Letermovir Resistance Analysis in a Clinical Trial of Cytomegalovirus Prophylaxis for Hematopoietic Stem Cell Transplant Recipients.

Abstract

BACKGROUND:

Letermovir (LET), a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) terminase inhibitor, was recently approved for prophylaxis of CMV infection in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. Cytomegalovirus genotyping was performed to identify LET-resistance-associated variants (RAVs) among subjects in a Phase 3 trial.

METHODS:

The CMV UL56 and UL89 genes, encoding subunits of CMV DNA terminase, were sequenced from plasma collected from subjects with clinically significant CMV infection (CS-CMVi). Novel variants were evaluated by recombinant phenotyping to assess their potential to confer resistance to LET.

RESULTS:

Genotyping was successful for 50 of 79 LET subjects with CS-CMVi. Resistance-associated variants (encoding pUL56 V236M and C325W) were detected independently in subjects 1 and 3 who experienced CS-CMVi while receiving LET prophylaxis, and 2 other variants (encoding pUL56 E237G and R369T) were detected >3 weeks after subjects 2 and 3, respectively, had discontinued LET prophylaxis and received preemptive therapy with ganciclovir.

CONCLUSIONS:

The detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low. The LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture.

• Authors: Cameron M Douglas, Richard Barnard, Daniel Holder, Randi Leavitt, Diane Levitan, Maureen Maguire, David Nickle, Valerie Teal, Hong Wan, Dirk C J G van Alewijk, Leen-Jan van Doorn, Sunwen Chou, Julie Strizki
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 221 Issue 7 Pg. 1117-1126 (03 16 2020) ISSN: 1537-6613 [Electronic] United States
• PMID: 31781762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Acetates
• Antiviral Agents
• Quinazolines
• letermovir

Topics

• Acetates (pharmacology, therapeutic use)
• Antibiotic Prophylaxis
• Antiviral Agents (pharmacology, therapeutic use)
• Clinical Trials, Phase III as Topic
• Cytomegalovirus (drug effects, genetics)
• Cytomegalovirus Infections (drug therapy, prevention & control, virology)
• Drug Resistance, Viral (drug effects, genetics)
• Hematopoietic Stem Cell Transplantation
• Humans
• Mutation (genetics)
• Quinazolines (pharmacology, therapeutic use)
• Randomized Controlled Trials as Topic