Cytomegalovirus Infection Clinical Trial
Official title:
Quantiferon - CMV and the Prediction of CMV Infection In High Risk Solid Organ Transplant Recipients
Cytomegalovirus (CMV) is a common cause of illness in patients who have undergone a transplant. Serious infections due to CMV can affect many parts of the body including the lungs, the gut, and the liver. Since transplant recipients are at risk for CMV or have evidence of infection with CMV, they are given an antiviral drug (usually ganciclovir or valganciclovir). Despite this, there are a chance that CMV infection may cause problems in the future. The purpose of this study is to assess how well patients'immune systems responds to the CMV virus, so that in the future it may be possible to predict which patients are at highest risk of CMV.
CMV is the most common viral infection after solid organ transplantation (SOT) and is
associated with significant morbidity1. Without prophylaxis, most CMV disease occurs in the
first 3 months post-transplant during the period of intense of immunosuppresion.2 SOT
recipients at the greatest risk are those that are seronegative recipients of organs from
seropositive donors (CMV D+/R-).3, 4 Antiviral agents have proven to be useful in the
prevention of CMV infection and disease in SOT recipients, including the high-risk D+/R-
patients.5-9 Upon completion of prophylaxis however, CMV infection and disease occurs in
about 50% and 25-30% respectively of D+/R- SOT recipients within the first year after
transplant [30% rate of investigator treated CMV disease in PV16000].9 The incidence of CMV
infection following prophylaxis in D+/R- lung transplant recipients may be as high as 80%.10
As CMV disease occurring after prophylaxis will continue to impact morbidity and mortality
in SOT recipients, it would be desirable to be able to predict which patient will develop
this complication. Currently, there are no reliable methods that are routinely available to
predict the risk of CMV infection or disease in an individual patient. CMV viral load
testing after prophylaxis in D+/R- patients has been shown to have poor predictive value for
subsequent CMV disease.11 CMV serology (a measure of humoral immunity) was also shown to be
only of marginal use in predicting the risk of late onset disease.12 Cell mediated immunity
(CMI) is known to be more important than humoral immunity in controlling CMV infection. CMV
infection elicits a strong virus specific CD4+ and CD8+ T-cell response. CD8+ T-cell
responses to the virus often contain multiple antigen-specific reactivities including to
viral pp65 or IE-1 antigens as well as pp50, glycoprotein B, and IE-2 and other antigens.13
CD4+ T cells also play a part in CMV control via promotion of priming, expansion and
maintenance of CD8+ CMV-specific CTLs.14 Measuring an individual's CMI response to CMV may
be a useful predictor of the risk of CMV infection or disease after prophylaxis. Patients
with a poor CMI response (especially a poor CD8+ T-cell response) could then be targeted
with longer courses of antiviral prophylaxis.
Cell mediated immunity testing Most of the previous studies have focused on CTL responses to
the CMV phosphoprotein pp65.15-17 However, since CD8+ T-cell responses to CMV often contain
multiple antigen-specific reactivities, measurement of CMI using epitopes restricted to a
single protein may not yield adequate results. In conjunction with Dr. Rajiv Khanna
(Queensland Institute of Medical Research, Australia), and Cellestis Ltd (Sydney,
Australia), we have done preliminary validation and assessment of a CMI (Quantiferon-CMV)
assay in which we measure the IFN-γ responses to a range of T-cell epitopes of CMV viral
proteins including pp65, pp50, the glycoprotein gB, and the immediate early IE-1 antigen
that are specific for a wide range of HLA class I specificities [See Appendix Table 1]. The
assay employs a peptide pool for stimulation of whole blood and is suitable for routine
clinical use and evaluation in multicenter studies.
The Quantiferon-CMV assay has been compared to an ELISPOT assay in a study involving 37
healthy volunteers and 25 SOT recipients.18 In this study, the Quantiferon-CMV assay was at
least as sensitive as the ELISPOT for some CMV epitopes, and more sensitive for other CMV
epitopes. In addition, the Quantiferon-CMV results highly correlated with the CMV
serostatus, in both healthy volunteers and transplant recipients. In another study,19 the
Quantiferon-CMV assay was used in HIV-infected individuals with and without a history of CMV
disease. The CMV specific immune response measured by the Quantiferon-CMV assay was higher
in patients without a history of CMV disease, suggesting that a positive result of the
Quantiferon-CMV may predict the likelihood for developing a protective immune response
against CMV.
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Observational Model: Cohort, Time Perspective: Prospective
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