubMed

133.

Dole K, Segal FP, Feire A, Magnusson B, Rondon JC, Vemula J, et al. A first-in-human study to assess the safety and pharmacokinetics of monoclonal antibodies against human cytomegalovirus in healthy volunteers. Antimicrob Agents Chemother. 2016;60(5):2881–7.PubMedPubMedCentralCrossRef

134.

Boeckh M, Bowden R, Storer B, Chao N, Spielberger R, Tierney D, et al. Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(6):343–51.PubMedCrossRef

135.

Gentry BG, Bogner E, Drach JC. Targeting the terminase: an important step forward in the treatment and prophylaxis of human cytomegalovirus infections. Antivir Res. 2019;161:116–24.PubMedCrossRef

136.

Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, Mugavero MJ, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA. 2018;320(4):379–96.PubMedPubMedCentralCrossRef

137.

Panel A-IHG. Hepatitis C guidance 2018 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Clin Infect Dis. 2018;67(10):1477–92.CrossRef

138.

Kornblit B, Maloney DG, Storer BE, Maris MB, Vindelov L, Hari P, et al. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation. Haematologica. 2014;99(10):1624–31.PubMedPubMedCentralCrossRef

139.

Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase. J Virol. 2004;78(20):11030–9.PubMedPubMedCentralCrossRef

140.

Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc Natl Acad Sci U S A. 2006;103(38):14182–7.PubMedPubMedCentralCrossRef

141.

Marty FM, Bryar J, Browne SK, Schwarzberg T, Ho VT, Bassett IV, et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110(2):490–500.PubMedPubMedCentralCrossRef

142.

Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, et al. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019;6(8):e409–e18.PubMedCrossRef

143.

Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJ, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis. 2008;47(6):804–11.PubMedCrossRef

144.

Shapira MY, Resnick IB, Chou S, Neumann AU, Lurain NS, Stamminger T, et al. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin Infect Dis. 2008;46(9):1455–7.PubMedCrossRef

145.

Wolf DG, Shimoni A, Resnick IB, Stamminger T, Neumann AU, Chou S, et al. Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation. Antivir Res. 2011;90(3):183–6.PubMedCrossRef

146.

Chong AS, Zeng H, Knight DA, Shen J, Meister GT, Williams JW, et al. Concurrent antiviral and immunosuppressive activities of leflunomide in vivo. Am J Transplant. 2006;6(1):69–75.PubMedCrossRef

147.

Waldman WJ, Knight DA, Blinder L, Shen J, Lurain NS, Miller DM, et al. Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. Intervirology. 1999;42(5–6):412–8.PubMedCrossRef

148.

Waldman WJ, Knight DA, Lurain NS, Miller DM, Sedmak DD, Williams JW, et al. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999;68(6):814–25.PubMedCrossRef

149.

Zhang C, Chu M. Leflunomide: a promising drug with good antitumor potential. Biochem Biophys Res Commun. 2018;496(2):726–30.PubMedCrossRef

150.

Herget T, Freitag M, Morbitzer M, Kupfer R, Stamminger T, Marschall M. Novel chemical class of pUL97 protein kinase-specific inhibitors with strong anticytomegaloviral activity. Antimicrob Agents Chemother. 2004;48(11):4154–62.PubMedPubMedCentralCrossRef

151.

Hutterer C, Hamilton S, Steingruber M, Zeittrager I, Bahsi H, Thuma N, et al. The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors. Antivir Res. 2016;134:130–43.PubMedCrossRef

152.

Schleiss M, Eickhoff J, Auerochs S, Leis M, Abele S, Rechter S, et al. Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo. Antivir Res. 2008;79(1):49–61.PubMedCrossRef

153.

Avery RK, Mossad SB, Poggio E, Lard M, Budev M, Bolwell B, et al. Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010;90(4):419–26.PubMedCrossRef

Titel: Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy
verfasst von: Morgan Hakki
Publikationsdatum: 24.01.2020
Verlag: Springer US
Erschienen in: Current Hematologic Malignancy Reports / Ausgabe 2/2020
Print ISSN: 1558-8211
Elektronische ISSN: 1558-822X
DOI: https://doi.org/10.1007/s11899-020-00557-6

Neu im Fachgebiet Onkologie

18.04.2024 | Wirbelsäulenmetastase | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

Abstract

Purpose of Review

Recent Findings

Summary

Neu im Fachgebiet Onkologie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Manche Gestagene können das Risiko für Meningeome erhöhen

Einladung zum PSA-Screening senkt die Krebssterblichkeit

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Purpose of Review

Recent Findings

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2020

Novel Therapies in Polycythemia Vera

Monoclonal Gammopathy of Undetermined Significance: Current Concepts and Future Prospects

Supportive Care in Multiple Myeloma

MLL-Rearranged Acute Lymphoblastic Leukemia

Is There a Role for Chemotherapy in the Era of Targeted Therapies?

Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Neu im Fachgebiet Onkologie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Manche Gestagene können das Risiko für Meningeome erhöhen

Einladung zum PSA-Screening senkt die Krebssterblichkeit

Update Onkologie