Detection of ganciclovir resistance after valacyclovir‐prophylaxis in renal transplant recipients with active cytomegalovirus infection

Abstract

Whether valaciclovir (VCV) prophylaxis could be responsible for ganciclovir (GCV)-resistance of Human cytomegalovirus (HCMV) in transplantation has never been documented. A multicentric retrospective pilot study was undertaken to detect GCV-resistance through mutations within the UL97 gene in renal transplant recipients who experienced active HCMV infection and received valacyclovir prophylaxis. Twenty-three patients who experienced HCMV antigenaemia or DNAemia during or at the end of prophylaxis were included. UL97 genotyping was carried out on peripheral blood samples, using a nested in-house PCR, which amplified the full-length UL97 gene. One patient has a resistance-related mutation (M460I); the major risk factor for emergence of resistance in this patient was the presence of early and persistent antigenaemia. GCV-resistance during VCV-prophylaxis was rare after renal transplantation. However, special attention must be paid to patients developing early active HCMV infection under prophylaxis.

Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis

“…The results reported in this study are consistent with the low level of resistance reported previously, 6,13 with three patients in each treatment arm (or 6 of 70 patients meeting the resistance analysis criteria) having GCV resistance mutations detected. The resistance analysis criteria used in different studies vary; in this study, they included any patient with a positive viral load at the end of prophylaxis, any 200-day patient with a positive viral load at day 100, and any patient experiencing CMV disease with a positive CMV viral load.…”

“…5,6 A similar incidence of resistance following 100 days of VGCV prophylaxis was also reported in the kidney transplant setting. 13 Analysis of UL97, but not UL54, detected a known GCV resistance mutation in 1/23 patients experiencing CMV antigenemia or DNAemia during or at the end of VGCV prophylaxis.…”

Temporal and Spatial Compartmentalization of Drug-Resistant Cytomegalovirus (CMV) in a Child with CMV Meningoencephalitis: Implications for Sampling in Molecular Diagnosis

“…At the time of diagnosis of CMV meningoencephalitis, the child had being treated with VACV prophylaxis for 9 months. Few previous retrospective reports supported the idea of selection of mutations conferring GCV/ACV cross-resistance (14)(15)(16). Further large prospective studies are needed to accurately assess the risk of selecting CMV mutations in UL97 and/or UL54 genes under conditions of ACV/ VACV prophylaxis.…”

Early Selection of a New UL97 Mutant with a Severe Defect of Ganciclovir Phosphorylation after Valaciclovir Prophylaxis and Short-Term Ganciclovir Therapy in a Renal Transplant Recipient

“…Michel et al (17) demonstrated in vitro selection of CMV resistant to ganciclovir from clinical isolates under selection pressure from acyclovir. In vivo, two recent studies have described the emergence of ganciclovir-resistant CMV after acyclovir or valacyclovir prophylaxis in transplant recipients (1,10), but the susceptibility of CMV isolates to acyclovir has not been assessed. In our case report, isolate G1 recovered after valacyclovir administration was susceptible to ganciclovir and acyclovir and antigenemia levels rapidly decreased under ganciclovir induction treatment, whereas G2 was eightfold less susceptible to ganciclovir and twofold less susceptible to acyclovir than G1 was.…”