Ganciclovir treatment failure in adult allogeneic hematopoietic stem cell transplant recipients with cytomegalovirus infection – a single centre experience
Authors:
E. Vejražková 1; P. Hubáček 2; R. Kutová 3; L. Plíšková 3; M. Košťál 1; V. Štěpánová 4; A. Zavřelová 1; J. Radocha 1; E. Malá 5; P. Žák 1
Authors‘ workplace:
IV. interní hematologická klinika, Fakultní nemocnice v Hradci Králové a Lékařská fakulta v Hradci Králové Univerzity Karlovy v Praze
1; Klinika dětské hematologie a onkologie a Ústav lékařské mikrobiologie, Fakultní nemocnice v Motole a 2. lékařská fakulta Univerzity Karlovy v Praze
2; Ústav klinické biochemie a diagnostiky, Fakultní nemocnice v Hradci Králové a Lékařská fakulta v Hradci Králové Univerzity Karlovy v Praze
3; Ústav klinické mikrobiologie, Fakultní nemocnice v Hradci Králové a Lékařská fakulta v Hradci Králové Univerzity Karlovy v Praze
4; Ústav klinické imunologie a alergologie, Fakultní nemocnice v Hradci Králové a Lékařská fakulta v Hradci Králové Univerzity Karlovy v Praze
5
Published in:
Epidemiol. Mikrobiol. Imunol. 64, 2015, č. 3, s. 160-168
Category:
Original Papers
Overview
Objective:
To determine the incidence of infection with ganciclovir-resistant cytomegalovirus (CMV) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. Clinical resistance or treatment failure was defined as persistent DNAemia or increasing viral load in peripheral blood after 2 weeks of virostatic treatment. The association between the treatment failure and viral resistance was analysed. The presence of ganciclovir – resistant CMV strains was confirmed by genotypic testing able to detect mutations conferring resistance.
Methods:
In 2012 and 2014, 40 patients who underwent allogeneic HSCT for hematologic malignancies and were treated for human CMV reactivation/disease were followed up prospectively. In patients with treatment failure, CMV DNA was isolated and analysed by nucleotide sequence analysis of the UL 97 and UL 54 genes conferring resistance to the virostatic agent.
Results:
The treatment failure occurred in seven patients, but ganciclovir resistance conferring mutations were only detected in two of them (mutations L595F and M460I in the UL 97 gene). Another mutation in the UL 97 gene (N510S) was found in a patient with recurrent CMV replication who needed to be retreated but did not meet the criteria for treatment failure.
Conclusion:
The low incidence of genetically confirmed ganciclovir-resistant CMV isolates in HSCT recipients with relatively common clinical treatment failure suggests that the mechanism underlying slower viral clearance is often other than mutations conferring ganciclovir resistance to the virus.
Key words:
human cytomegalovirus – ganciclovir – valganciclovir – viral resistance – hematopoietic stem cell transplantation
Sources
1. Mori T, Kato J. Cytomegalovirus infection/disease after hematopoietic stem cell transplantation. Int J Hematol, 2010;91:588–595.
2. Prentice HG, Gluckman E, Powles RL, et al. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet, 1994;343:749–753.
3. Chevillotte M, von Einem J. Meier BM, et al. A new tool linking human cytomegalovirus drug resistance mutations to resistance phenotypes. Antiviral Research, 2010;85:318–327.
4. Boutolleau D, Deback C, Bressollette-Bodin C, et al. Resistance pattern of cytomegalovirus (CMV) after oral valganciclovir therapy in transplant recipients at high-risk for CMV infection. Antiviral Research, 2009;81:74–179.
5. Patel N, Snyder LD, Finlen-Copeland CA, et al. Is Prevention the Best Treatment? CMV After Lung Transplantation. Am J Transplant, 2012;12:539–544.
6. Shmueli E, Or R, Shapira MY, et al. High Rate of Cytomegalovirus Drug Resistance Among Patients Receiving Preemptive Antiviral Treatment After Haploidentical Stem Cell Transplantation. J Infect Dis, 2014;209:557–561.
7. Gilbert C, Boivin G. Minireview. Human Cytomegalovirus Resistance to Antiviral Drugs. Antimicrob Agents Chemother, 2005;49(3):873–883.
8. Lengerová M, Volfová P, Ráčil Z. Laboratorní diagnostika CMV infekce u nemocných s hematologickou malignitou. Postgrad med, 2013;15(4):45–50.
9. Rozsypal H. Chemoterapie infekcí vyvolaných cytomegalovirem. Remedia, 2002;12(5):339–342.
10. Marfori JE, Exner MM, Marousek GI, et al. Development of new cytomegalovirus UL97 and DNA polymerase mutations conferring drug resistance after valganciclovir therapy in allogeneic stem cell recipients. J Clin Virol, 2007;38:120–125.
11. Psohlavec J, Förstl M, Horáček J, et al. Možnosti rychlého průkazu ganciclovir rezistentních kmenů lidského cytomegaloviru (HCMV, CMV) u pacientů po transplantaci ledviny. Detekce bodových mutací v UL 97 genu CMV spojených s rezistencí vůči gancykloviru. Klin Farmakol Farm, 2006;18:70–74.
12. Gordon E. Treatment of Ganciclovir - Resistant Cytomegalovirus in Adult Solid Organ Transplant Recipients. Caught Between a Rock and a Hard Place? [online]. Univerzity of Texas, 2013 [cit.2014-05-05]. Dostupný na www: http://www.utexas.edu/pharmacy/divisions/pharmaco/rounds/gordon11-01-13.pdf
13. Volfova P, Lengerova M, Lochmanova J, et al. Detecting human cytomegalovirus drug resistant mutations and monitoring the emergence of resistant strains using real-time PCR. J Clin Virol, 2014 Oct;61(2):270–274.
14. Van der Beek MT, Marijt EW, Vossen AC, et al. Failure of pre-emptive treatment of cytomegalovirus infections and antiviral resistance in stem cell transplant recipients. Antivir Ther, 2012;17(1):45–51.
15. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients. Hematol Oncol Clin North Am, 2011;25(1):151–169.
16. Hantz S, Garnier-Geoffroy F, Mazeron MC, et al. Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. J Antimicrob Chemother, 2010;65:2628–2640.
17. Lurain NS, Bhorad SM, Pursell KJ, et al. Analysis and characterization of antiviral drug–resistant cytomegalovirus isolates from solid organ transplant recipients. J Infect Dis, 2002;186:760–768.
18. Chou S, van Wechel LC, Lichy HM, et al. Phenotyping of cytomegalovirus drug resistance mutations by using recombinant viruses incorporating a reporter gene. Antimicrob Agents Chemother, 2005;49:2710–2715.
19. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prevention and Treatment of Cancer-Related Infections. Version 2.2014 [online]. 2014-11-08 [cit. 2014-12-12]. Dostupný na www: http://file.trsgo.org/userfiles/file/NCCN%20Cancer-Related%20Infections%20Guideline%202015.pdf
20. Ljungman P, de la Camara R, Einsele H, et al. Recommendations for CMV and HHV 6 management in patients with haematological diseases [online]. ECIL 4 Update, 2011 [cit. 2015-06-01]. Dostupný na www: http://www.ebmt.org/Contents/Resources/Library/ECIL/Documents/ECIL%204%20%20Update%202011%20CMV.pdf
21. Scott GM, Isaacs MA, Zeng F, et al. Cytomegalovirus Antiviral Resistance Associated With Treatment Induced UL97 (Protein Kinase) and UL54 (DNA Polymerase) Mutations. J Med Virol, 2014;74:85–93.
22. Ljungman P, Griffiths P, Paya C. Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients. Clin Inf Dis, 2002;34:1094–1097.
23. Chou S, Guentzel S, Michels KR, et al. Frequency of UL97 phosphotransferase mutations related to ganciclovir resistance in clinical cytomegalovirus isolates. J Infect Dis, 1995;172:239–242.
24. Smith IL, Cherrington JM, Jiles RE, et al. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis, 1997;176:69–77.
25. Baldanti F, Underwood MR, Stanat SC, et al. Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow-growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS. J Virol, 1996;70:1390–1395.
26. Erice A, Borrell N, Li W, et al. Ganciclovir susceptibilities and ana-lysis of UL97 region in cytomegalovirus isolates from bone marrow recipients with CMV disease after antiviral prophylaxis. J Infect Dis, 1998;178:531–534.
27. Chou S, Erice A, Jordan MC, et al. Analysis of the UL97 phosphotransferase coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. J Infect Dis, 1995;171:576–583.
28. Wolf DG, Smith IL, Lee DJ, et al. Mutations in human cytomega-lovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma. J Clin Investig, 1995;95(1):257–263.
29. Gilbert C, Roy J, Belanger R, et al. Lack of Emergence of Cytomegalovirus UL97 Mutations Conferring Ganciclovir (GCV) Resistance following Preemptive GCV Therapy in Allogeneic Stem Cell Transplant Recipients. Antimicrobial Agents Chemoter, 2001;45:3669–3367.
30. Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNAload, and outcomes. Blood, 2001;97(4):867–874.
31. Boeckh M, Ljungman. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood, 2009;113(23):5711–5719.
32. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Inf Dis, 2002;35:866–872.
33. Chou S, Waldemer RH, Senters AE, et al. Cytomegalovirus UL97 phosphotransferase mutations that affect susceptibility to ganciclovir. J Infect Dis, 2002;185(2):162–169.
34. Kleiboeker S, Nutt J, Schindel B, et al. Cytomegalovirus antiviral resistance: characterization of results from clinical specimens. Transpl Infect Dis, 2014;16(4):561–567.
35. Emery VC, Griffiths P. Prediction of cytomegalovirus load and resistence patterns after antiviral chemotherapy. Proc Natl Acad Sci USA, 2000;97(14):8039–8044.
36. Ruutu T. Engraftment [online]. EBMT, 2011 [cit. 2016-06-02]. Dostupný na www: http://www.ebmt.org/Contents/Resources/Library/Slidebank/Documents/EBMT%202011%20SC%20Slide%20Bank/1439%20Ruutu.pdf
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Hygiene and epidemiology Medical virology Clinical microbiologyArticle was published in
Epidemiology, Microbiology, Immunology
2015 Issue 3
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