Clinical Validation of the Definitions of Resistant and Refractory Cytomegalovirus (CMV) Infection and Disease in Hematopoietic Cell Transplant (HCT) Recipients.

Abstract

Introduction Resistant or refractory CMV infections are not well defined and are associated with high morbidity and mortality in HCT recipients. Ganciclovir (GCV), Foscarnet (FOS) and valganciclovir (VGC) are available for treatment of CMV infections with successful results, however, toxicities from these drugs are common and associated resistance have been reported. Definitions for “resistant and refractory CMV infections” were published recently for clinical trials use and to provide guidance for clinical practice (Chemaly RF et al, CID, 2018). Methods We performed a single center retrospective chart review (1/2010 to 9/2018) of HCT recipients who had CMV genotype performed for suspected antiviral resistance. Based on the published definitions, we categorized patients as either having refractory CMV (defined as CMV viremia that fails to decrease after at least 2 weeks of appropriately dosed and delivered antiviral therapy; and in the absence of known genetic mutations to the available antiviral agents) or resistant CMV infection (defined as refractory infection with identification of genetic mutations in the UL97 and/or UL54 genes correlating with in vitro antiviral resistance). Primary outcomes were CMV disease and non-relapse mortality (NRM). Results CMV genotype analysis was performed in 120 patients and 29 (24%) patients had UL 97 and/or UL54 mutations. When compared to refractory CMV infection, patients with resistant CMV infection were more likely to have AML (38% vs 76%), had cord blood transplant (8% vs 24%), were diagnosed with resistant infection later after HCT (59 d vs 120 d), had greater number of prior episodes of CMV infections, had more CMV diseases (34% vs 62%), and specifically more CMV GI diseases (22% vs 55%); (all, p Conclusion Our data showed that resistant CMV infections are associated with higher morbidity including CMV disease while refractory CMV infections are associated with higher NRM. Whether this high NRM in patients with refractory CMV infections is a reflection of the host immunosuppression with persistent CMV infection needs to be determined.