Intensified CMV prophylaxis does not reduce infection incidence in kidney recipients

Strengthening cytomegalovirus (CMV) prophylaxis with exclusive use of valganciclovir and by extending the course results in longer time to first CMV infection but does not lower the incidence of the disease at 24 months, a Singapore study has shown. Valacyclovir appears to be a good substitute for valganciclovir, especially in resource-limited settings or in situations when the latter cannot be tolerated.

“After prophylaxis is discontinued, CMV surveillance and careful titration of immunosuppression are adjunct strategies for the prevention of CMV infection/disease,” the researchers said.

This single-centre retrospective before/after observational study compared kidney transplant recipients who received protocol 1, a valacyclovir- or valganciclovir-based regimen prescribed for 1 to 3 months based on the CMV risk status between 2004 and 2008, to those who received protocol 2, a valganciclovir-based regimen prescribed for 3 and 6 months for those at moderate and high risk, respectively, between 2010 and 2014.

The researchers reviewed the impact of different prophylaxis regimens on the incidence of CMV infections, disease, recurrent infections, and onset of CMV infection at 24 months.

Of the 192 patients included, 106 received protocol 1 and 86 protocol 2. The incidence of CMV infection at 24 months was 53.8 percent in protocol 1 and 55.8 percent in protocol 2 (p=0.884). Protocol 1 showed higher incidence rates of CMV disease and recurrent CMV infections, but this did not reach statistical significance. [Proc Singapore Healthc 2021;30:117-124]

Of note, patients who received protocol 1 had significantly shorter median time to first CMV infection: 132 (interquartile range [IQR] 125–139) vs 185 (IQR 178–192) days (p=0.001). Both prophylaxis protocols were well tolerated.

“Contrary to our hypothesis that an intensified prophylaxis regimen would reduce the incidence of CMV infection, this was not observed in our study; the rates of CMV infections were similar between both groups,” the researchers said. “This could be attributed to the heterogeneity of the patients’ baseline characteristics in the two groups.”

Overall, patients who received protocol 1 had a higher CMV risk, with a greater proportion receiving thymoglobulin, but CMV incidence was not increased relative to protocol 2.

“The increased number of ABO incompatible transplants, use of expanded criteria donors and older recipients in protocol 2—known risk factors for CMV infections—could have blunted the effects of the differences in prophylaxis regimen,” the researchers said. [Ann Surg Treat Res 2016;91:37-44; Front Immunol 2019;10:3142; Eur J Clin Microbiol Infect Dis 2020;39:455-463]

Furthermore, the current study revealed a high incidence of asymptomatic CMV reactivation upon discontinuation of prophylaxis, indicating the possibility that the current immunosuppression dosing regimen might be excessive for the local Asian population.

“To date, except for the evaluation of trough levels of select immunosuppressants, there is lack of established clinical tools to guide individualization of immunosuppression therapy for transplant recipients,” the researchers said. [Int J Mol Sci 2015;16:4281-4305]

Strategies for the lessening of immunosuppression depth could include the following: use of a steroid-sparing regimen, calcineurin inhibitor (CNI) reduction, or use of a CNI-sparing regimen. [Transplantation 2004;78:1548-1556; N Engl J Med 2008;358:2518-2519; Transplantation 2009;87:233-242]

“However, these strategies are often applied empirically after the diagnosis of CMV reactivation,” the researchers said. “There is an impetus to develop pharmacogenetic and pharmacogenomic strategies to guide selection of immunosuppression regimen in the era of individualized therapy in transplantation medicine.”