Successful Cost-Effective Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients Using Low-Dose Valganciclovir

Exp Clin Transplant. 2017 Feb;15(Suppl 1):156-163 doi: 10.6002/ect.mesot2016.P34.
Abstract
OBJECTIVES:

Low-dose valganciclovir prophylaxis is still under investigation in renal transplant procedures. Our aim was to assess the cost effectiveness of 450 mg versus 900 mg valganciclovir prophylaxis in kidney transplant recipients.

MATERIALS AND METHODS:

In this prospective trial, 201 kidney transplant patients were randomized (1:1) to receive 450 mg/d (group 1, n = 100) or 900 mg/d (group 2, n = 101) valganciclovir prophylaxis for the first 6 months after transplant. Patients were studied for incidence of cytomegalovirus disease, leucopenia episodes, rejection episodes, and graft outcomes along with associated costs over 1 year. Costs (in US dollars) of treatment of rejection were also analyzed.

RESULTS:

Demographic features of the studied groups were comparable. We found that the cost of cytomegalovirus care in group 1 patients was significantly lower (by 50% at 6 months; P < .001), with less leukopenia episodes (P = .04), lower doses of granulocyte colony-stimulating factor (by 30% at 6 months; P = .03), higher doses of mycophenolate mofetil (P = .04), and less rejection episodes (P = .01) compared with group 2. In group 2, there were more episodes of cytomegalovirus infection (P = .052) and BK virus nephropathy (P = .04). Graft and patient outcomes were satisfactory in both groups.

CONCLUSIONS:

Low-dose valganciclovir for cytomegalovirus prophylaxis after renal transplant is safer, effective and without breakthrough infection, and less costly than using the usual dose.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This RCT compared standard (900 mg/d) to low (450 mg/d) dose valganciclovir for CMV prophylaxis in renal transplant recipients for 6 months. The study demonstrated less leucopenia, lower G-CSF use and less rejection in the low-dose group, with a non-significant trend toward less CMV infection. Cost of CMV treatment was lower in the low-dose group, although the overall cost was lower in the high-dose arm due to more frequent reductions in MMF dose (presumably secondary to leucopenia). There was no difference in graft function, graft or patient survival. These results appear to suggest that in an intermediate risk population (mainly CMV +/+ transplant) low dose valganciclovir for 6 months offers effective prophylaxis. Whether this holds true for higher risk seronegative recipients is unclear. There are also some methodological concerns – method of randomisation is not reported and the study is not blinded. There is a significant difference in baseline immunosuppression between the arms (higher tacrolimus use in the low-dose arm) which may be important as tacrolimus has previously been associated with lower rates of CMV infection in the literature.
Expert Review
Reviewer: Professor Didier Mandelbrot, University of Wisconsin Hospital and Clinics, USA.
Conflicts of Interest: No
Clinical Impact Rating 2
Review: The study by Gheith et al. randomized 201 patients at intermediate risk for CMV (essentially all D+/R+) to six months of valganciclovir 450 mg or 900 mg daily. The results highlight the fact that leukopenia is a significant, dose-dependent side effect of valganciclovir. Not surprisingly, the study finds that the high dose group required more MMF dose reductions, more G-CSF injections and more valganciclovir dose reductions. The primary endpoint of the study is cost and the authors calculate the cost of valganciclovir itself as twice higher in the high dose group, since two 450mg pills costs twice as much as one 450mg pill. However, overall cost was actually higher in the low dose group, due to reduced usage of MMF. The study does show that CMV disease is rare (2%) in the low dose group. However, the authors’ conclusion that low dose valganciclovir “after renal transplant is safer, effective without breakthrough infection” is not generalizable to the high-risk patients (D+/R-) that we struggle with the most. It may be that the downsides to using low dose ganciclovir, including ganciclovir-resistant CMV and breakthrough CMV infections, are not detected when high-risk patients are not included. Study weaknesses limit the direct implications for clinical practice. While this study did not find worse outcomes in the low dose group, the major concerns with this approach are not sufficiently addressed to recommend widely using it.
Methodological quality
Jadad score 2
Allocation concealment NO
Data analysis PER PROTOCOL
Study Details
Aims: To assess the cost effectiveness of 450 mg versus 900 mg valganciclovir prophylaxis in kidney transplant recipients.
Interventions: Participants were randomized into two groups and received for 6 months post-transplant either low-dose valganciclovir (450 mg/d), or full-dose valganciclovir (900 mg/d).
Participants: 201 kidney transplant recipients who could tolerate oral valganciclovir within 1 week post-transplant and were not allergic to valganciclovir.
Outcomes: Measured outcomes included the incidence of cytomegalovirus disease, leukopenia episodes, mycophenolate mofetil and valganciclovir dose reduction, requirement for granulocyte colony-stimulating factor treatment, patient survival, graft survival, rejection episodes, and associated costs.
Follow Up: 12 months
Metadata
Funding: No funding was received for this study
Publication type: Randomized Controlled Trial, Randomised Controlled Trial
Organ: Kidney
Language: English
Author email: ogheith@yahoo.com
MeSH terms: Adult; Antiviral Agents; Cost-Benefit Analysis; Cytomegalovirus Infections; Drug Administration Schedule; Drug Costs; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Valganciclovir; 0 (Antiviral Agents); 0 (Immunosuppressive Agents); GCU97FKN3R (Valganciclovir); P9G3CKZ4P5 (Ganciclovir)