Cytomegalovirus Replication Kinetics in Solid Organ Transplant Recipients Managed by Preemptive Therapy

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

[1]  V. Emery,et al.  Cytomegalovirus quantification: where to next in optimising patient management? , 2011, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[2]  A. Davenport,et al.  Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial , 2011, The Lancet.

[3]  D. Abramowicz,et al.  The Efficacy and Safety of 200 Days Valganciclovir Cytomegalovirus Prophylaxis in High‐Risk Kidney Transplant Recipients , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  O. Hes,et al.  Intragraft Cytomegalovirus Infection: A Randomized Trial of Valacyclovir Prophylaxis versus Pre-Emptive Therapy in Renal Transplant Recipients , 2010, Antiviral therapy.

[5]  P. Klenerman,et al.  Polyfunctional Cytomegalovirus‐Specific CD4+ and pp65 CD8+ T Cells Protect Against High‐Level Replication After Liver Transplantation , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[6]  P. Klenerman,et al.  Functional Impairment of Cytomegalovirus Specific CD8 T Cells Predicts High‐Level Replication After Renal Transplantation , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  M. Schnitzler,et al.  Prophylactic Versus Preemptive Oral Valganciclovir for the Management of Cytomegalovirus Infection in Adult Renal Transplant Recipients , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  A. Burroughs,et al.  Modelling cytomegalovirus replication patterns in the human host: factors important for pathogenesis , 2006, Proceedings of the Royal Society B: Biological Sciences.

[9]  H. Schäfers,et al.  Differences in CMV‐Specific T‐Cell Levels and Long‐Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[10]  A. Bertoletti,et al.  Evolution of hepatitis B virus during primary infection in humans: transient generation of cytotoxic T-cell mutants. , 2004, Gastroenterology.

[11]  Guy Boivin,et al.  Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease. , 2002, The Journal of infectious diseases.

[12]  Andrew K Burroughs,et al.  Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts. , 2002, The Journal of infectious diseases.

[13]  P. Griffiths,et al.  Definitions of cytomegalovirus infection and disease in transplant recipients. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  J. Preiksaitis,et al.  The risk of transfusion‐acquired CMV infection in seronegative solid‐organ transplant recipients receiving non‐WBC‐reduced blood components not screened for CMV antibody (1984 to 1996): experience at a single Canadian center , 2002, Transfusion.

[15]  K. Borner,et al.  Preemptive oral ganciclovir therapy versus prophylaxis to prevent symptomatic cytomegalovirus infection after kidney transplantation. , 2001, Transplantation proceedings.

[16]  A. Meyerhans,et al.  LEVELS OF VIRUS-SPECIFIC CD4 T CELLS CORRELATE WITH CYTOMEGALOVIRUS CONTROL AND PREDICT VIRUS-INDUCED DISEASE AFTER RENAL TRANSPLANTATION1 , 2001, Transplantation.

[17]  D. Mclone The Risk , 2001, Pediatric Neurosurgery.

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

[19]  C. Sabin,et al.  Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation , 2000, The Lancet.

[20]  Vincent C. Emery,et al.  The Dynamics of Human Cytomegalovirus Replication in Vivo , 1999, The Journal of experimental medicine.

[21]  J. Gómez-Moreno,et al.  Infection in organ-transplant recipients. , 1998, The New England journal of medicine.

[22]  C. Sabin,et al.  Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation. , 1997, The Journal of infectious diseases.

[23]  C. Sabin,et al.  Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation , 1997, Journal of medical virology.

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

[25]  A. Limaye,et al.  Programmed death-1 expression in liver transplant recipients as a prognostic indicator of cytomegalovirus disease. , 2008, The Journal of infectious diseases.

[26]  A. Burroughs,et al.  Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir. , 2005, Journal of Infectious Diseases.