Queen's School of Business Presentation
Issue link: http://invivo.uberflip.com/i/1501332
Dialogues in Cytomegalovirus 9 A Case-Based Approach to CMV Management Zain Chagla, MD, FRCPC Dr. Zain Chagla is an Associate Professor at McMaster University and an Infectious Diseases Physician and Co-Medical Director of Infection Control at St. Joseph's Healthcare, Hamilton. Dr. Chagla's work includes support for the renal transplant program at St. Joseph's Healthcare, leading inpatient and outpatient consultative services, as well as COVID therapeutics for this population. Affiliations: McMaster University, Hamilton, Ontario, Canada St. Joseph's Healthcare, Hamilton, Ontario, Canada Case 1 A 57-year-old male undergoes deceased donor renal transplant for underlying focal segmental glomerulosclerosis (FSGS). He is given antithymocyte globulin induction (ATG), and is managed with tacrolimus, mycophenolate mofetil (MMF) and prednisone. His donor is seropositive for cytomegalovirus (CMV), and he is seronegative for CMV (D+/R-). He is a put on renally adjusted prophylactic valganciclovir for six months. At eight months (two months post-discontinuation of valganciclovir) he has some abdominal pain, and is found to have a pyelonephritis with Escherichia coli (E. coli) bacteremia. The CMV viral load at the time is 10,000 IU/mL. Treatment with valganciclovir is initiated. You reassess the patient in two weeks. The patient has now recovered from their urinary tract infection (UTI) and is asymptomatic. However, the CMV viral load is now 50,000 IU/mL. What are your next steps? Rationale CMV reactivation in post-solid organ transplant is a significant issue that can be associated with illnesses implying viremia, gra› dysfunction and opportunistic infections. 1 In this patient example, discordant CMV serostatus (D+/R-), and the use of ATG both represent significant risk factors for CMV reactivation post- transplant. 2 There are two approaches to manage reactivation of CMV post-transplant. The first is pre-emptive, using serial monitoring of CMV viremia, followed by the initiation of an antiviral, typically valganciclovir, at a set threshold. The alternate approach is prophylaxis, initiating with immediate antiviral therapy, and then discontinuing a›er a set period. While no head-to- head, randomized clinical trials have compared these approaches, both are considered adequate in renal transplant. 3 However, considerations such as access to rapid turnaround CMV viral load testing, drug toxicity, and patient adherence should all be considered as key factors in this decision-making. Given that this patient resided a considerable distance from the transplant centre, prophylaxis was chosen. This patient completes a full course of prophylaxis and is then transitioned to a symptom-based approach. During the stress of an intercurrent infection, the patient develops a detectable viremia, which is a common scenario. The patient is administered valganciclovir, and a repeat CMV viral load is done in two weeks, showing inadequate response, typically defined as 1 log decline in two weeks. 4 The approach to an inappropriate decline includes consideration of pharmacologic issues or resistance. Pharmacologic issues include drug adherence and inappropriate dosing. As valganciclovir dosing is based on glomerular filtration rate (GFR), which frequently can be altered by post-renal transplantation, it is important to ensure that dosing is optimized to address the patient's underlying renal function issues. Upon review, the patient's dosing was determined to be adequate for GFR, and there were no missed medication doses. Resistance can occur at a molecular level due to a number of mutations. The most common of these is UL97 mutation, which is located on the serine/threonine kinase. This mutation leads to impaired phosphorylation of ganciclovir and valganciclovir; phosphorylation is needed for inhibition of the viral DNA polymerase; hence, phenotypic resistance occurs. 5 The UL54 mutation, located on the viral DNA polymerase, not only leads to resistance to valganciclovir or ganciclovir, but may also diminish the biologic function of foscarnet and cidofovir. 6 Individuals with a suspicion of resistance should have molecular genotyping performed as part of their workup, in order to determine appropriate next steps for short- and longer-term management.