Response to Letter About Intensity of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease (2011)

To the Editor: We thank Hosseini-Moghaddam et al. (1Hosseini-Moghaddam S Rotstein C Husain S Letter to the editor: Effects of the Intensity of Immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients.Am J Transplant. 2011; 11: 407Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar) for their interest in our posthoc analysis of the influence of immunosuppressive intensity on CMV outcomes in the VICTOR-trial (2Åsberg A Humar A Jardine AG et al.Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients.Am J Transplant. 2009; 9: 1205-1213Crossref PubMed Scopus (144) Google Scholar, 3Åsberg A Humar A Rollag H et al.Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients.Am J Transplant. 2007; 7: 2106-2113Crossref PubMed Scopus (343) Google Scholar, 4Åsberg A Jardine AG Bignamini AA et al.Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients.Am J Transplant. 2010; PubMed Google Scholar). Although predefined end-points were used in this posthoc analysis, these were not end-points in the primary study (VICTOR-trial) and, as mentioned in the paper, the analysis was intended as a pure hypothesis generating work. The type of data collected limited the use of specific statistical methods, for example, that the CNI levels had to be dichotomized and analyzed together in groups without correction for other immunosuppressive drugs. The VICTOR-trial was a clinical trial on treatment of CMV disease. The occurrence of patients with tissue-invasive (TI) CMV disease was reported by the investigators, although recording the documentation for such reporting was not compulsory. However, the objective documentation of TI-disease in over 90% of patients appears satisfactory. Tests for CMV DNAemia in the VICTOR-trial were analyzed frequently up to 6 months but only clinical data were reported at 12 months. In the present analysis, we chose to investigate the more objective virological parameters. May be Hosseini-Moghaddam et al. are misinterpreting the use of the term ‘virological efficacy population’ in previous papers (2Åsberg A Humar A Jardine AG et al.Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients.Am J Transplant. 2009; 9: 1205-1213Crossref PubMed Scopus (144) Google Scholar,3Åsberg A Humar A Rollag H et al.Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients.Am J Transplant. 2007; 7: 2106-2113Crossref PubMed Scopus (343) Google Scholar). We were also surprised by the finding that tacrolimus (Tac) was indicated to reduce CMV recurrence but not to affect early viral eradication. This may reflect the nature of the posthoc analysis, especially since the effect size is weak. Hosseini-Moghaddam et al. raise a question concerning ‘the frequency of CMV infection in the D+/R- group’. All patients included in the VICTOR-trial had CMV DNAemia. The different immunosuppressive regimens could not be specified due to space limitations. However, from the presented data one can identify 65 patients who received induction treatment, with ATG/OKT3, and that 138 used cyclosporine (CsA) and 108 used Tac. Only one patient received sirolimus, whilst 237 patients used corticosteroids. As mentioned in the primary paper from the VICTOR trial (3Åsberg A Humar A Rollag H et al.Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients.Am J Transplant. 2007; 7: 2106-2113Crossref PubMed Scopus (343) Google Scholar) 22 patients experienced a total of 25 acute rejection episodes during the study; too small a sample for detailed statistical analyses. The end-points and cut-off values for whole blood CsA and Tac concentrations to be used to reflect the immunosuppressive intensity were predefined. Since the patients were stable and on average almost 1 year post transplant cut-off values of 150 μg/L (CsA) and 5 μg/L (Tac) were accepted by the steering committee. Weight adjusted doses of CsA and Tac would add further confounders due to the variable bioavailability of these drugs. We hope the response above relieves the skepticism of our analyses. We agree that the interrelationship between immunosuppressive intensity and use of individual agents, and CMV outcomes needs further study. Nonetheless we believe our data add important insight into this issue. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. The manuscript was prepared by the authors but F. Hoffmann-La Roche Ltd. funded the study and local affiliates of F. Hoffmann-La Roche Ltd. were responsible for monitoring the study in most centers while local CRO’s were hired for monitoring of some centers. Hyperphar was sub-contracted by F. Hoffmann-La Roche Ltd. to be the central CRO and study leader, also taking care of the electronic CRF program, data management and statistical analysis. Dr. Åsberg is a former employee of F. Hoffmann-La Roche Ltd. (between 2000 and 2003) and served as a consultant to F. Hoffmann-La Roche Ltd. during the study dealing with study specific issues. Drs. Humar, Jardine and Hartmann have performed consultancy work for F. Hoffmann–La Roche Ltd. Dr. Rollag has no conflicts of interest to report. Dr. Gahlemann is an employee of F. Hoffmann-La Roche Ltd. Dr. Bignamini was employed by Hyperphar during the study, which was a sub-contractor for F. Hoffmann-La Roche Ltd, hired to perform data management and statistical analyses.