Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients.

Despite advances in the prophylaxis and acute treatment of cytomegalovirus (CMV), it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. There is increasing use of antiviral prophylaxis after transplant with little expansion in the range of antiviral agents effective in treatment of CMV. Further understanding is needed of the risk factors for development of CMV antiviral resistance and of therapeutic strategies for treating patients infected with resistant viruses. We review the current status of CMV resistance in solid organ transplant recipients, and provide diagnostic and therapeutic suggestions for the clinician in managing antiviral resistance.

[1]  H. Kestler,et al.  A new tool linking human cytomegalovirus drug resistance mutations to resistance phenotypes. , 2010, Antiviral research.

[2]  R. Avery,et al.  Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: a single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial. , 2011, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[3]  A. Limaye Ganciclovir-resistant cytomegalovirus in organ transplant recipients. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  M. Woods,et al.  Artesunate is ineffective in controlling valganciclovir-resistant cytomegalovirus infection. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  J. Cohen,et al.  Update on New Antivirals Under Development for the Treatment of Double‐Stranded DNA Virus Infections , 2010, Clinical pharmacology and therapeutics.

[6]  A. Neumann,et al.  Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation. , 2011, Antiviral research.

[7]  D. Knight,et al.  Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. , 1999, Intervirology.

[8]  Angela M Caliendo,et al.  International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. , 2010, Transplantation.

[9]  S. Chou,et al.  Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients , 2010, Transplant infectious disease : an official journal of the Transplantation Society.

[10]  H Rollag,et al.  Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  B. Iglesias,et al.  Assay of cytomegalovirus susceptibility to ganciclovir in renal and heart transplant recipients , 2002, Transplant International.

[12]  S. Chou,et al.  Antiviral Drug Resistance of Human Cytomegalovirus , 2010, Clinical Microbiology Reviews.

[13]  C. Mengelle,et al.  Detection of ganciclovir resistance after valacyclovir‐prophylaxis in renal transplant recipients with active cytomegalovirus infection , 2004, Journal of medical virology.

[14]  E. Mylonakis,et al.  Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  V. Emery,et al.  Importance of the cytomegalovirus seropositive recipient as a contributor to disease burden after solid organ transplantation , 2012, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[16]  S. Chou,et al.  Cytomegalovirus UL97 Mutations Affecting Cyclopropavir and Ganciclovir Susceptibility , 2010, Antimicrobial Agents and Chemotherapy.

[17]  E. Benedetti,et al.  Use of high‐dose ganciclovir for a resistant cytomegalovirus infection due to UL97 mutation , 2008, Transplant infectious disease : an official journal of the Transplantation Society.

[18]  W. Braun,et al.  Utility of Leflunomide in the Treatment of Complex Cytomegalovirus Syndromes , 2010, Transplantation.

[19]  J. Cherrington,et al.  Characterization of Drug Resistance-Associated Mutations in the Human Cytomegalovirus DNA Polymerase Gene by Using Recombinant Mutant Viruses Generated from Overlapping DNA Fragments , 1998, Journal of Virology.

[20]  D. Snydman,et al.  The impact of CMV prevention on long‐term recipient and graft survival in heart transplant recipients: analysis of the Scientific Registry of Transplant Recipients (SRTR) database , 2011, Clinical transplantation.

[21]  S. Mackinnon,et al.  Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[22]  C. Mengelle,et al.  Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. , 2010, The Journal of antimicrobial chemotherapy.

[23]  P. Griffiths,et al.  Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Elston,et al.  Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis. , 2012, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[25]  A. Limaye,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 , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  R. Razonable,et al.  Emergence of drug‐resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes , 2007, Clinical transplantation.

[27]  S. Chou,et al.  Cytomegalovirus UL97 phosphotransferase mutations that affect susceptibility to ganciclovir. , 2002, The Journal of infectious diseases.

[28]  T. Efferth,et al.  The antiviral activities of artemisinin and artesunate. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[29]  J. D. de Fijter,et al.  Preemptive Versus Sequential Prophylactic-Preemptive Treatment Regimens for Cytomegalovirus in Renal Transplantation: Comparison of Treatment Failure and Antiviral Resistance , 2010, Transplantation.

[30]  D. Engelthaler,et al.  Cyclopropavir Inhibits the Normal Function of the Human Cytomegalovirus UL97 Kinase , 2011, Antimicrobial Agents and Chemotherapy.

[31]  A. Åsberg,et al.  Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients , 2011, Transplantation.

[32]  W. Drew,et al.  Antiviral susceptibility testing of cytomegalovirus: criteria for detecting resistance to antivirals. , 1993, Clinical and diagnostic virology.

[33]  D. Knight,et al.  Inhibition of Cytomegalovirus in vitro and in vivo by the Experimental Immunosuppressive Agent Leflunomide , 2000, Intervirology.

[34]  P. Griffiths,et al.  Ganciclovir treatment in children: evidence of subtherapeutic levels. , 2011, International journal of antimicrobial agents.

[35]  J. Stockman Vaccine Prevention of Maternal Cytomegalovirus Infection , 2011 .

[36]  S. Chou,et al.  Phenotyping of Cytomegalovirus Drug Resistance Mutations by Using Recombinant Viruses Incorporating a Reporter Gene , 2005, Antimicrobial Agents and Chemotherapy.

[37]  G. Boivin,et al.  Analysis of cytomegalovirus DNA polymerase (UL54) mutations in solid organ transplant patients receiving valganciclovir or ganciclovir prophylaxis , 2005, Journal of medical virology.

[38]  S. Chou,et al.  Successful valganciclovir treatment of post‐transplant cytomegalovirus infection in the presence of UL97 mutation N597D , 2009, Journal of medical virology.

[39]  E. Kern,et al.  The search for new therapies for human cytomegalovirus infections. , 2011, Virus research.

[40]  P. Angus,et al.  Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients. , 2011, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[41]  T. Bachelet,et al.  High Incidence of Anticytomegalovirus Drug Resistance Among D+R− Kidney Transplant Recipients Receiving Preemptive Therapy , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[42]  D. Abramowicz,et al.  Extended Valganciclovir Prophylaxis in D+/R− Kidney Transplant Recipients is Associated With Long-Term Reduction in Cytomegalovirus Disease: Two-Year Results of the IMPACT Study , 2010, Transplantation.

[43]  H. Zimmermann,et al.  First Report of Successful Treatment of Multidrug‐Resistant Cytomegalovirus Disease with the Novel Anti‐CMV Compound AIC246 , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[44]  D. Michel,et al.  Improved Detection of Mutated Human Cytomegalovirus UL97 by Pyrosequencing , 2010, Antimicrobial Agents and Chemotherapy.

[45]  S. Berger,et al.  Preemptive versus sequential prophylactic-preemptive treatment regimens for CMV in renal transplantation: comparison of treatment failure and antiviral resistance , 2012 .

[46]  H. Balfour Management of cytomegalovirus disease with antiviral drugs. , 1990, Reviews of infectious diseases.

[47]  H. Einsele,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. , 2011, The Lancet. Infectious diseases.

[48]  M. Isaacs,et al.  Cytomegalovirus antiviral resistance associated with treatment induced UL97 (protein kinase) and UL54 (DNA polymerase) mutations , 2004, Journal of medical virology.

[49]  G. Boivin,et al.  Human Cytomegalovirus Resistance to Antiviral Drugs , 2005, Antimicrobial Agents and Chemotherapy.

[50]  M. Kazatchkine,et al.  Monitoring plasma levels of ganciclovir in AIDS patients receiving oral ganciclovir as maintenance therapy for CMV retinitis. , 2000, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[51]  A. Åsberg,et al.  Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir , 2009, Antiviral therapy.

[52]  R. Ettenger,et al.  Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[53]  S. Chou Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir , 2008, Reviews in medical virology.

[54]  W. Rawlinson,et al.  Diversity of antiviral‐resistant human cytomegalovirus in heart and lung transplant recipients , 2011, Transplant infectious disease : an official journal of the Transplantation Society.

[55]  H. Einsele,et al.  Ganciclovir-resistant cytomegalovirus disease after allogeneic stem cell transplantation: pitfalls of phenotypic diagnosis by in vitro selection of an UL97 mutant strain. , 2003 .

[56]  R. Crooke,et al.  Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region , 1993, Antimicrobial Agents and Chemotherapy.

[57]  W. Freeman,et al.  High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. , 1997, The Journal of infectious diseases.

[58]  G. Filler,et al.  Unexpectedly high inter‐ and intrapatient variability of Ganciclovir levels in children , 2007, Pediatric transplantation.

[59]  A. Limaye,et al.  Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants , 2000, The Lancet.

[60]  N. Câmara,et al.  The use of sirolimus in ganciclovir‐resistant cytomegalovirus infections in renal transplant recipients , 2007, Clinical transplantation.

[61]  J. Bermejo,et al.  Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease. , 2005, International immunopharmacology.

[62]  H. Volk,et al.  Adoptive T‐Cell Therapy of a Lung Transplanted Patient with Severe CMV Disease and Resistance to Antiviral Therapy , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[63]  D. Michel,et al.  Aciclovir selects for ganciclovir‐cross‐resistance of human cytomegalovirus in vitro that is only in part explained by known mutations in the UL97 protein * , 2001, Journal of medical virology.