Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection

Background. Among 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug. Methods. Viral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and posttreatment. Results. Prior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n = 241) received valganciclovir or maribavir for at least 21 days (median, 55–56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35–125 days (median, 56 days) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66–110 days (median, 90 days). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after retreatment with an alternative CMV antiviral drug. Conclusions. After 3–8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy.