Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1117-1126
Number of pages10
JournalJournal of Infectious Diseases
Volume221
Issue number7
DOIs
StatePublished - Mar 16 2020

Keywords

  • Antiviral drug resistance
  • Cytomegalovirus
  • Letermovir
  • Prophylaxis
  • RAV

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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