Reversion of Val(Ganciclovir)-Resistance-Associated Mutations in Two SOT Patients with Mismatched Serostatus for CMV (D+/R-)

The emergence of drug-resistant cytomegalovirus (CMV) complicates viral response to therapy. We present two cases of solid organ transplant (SOT) recipients, highlighting the reversion of UL97 mutations associated with val(ganciclovir) resistance. Patient 1, a heart transplant recipient, initially received pre-emptive treatment with val(ganciclovir), followed by foscarnet for recurrent CMV episodes. Mutations A594V in the UL97-kinase gene and V715M in the UL54-polymerase gene were detected. He developed CMV colitis and was then treated with maribavir. After discontinuing val(ganciclovir), genotyping revealed no resistance mutations. Following CMV DNA suppression, secondary prophylaxis with letermovir and val(ganciclovir) was initiated. Patient 2, a double-lung transplant recipient, experienced several CMV episodes. Initially treated with val(ganciclovir), he developed the L595S mutation in the UL97 kinase gene, conferring resistance. Therapy was then switched to foscarnet, which was suspended due to renal failure, and then to maribavir. Subsequently, the H411Y mutation in the UL97 was detected, conferring maribavir resistance, while val(ganciclovir) mutation was no longer detectable. He was then treated with val(ganciclovir) and letermovir, achieving undetectable CMV DNA, and then continued letermovir alone as prophylaxis. Detecting gene mutations that confer drug resistance is crucial for managing antiviral therapy when virological response is lacking. In our cases, the reversion of (va)ganciclovir-resistance mutations occurred after drug withdrawal, a previously unreported finding.