OUP accepted manuscript

OBJECTIVES To analyse mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis. METHODS Mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis were analysed in four patients from the French Named Patient Programme by the French National Reference Centre for Herpesviruses. RESULTS Of three absolute resistance cases, two were associated with treatment interruption or low letermovir concentrations in blood. A fourth case of breakthrough was not associated with resistance. Next-generation sequencing (NGS) genotyping confirmed rapid emergence of resistant mutants, within 3 months of treatment initiation. CONCLUSIONS Measurement of letermovir concentration and genotyping should be recommended for patient follow-up during letermovir therapy.