Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients

Authors

Sunwen Chou
Sophie Alain
Carlos Cervera
Roy F Chemaly
Camille N Kotton
Jens Lundgren
Genovefa A Papanicolaou
Marcus R Pereira
Jingyang J Wu
Rose Ann Murray
Neil E Buss
Martha Fournier

Publication Date

2-14-2024

Journal

The Journal of Infectious Diseases

Abstract

Background: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).

Methods: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.

Results: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir.

Conclusions: Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance.

Clinical trials registration: NCT02931539.

Keywords

Humans, Antiviral Agents, Benzimidazoles, Cytomegalovirus, Cytomegalovirus Infections, Dichlororibofuranosylbenzimidazole, DNA, Drug Resistance, Viral, Ganciclovir, Mutation, Phosphotransferases (Alcohol Group Acceptor), Ribonucleosides, Transplant Recipients, antiviral drug resistance, antiviral therapy, cytomegalovirus, maribavir

DOI

10.1093/infdis/jiad293

PMID

37506264

PMCID

PMC10873177

PubMedCentral® Posted Date

7-28-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes