Dynamics of dual CMV and EBV co-reactivation and emergence of resistance in an HSCT recipient

Abstract Background Herpesvirus infections [e.g. Epstein–Barr virus (EBV) or cytomegalovirus (CMV)] are a major cause of mortality and morbidity in post-transplant patients despite antiviral therapy, with the emergence of drug resistance further complicating patients’ care. Objectives To evaluate the dynamics and drug resistance of simultaneous EBV and CMV reactivations in an HSCT recipient. Patients and methods Twenty-two samples derived from blood, one sample from bone marrow and one sample from colon biopsy over an 8 month period while under different anti-CMV treatments were analysed. CMV, EBV and torque teno virus (TTV) DNA loads were determined and viral dynamics were investigated by genotyping of the CMV and EBV genes involved in drug resistance by Sanger sequencing (prospectively) and next-generation sequencing (NGS) (retrospectively). Results EBV reactivation was seen simultaneously with CMV reactivation and rising of TTV DNA load, suggesting increased immunosuppression. A reduction of EBV viraemia under maribavir was observed. Emergence of the CMV DNA polymerase (DP) L773V MDR mutation occurred following antiviral treatment and was subsequently replaced by the CMV UL97 protein kinase (PK) ganciclovir resistance A594P mutation, which could be detected earlier by NGS than by Sanger sequencing. At 273 days post-transplantation, the patient still had active CMV/EBV co-reactivation, with CMV being refractory to antiviral therapy. Conclusions The use of NGS and Sanger sequencing revealed evolution of CMV drug resistance under antiviral treatment. Our findings highlight the potential of maribavir to treat EBV infection and the difficulties in managing CMV/EBV co-reactivation in immunocompromised hosts.