Emergence of letermovir resistance in a lung transplant recipient with ganciclovir‐resistant cytomegalovirus infection

Following a year of valganciclovir prophylaxis, a lung transplant recipient developed cytomegalovirus (CMV) infection that became resistant to ganciclovir, as confirmed by detection of UL97 kinase mutation M460V and a previously uncharacterized UL54 DNA polymerase mutation L516P. The latter mutation is now shown to confer ganciclovir and cidofovir resistance. As predicted from the viral genotype, foscarnet therapy was effective, but resumption of valganciclovir as secondary prophylaxis resulted in a plasma viral load rebound to 3.6 log10copies/mL several weeks later. Valganciclovir was then replaced by letermovir, resulting in gradual viral load reduction in the first 5 weeks to below the quantitation limit (2.7 log10copies/mL) for 1 week, followed by 10 weeks of rising viral loads reaching 4.3 log10copies/mL while on letermovir. At this point, CMV genotypic testing revealed UL56 mutation C325Y, which confers absolute resistance to letermovir. Retreatment with foscarnet was successful. This case adds to the considerable list of proven ganciclovir resistance mutations, and provides an early experience with letermovir resistance after off‐label therapeutic use. This experience is consistent with in vitro observations of rapid emergence of letermovir‐resistant CMV after drug exposure. A case of high‐grade letermovir resistance developing over a 15‐week treatment course suggests caution in the off‐ label use of this new antiviral drug for ganciclovir‐resistant cytomegalovirus infection.