Ganciclovir Resistant/Refractory Cytomegalovirus Infection in SOT Recipients and HSCT Patients

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in solid organ transplant (SOT) patients and hematopoietic stem cell transplant (HSCT) patients. Ganciclovir (GCV) is the first line therapy for treatment and prevention of CMV infection in SOT and HSCT recipients, with established efficacy and relatively safe profile. Ganciclovir-resistant or refractory (GCV-RR) CMV is an uncommon but frightening clinical problem due to limited, toxic and less effective therapeutic alternative drugs. Indeed, some studies indicate that GCV-RR is associated with significant additional attributable morbidity and mortality in SOT and HSCT recipients compared with ganciclovir susceptible (GCV-S) CMV disease. Few data are available about the incidence of GCV-RR-CMV in SOT and HSCT patients showing a range from 0% to 3% . The serological mismatch group and the type of SOT have been reported as the main factors influencing such range. Indeed, in one of the largest experience now available in SOT, the incidence of GCV-resistant (GCV-RT) CMV infection accounted up to 12% in a cohort of lung transplant recipients. Among HSCT patients, haploidentical, allogeneic unrelated, and cord blood HSCT have been associated with increased risk of GCV-RR CMV infection. Among risk factors for GCV-RR, high-risk D/R subset (R- in SOT and R+ in HSCT), high viral loads, inadequate drug delivery, increased durations of antiviral drug exposure and the use of more potent immunosuppressive regimens have been reported. However, these reports come from small, monocentric experiences with a limited number of cases, providing a fragmentary picture of the overall burden and epidemiological characteristics of GCV-RR in transplant patients. Information of the epidemiological background of GCV-RR after transplantation could be helpful in improving preventive management and reducing the emergence of GCV-RT episodes. Indeed, studies investigating viral genetic alterations showed that mutations conferring ganciclovir resistance are not present at baseline but emerge and become amplified over time, especially in the presence of an incompletely suppressive drug exposure. The GCV-RT is due to mutations in UL97 and UL54 genes. UL97 mutations confer various degrees of phenotypic resistance to ganciclovir. Mutations in UL54 determine higher-level resistance to ganciclovir and usually appear as a second step after mutations in UL97. The investigators carry-out a multicenter retrospective observational study to define incidence of GCV-RR CMV-infection in SOT and HSCT patients and to identify the risk factors for its development in SOT and HSCT recipients. Data from this study could be useful to design further studies aimed at preventing and improving the patient management of GCV-RR CMV infections.