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Clinical Trial
. 2024 Feb 14;229(2):413-421.
doi: 10.1093/infdis/jiad293.

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

Sunwen Chou  1   2 , Sophie Alain  3 , Carlos Cervera  4 , Roy F Chemaly  5 , Camille N Kotton  6 , Jens Lundgren  7 , Genovefa A Papanicolaou  8   9 , Marcus R Pereira  10 , Jingyang J Wu  11 , Rose Ann Murray  11 , Neil E Buss  12 , Martha Fournier  11
Affiliations
Clinical Trial

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

Sunwen Chou et al. J Infect Dis. .

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: antiviral drug resistance; antiviral therapy; cytomegalovirus; maribavir.

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Conflict of interest statement

Potential conflicts of interest . J. J. W., R. A. M., and M. F. are Takeda employees and stockholders. N. E. B. is a paid consultant for Takeda. S. A. reports research grants or contracts paid to institution from BioMérieux, Biotest, Elitech, Hologic, Merck, Merck Sharp & Dohme, and Takeda; honoraria for lectures paid to institution from Biotest, Merck Sharp & Dohme France, and Takeda; support for attending meetings from Biotest, Merck Sharp & Dohme France; advisory board paid to institution from Biotest, Merck Sharp & Dohme, and Takeda; and primary investigator for Solstice 303 study in France. C. C. reports consulting fees from Merck and Takeda; honoraria for lectures from Avir Pharma and Takeda; and advisory board membership for Takeda. R. F. C. reports consultancy fees from Merck/MSD, Oxford Immunotec, Takeda, and Viracor-Eurofins. C. N. K. reports paid consultant/clinical trial adjudication, honoraria for lectures, meeting support, and expert testimony for Takeda. J. L. reports research grants from the Danish Government, Danish National Research Foundation, and National Institutes of Allergy and Infectious Diseases. G. A. P. has received partial funding from P30 CA008748 Cancer Center Support Grant; and consulting fees from AlloVir, Cidara, Octapharma, Takeda, MSK, Symbio, and Vera Armatta; research funding paid to the institution from MSD and Takeda; and honoraria from MSD. M. R. P. reports consulting fees from Union Therapeutics; honoraria for presentations from Takeda; and advisory board membership for Takeda. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Baseline drug resistance mutations by assigned drug and viral gene. Asterisks indicate number of patients with genotyping in the indicated gene, and in square brackets the number of patients with incomplete data for the gene. Abbreviations: DRM, drug resistance mutation; IAT, investigator-assigned therapy.
Figure 2.
Figure 2.
Treatment-emergent drug resistance mutations by patient category. Each treatment and outcome category is listed in bold with the number of patients (n). The number and percent of each group that developed maribavir-DRMs or IAT-DRMs is listed. UL97 F342Y and C480F are counted under both maribavir-DRMs and IAT-DRMs, and also listed separately if present. Abbreviations: DRM, drug resistance mutation; IAT, investigator-assigned therapy.
See this image and copyright information in PMC

References

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