MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 1

Cover Page


Cite item

Full Text

Abstract

Modern chemotherapy of cytomegalovirus (CMV) infections has a very limited arsenal of first-line drugs. These are preparations of ganciclovir (GCV) belonging to the class of modified nucleosides and its metabolic precursor ganciclovir valine ester. After three-step phosphorylation, GCV, as a structural analogue of the natural nucleotide, competes with it for binding to DNA polymerase and, due to its structural features, inhibits its activity. However, with prolonged use of GCV, mainly under conditions of immunosuppression, the virus develops drug resistance associated in most cases with changes in pUL97 catalyzing the first stage of GCV phosphorylation, as well as in the catalytic subunit of DNA polymerase. When variants of viruses resistant to GCV appear, second-line drugs are used: pyrophosphate analog of foscarnet and nucleotide cidofovir. Resistance to second-line drugs is due to mutations in the pol-gene and in a number of cases leads to multiresistance, which makes it impossible to use traditional anti-CMV drugs. In addition, the use of all of the above drugs is accompanied by the development of severe side effects. All of the above determines the need to search for new compounds that can effectively inhibit the reproduction of the virus, harmless to the macroorganism, convenient to use, overcoming the drug resistance barrier in viruses. As a result of the search in international databases (PubMed, MedLine, eLIBRARY.RU, ClinicalTrials.gov, etc.), the main trends in the search for new anti-CMV agents were identified. In the first part of the review, we concentrated on compounds that are modifications of known antiviral agents currently used in clinical practice, the most promising for the development of drug anti-CMV drugs.

About the authors

V. L. Andronova

National Research Center for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya

Author for correspondence.
Email: noemail@neicon.ru
Russian Federation

References

  1. Lanzieri T.M., Dollard S.C., Bialek S.R., Grosse S.D. Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries. Int. J. Infect. Dis. 2014; 22: 44-8. doi: 10.1016/j.ijid.2013.12.010
  2. Цитомегаловирусная инфекция у взрослых (исключая больных ВИЧ-инфекцией). Клинические рекомендации (Утверждены решением Пленума правления Национального научного общества инфекционистов 30 октября 2014 года). Available at: http://nnoi.ru/uploads/files/protokoly/CMV_adult.pdf
  3. Kotton C.N., Kumar D., Caliendo A.M., Asberg A., Chou S., Danziger-Isakov L., et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013; 96(4): 333-60. PMID: 23896556 doi: 10.1097/TP.0b013e31829df29d
  4. Ljungman P., Hakki M., Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect. Dis. Clin. North. Am. 2010; 24(2): 319-37. PMID: 20466273 doi: 10.1016/j.idc.2010.01.008
  5. Леонова О.Н., Виноградова Т.Н., Сизова Н.В., Степанова Е.В. Проблемы лечения больных с тяжелыми формами ВИЧ-инфекции. ВИЧ-инфекция и иммуносупрессии. 2013; 5(2): 58-65
  6. do Carmo A.M., Santos F.M., Ortiz-Agostinho C.L., Nishitokukado I., Frota C.S., Gomes F.U., et al. Cytomegalovirus infection in inflammatory bowel disease is not associated with worsening of intestinal inflammatory activity. PLoS One. 2014; 9(11): e111574.
  7. Product monograph “Valcyte”. Available at: http://www.rochecanada.com/content/dam/roche_canada/en_CA/documents/Research/ClinicalTrialsForms/Products/ConsumerInformation/MonographsandPublicAdvisories/Valcyte/Valcyte_PM_E.pdf
  8. Галегов Г.А., Андронова В.Л., Колобухина Л.В., Львов Н.Д. Специфическая лекарственная терапия распространенных и социально значимых вирусных инфекций человека. Вопросы вирусологии. 2012; (Прил. 1): 180-9
  9. Boeckh M., Geballe A.P. Cytomegalovirus: pathogen, paradigm, and puzzle. J. Clin. Invest. 2011; 121(5): 1673-80. doi: 10.1172/JCI45449
  10. Foscavir - FDA prescribing, side effects and uses. Availabe at: https://www.drugs.com/pro/foscavir.html
  11. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. Arch. Ophthalmol. 1996; 114(1): 23-33.
  12. Vistide® (cidofovir injection). Available at: http://www.gilead.com/~/media/files/pdfs/medicines/other/vistide/vistide.pdf
  13. Lurain N.S., Chou S. Antiviral drug resistance of human cytomegalovirus. Clin. Microbiol. Rev. 2010; 23(4): 689-712. doi: 10.1128/CMR.00009-10
  14. Drew W.L. Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin. Infect. Dis. 2010; 50(5): 733-6. doi: 10.1086/650463
  15. Jabs D.A., Martin B.K., Forman M.S. Cytomegalovirus Retinitis and Viral Resistance Research Group. Mortality associated with resistant cytomegalovirus among patients with cytomegalovirus retinitis and AIDS. Ophthalmology. 2010; 117(1): 128-32.
  16. Значимость устойчивости к противомикробным препаратам для общественного здравоохранения. Available at: http://www.who.int/drugresistance/AMR_Importance/ru/
  17. Jabs D.A., Enger C., Dunn J. P., Forman M. Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. CMV Retinitis and Viral Resistance Study Group. J. Infect. Dis. 1998; 177(3): 770-3. PMID: 9498461
  18. Limaye A.P., Raghu G., Koelle D.M., Ferrenberg J., Huang M.L., Boeckh. M. High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy. J. Infect. Dis. 2002; 185(1): 20-7. PMID: 11756977 doi: 10.1086/338143
  19. Lurain N.S., Bhorade S.M., Pursell K.J., Avery R.K., Yeldandi V.V., Isada C.M., et al. Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients. J. Infect. Dis. 2002; 186(6): 760-8. PMID: 12198609 doi: 10.1086/342844
  20. Gilbert C., Bestman-Smith J., Boivin G. Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist. Updat. 2002; 5(2): 88-114. PMID: 12135584
  21. Jabs D.A., Martin B.K., Forman M.S., Dunn J.P., Davis J.L., Weinberg D.V., et al. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J. Infect. Dis. 2001; 183(2): 333-7. PMID: 11120934 doi: 10.1086/317931
  22. Chou S., Lurain N.S., Thompson K.D., Miner R.C., Drew W.L. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J. Infect. Dis. 2003; 188(1): 32-9. PMID: 12825168 doi: 10.1086/375743
  23. Scott G.M., Weinberg A., Rawlinson W.D., Chou S. Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates. Antimicrob. Agents Chemother. 2007; 51(1): 89-94. PMID: 17043128 PMCID: PMC1797699 doi: 10.1128/AAC.00633-06
  24. Jabs D.A., Enger C., Forman M., Dunn J.P. Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. Antimicrob. Agents Chemother. 1998; 42(9): 2240-4. PMID: 9736542 PMCID: PMC105794
  25. West P., Schmiedeskamp M., Neeley H., Oberholzer J., Benedetti E., Kaplan B. Use of high-dose ganciclovir for a resistant cytomegalovirus infection due to UL97 mutation. Transpl. Infect. Dis. 2008; 10(2): 129-32. PMID: 17605740 doi: 10.1111/j.1399-3062.2007.00249.x
  26. Jacobsen T., Sifontis N. Drug interactions and toxicities associated with the antiviral management of cytomegalovirus infection. Am. J. Health Syst. Pharm. 2010; 67(17): 1417-25. PMID: 20720240 doi: 10.2146/ajhp090424
  27. Raggers R.J., Pomorski T., Holthuis J.C.M., Kälin N., van Meer G. Lipid traffic: the ABC of transbilayer movement. Traffic. 2000; 1(3): 226-34. PMID: 11208106
  28. Ciesla S.L., Trahan J., Winegarden K.L., Aldern K.A., Painter G.R., Hostetler K.Y. Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral. Res. 2003; 59(3): 163-71. PMID: 12927306
  29. Hostetler K.Y. Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. Antiviral. Res. 2009; 82: A84-98. PMID: 19425198 PMCID: PMC2768545
  30. Quenelle D.C., Lampert B., Collins D.J., Rice T.L., Painter G.R., Kern E.R. Efficacy of CMX001 against herpes simplex virus infections in mice and correlations with drug distribution studies. J. Infect. Dis. 2010; 202(10): 1492-9. PMID: 20923374 PMCID: PMC2957530 doi: 10.1086/656717
  31. Williams-Aziz S.L., Hartline C.B., Harden E.A., Daily S.M., Prichard M.N., Kushner N.L., et al. Comparative activity of lipid esters of cidofovir and cyclic cidofovir against replication of Herpesviruses in vitro. Antimicrob. Agents Chemother. 2005; 49(9): 3724-33. PMID: 16127046 PMCID: PMC1195409 doi: 10.1128/AAC.49.9.3724-3733.2005
  32. Prichard M.N., Kern E.R., Hartline C.B., Lanier E.R., Quenelle D.C. CMX001 potentiates the efficacy of acyclovir in herpes simplex virus infections. Antimicrob. Agents Chemother. 2011; 55(10): 4728-34. PMID: 21788472 PMCID: PMC3186990 doi: 10.1128/AAC.00545-11
  33. Painter W., Robertson A., Trost L.C., Godkin S., Lampert B., Painter G. First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, abroad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob. Agents Chemother. 2012; 56(5): 2726-34. PMID: 22391537 PMCID: PMC3346600 doi: 10.1128/AAC.05983-11
  34. Wang H., Chhablani J., Freeman W.R., Beadle J.R., Hostetler K.Y., Hartmann K., et al. Intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV) as a long-lasting intravitreal antiviral drug. Invest. Ophthalmol. Vis. Sci. 2011; 52(13): 9391-6. doi: 10.1167/iovs.11-8293
  35. Ma F., Nan K., Lee S., Beadle J.R., Hou H., Freeman W.R., et al. Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system. Eur. J. Pharm. Biopharm. 2015; 89: 271-9. PMID: 25513956 PMCID: PMC4355386 doi: 10.1016/j.ejpb.2014.12.010
  36. Scott H.J., Price N.B, Hartline C.B, Lanier E.R., Pricharda M.N. Selection and Recombinant Phenotyping of a Novel CMX001 and Cidofovir Resistance Mutation in Human Cytomegalovirus. Antimicrob. Agents Chemother. 2013; 57(7): 3321-5. PMID: 23650158 PMCID: PMC3697342 doi: 10.1128/AAC.00062-13
  37. Chou S., Ercolani R.J. Lanier E.R. Novel cytomegalovirus UL54 DNA polymerase gene mutations selected in vitro that confer brincidofovir resistance. Antimicrob. Agents Chemother. 2016; 60(6): 3845-8. PMID: 27044553 PMCID: PMC4879386 doi: 10.1128/AAC.00214-16
  38. Marty F.M., Winston D.J., Rowley S.D., Vance E., Papanicolaou G.A., Mullane K.M., et al. CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation. N. Engl. J. Med. 2013; 369(13):1227-36. PMID: 24066743 doi: 10.1056/NEJMoa1303688
  39. El-Haddad D., El Chaer F., Vanichanan J., Shan D.P., Ariza-Heredia E.J., Mulanovich V.E., et al. Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience. Antiviral. Res. 2016; 134: 58-62. doi: 10.1016/j.antiviral.2016.08.024
  40. Vial R., Zandotti C., Alain S., Decourt A., Jourde-Chiche N., Purgus R., et al. Brincidofovir use after foscarnet crystal nephropathy in a kidney transplant recipient with multiresistant Cytomegalovirus Infection. Case Rep. Transplant. 2017; 2017: 3624146. PMID: 28348914 PMCID: PMC5350387 doi: 10.1155/2017/3624146
  41. Brincidofovir clinical research. Available at: http://www.chimerix.com/research-development/clinical-trials/
  42. Cheng L., Hostetler K.Y., Lee J., Koh H.J., Beadle J.R., Bessho K., et al. Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir. Invest. Ophthalmol. Vis. Sci. 2004; 45(11): 4138-44. PMID: 15505067 PMCID: PMC2666013 doi: 10.1167/iovs.04-0064
  43. Siberry G.K., Abzug M.J., Nachman S. Panel on Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children - a working group of the Office of AIDS Research (OAR) Advisory Council. Executive Summary: Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children: Recommendations from the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. J. Pediatric. Infect. Dis. Soc. 2013; 2(4): 293-308. PMID: 26619492 doi: 10.1093/jpids/pit074
  44. Grinsztejn B., Nguyen B.Y., Katlama C., Gatell J.M., Lazzarin A., Vittecoq D., et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007; 369(9569): 1261-9. PMID: 17434401 doi: 10.1016/S0140-6736(07)60597-2
  45. Summa V., Petrocchi A., Bonelli F., Crescenzi B., Donghi M., Ferrara M., et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 2008; 51(18): 5843-55. PMID: 18763751 doi: 10.1021/jm800245z
  46. Zhou B., Yang K., Wills E., Tang L., Baines J.D. A mutation in the DNA polymerase accessory factor of herpes simplex virus 1 restores viral DNA replication in the presence of raltegravir. J. Virol. 2014; 88(19): 11121-9. doi: 10.1128/JVI.01540-14
  47. Nodal M., Mas P.J., Blanco A.G., Arnan C., Sola M., Hart D.J., et al. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc. Natl. Acad. Sci. USA. 2010; 107(37): 16078-83. PMID: 20805464 PMCID: PMC2941324 doi: 10.1073/pnas.1007144107
  48. Wang Y., Mao L., Kankanala J., Wang Z., Geraghty R.J. Inhibition of Human Cytomegalovirus pUL89 Terminase Subunit Blocks Virus Replication and Genome Cleavage. J. Virol. 2017; 91(3): e02152-16. doi: 10.1128/JVI.02152-16
  49. Gantt S., Carlsson J., Ikoma M., Gachelet E., Gray M., Geballe A.P., et al. The HIV protease inhibitor nelfinavir inhibits Kaposi’s sarcoma-associated herpesvirus replication in vitro. Antimicrob. Agents Chemother. 2011; 55(6): 2696-703. doi: 10.1128/AAC.01295-10
  50. Unal A., Pray T.R., Lagunoff M., Pennington M.W., Ganem D., Craik C.S. The protease and the assembly protein of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8). J. Virol. 1997; 71(9): 7030-8. PMID: 9261433 PMCID: PMC191989
  51. Kalu N.N., Desai P.J., Shirley C.M., Gibson W., Dennis P.A., Ambinder R.F. Nelfinavir inhibits maturation and export of herpes simplex virus 1. J Virol. 2014; 88(10): 5455-61. PMID: 24574416 PMCID: PMC4019105 doi: 10.1128/JVI.03790-13
  52. Gantt S., Gachelet E., Carlsson J., Barcy S., Casper C., Lagunoff M. Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation. Adv. Virol. 2015; 2015: 687162. PMID: 25709648 PMCID: PMC4325974 doi: 10.1155/2015/687162
  53. Kilewo C., Karlsson K., Ngarina M., Massawe A., Lyamuya E., Swai A., et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J. Acquir. Immune Defic. Syndr. 2009; 52(3): 406-16. PMID: 19730269 doi: 10.1097/QAI.0b013e3181b323ff
  54. Gantt S., Leister E., Jacobsen D.L., Boucoiran I., Huang M.L., Jerome K.R., et al. Risk of congenital cytomegalovirus infection among HIV-exposed uninfected infants is not decreased by maternal nelfinavir use during pregnancy. J. Med. Virol. 2016; 88(6): 1051-8. doi: 10.1002/jmv.24420
  55. McCormack S.A., Best B.M. Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals. Clin. Pharmacokinet. 2014; 53: 989-1004
  56. ВИЧ/СПИД. Информационный бюллетень. Available at: http://www.who.int/mediacentre/factsheets/fs360/ru/
  57. Stewart M.W. Optimal management of cytomegalovirus retinitis in patients with AIDS. Clin. Ophthalmol. 2010; 4: 285-99. PMID: 20463796 PMCID: PMC2861935

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2018 Andronova V.L.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС77-77676 от 29.01.2020.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies