Discussion

This case series describes our real-world utilization of maribavir for CMV in adult SOTR who were primarily intolerant or resistant to first-line agents, aligning with international consensus guideline recommendations. ^{Reference Kotton, Kumar and Manuel2} Clinical success (60.9%) was consistent with previously published trials and observational studies. ^{Reference Avery, Alain and Alexander3–Reference Sabatino, Hedvat, Salerno, Pereira and Lange6}

Emergence of maribavir resistance remains a significant concern, which was corroborated in our series, as 39% of episodes led to high level maribavir resistance during or after treatment. ^{Reference Avery, Alain and Alexander3–Reference Sabatino, Hedvat, Salerno, Pereira and Lange6} Optimal CMV VL to initiate maribavir is an important stewardship consideration. While studies have not shown a significant correlation between baseline CMV VL and maribavir response or development of resistance, there appears to be a declining response to maribavir when initiated at a higher CMV VL. ^{Reference Avery, Alain and Alexander3} Some experts recommend initiating maribavir at lower CMV VL, such as <50,000 IU/mL or ideally <5,000–10,000 IU/mL. ^{Reference Kotton, Kumar and Manuel2,Reference Pham and Razonable7} Given no foscarnet resistance was identified in our cohort and 12/14 (86%) of successful maribavir courses in our study were initiated when CMV VL was <10,000 IU/mL, our data support the transition to maribavir after CMV VL has significantly declined. Our stewardship practice has evolved to start maribavir when CMV VL is <10,000 IU/mL, whenever feasible

Despite initial success, 35% of patients developed CMV recurrence within 4 weeks of discontinuing maribavir, aligning with findings from other observational cohorts (33%–45%), but higher than observed in the randomized clinical trial (26%). ^{Reference Avery, Alain and Alexander3–Reference Sabatino, Hedvat, Salerno, Pereira and Lange6} Management after maribavir treatment success was heterogenous, as some continued maribavir treatment despite response, discontinued therapy, or implemented secondary prophylaxis, highlighting areas for stewardship intervention. In the 3 patients who developed recurrence with maribavir resistance, maribavir was extended for a median of 33 days after achieving initial treatment success. Perhaps continued antiviral exposure, despite low VL, placed additional selective pressure and increased resistance risk. ^{Reference Gardiner, Chow, Price, Nierenberg, Kent and Snydman8} While none of our patients had a CMV-cell mediated immunity (CMV-CMI) assay, CMV-CMI monitoring is a promising opportunity for AS to individualize duration of therapy and secondary prophylaxis, as it may reduce relapse and recurrent CMV. ^{Reference Doligalski, Bartelt, Lachiewicz and Chandran9} Lastly, secondary prophylaxis with letermovir may be another intriguing option as it has been associated with corresponding acquisition of CMV-CMI. ^{Reference Jorgenson, Kleiboeker and Garg10}

This study is limited by its retrospective and single center design, small cohort, single electronic health record, and lack of comparator group precluding inferential analysis. We were unable to assess immunosuppression modifications during CMV treatment, which may influence treatment outcomes or resistance acquisition. Lastly, given the lack of an institutional CMV treatment protocol, CMV management remains heterogenous. Utilization of adjunctive therapies, treatment duration, and decision to use secondary prophylaxis, was at the discretion of the treating provider, which may influence outcomes.

Maribavir is an important therapeutic advancement in the management of R/R CMV infection. Ongoing AS efforts focused on treatment timing, immune guided-management, and duration optimization are paramount to maximizing treatment success and preserving maribavir’s efficacy.