Epidemiological Burden of and Risk Factors for Ganciclovir Resistant Cytomegalovirus in Solid Organ Transplant Patients: Multicentre Cohort Study

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in solid organ transplant (SOT) patients. Ganciclovir is the first line therapy for treatment and prevention of CMV infection in SOT recipients, with established efficacy and relatively safe profile.

Ganciclovir-resistant (GCV-R) CMV is an uncommon but frightening clinical problem due to limited, toxic and less effective therapeutic alternative drugs. Indeed, some studies indicate that GCV-R is associated with significant additional attributable morbidity and mortality in SOT recipients compared with ganciclovir susceptible (GCV-S) CMV disease.

Few data are available about the incidence of GCV-R-CMV in SOT 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, the incidence of GCV-R accounted up to 12% in a cohort of lung transplant recipients.Risk factors for ganciclovir resistance development appear to be the high-risk D+/R- subset, high viral loads, increased durations of antiviral drug exposure and the use of more potent immunosuppression. However, these reports come from small, monocentric experiences with a limited number of cases.

In general, mutations that confer resistance to ganciclovir are not present at baseline but emerge and become amplified over time, especially in the presence of an incompletely suppressive drug exposure. The GCV-R 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.

Second-line strategies for the treatment of GCV-R CMV are based on high dose of GCV administration or foscarnet/cidofovir use, both with a high risk of metabolic and renal dysfunction. Alternative strategies are based on the use of adjunctive treatments such as cytomegalovirus immunoglobulins (IVIG), infusions of CMV-specific Tcells or several drugs with indirect anti-CMV action (mTOR inhibitors sirolimus and everolimus, leflunomide and artesunate). Finally, the new antiviral drugs approved for prophylaxis (letermovir) or in advanced clinical development (maribavir, brincidofovir), are reported as anecdotical alternative strategies for the treatment of GCV-R CVM infection. The limited therapeutic strategies for GCV-R CMV treatment highlight the need for new strategies to prevent resistance development.