Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus


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Abstract

The human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir is in Phase III clinical trials as antiviral therapy, including use for infections refractory or resistant to standard therapy. To assess its activity in combination with approved and experimental CMV antivirals, and with the mTor inhibitor rapamycin (sirolimus), drug effects were tested by in vitro checkerboard assays and the data were analyzed using a three dimensional model based on an independent effects definition of additive interactions. Baseline virus and representative drug-resistant mutants were tested. According to the volume of synergy at 95% confidence, maribavir showed additive interactions with foscarnet, cidofovir, letermovir and GW275175X when tested against wild type and mutant viruses, strong antagonism with ganciclovir, and strong synergy with rapamycin, the latter suggesting a potentially useful therapeutic combination.HighlightsMaribavir was tested for anti-CMV effect in vitro in combination with other antivirals or with rapamycin (sirolimus).Multiple checkerboard assays were analyzed using a 3-dimensional independent effects model.Maribavir showed additive interactions with foscarnet, cidofovir, letermovir and GW275175XThe combination of maribavir and ganciclovir is confirmed to be strongly antagonistic.The strongly synergistic combination of maribavir and sirolimus may be therapeutically useful.

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