Cameron M Douglas1, Richard Barnard1, Daniel Holder2, Randi Leavitt3, Diane Levitan4, Maureen Maguire4, David Nickle5, Valerie Teal2, Hong Wan2, Dirk C J G van Alewijk6, Leen-Jan van Doorn6, Sunwen Chou7, Julie Strizki1. 1. Infectious Disease Research, Merck & Co., Inc., Kenilworth, New Jersey, USA. 2. Biostatistics and Research Decision Sciences, Merck & Co., Inc., Kenilworth, New Jersey, USA. 3. Clinical Research, Merck & Co., Inc., Kenilworth, New Jersey, USA. 4. Translational Molecular Biomarkers, Merck & Co., Inc., Kenilworth, New Jersey, USA. 5. Pharmacogenomics and Genetics, Merck & Co., Inc., Kenilworth, New Jersey, USA. 6. DDL Diagnostics Laboratory, Rijswijk, the Netherlands. 7. Department of Veterans Affairs Medical Center, Oregon Health and Science University, Portland, Oregon, USA.
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.
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: I Buerger; J Reefschlaeger; W Bender; P Eckenberg; A Popp; O Weber; S Graeper; H D Klenk; H Ruebsamen-Waigmann; S Hallenberger Journal: J Virol Date: 2001-10 Impact factor: 5.103
Authors: Nicholas Turner; Andrew Strand; Dilraj S Grewal; Gary Cox; Sana Arif; Arthur W Baker; Eileen K Maziarz; Jennifer H Saullo; Cameron R Wolfe Journal: Antimicrob Agents Chemother Date: 2019-02-26 Impact factor: 5.191
Authors: Roy F Chemaly; Andrew J Ullmann; Susanne Stoelben; Marie Paule Richard; Martin Bornhäuser; Christoph Groth; Hermann Einsele; Margarida Silverman; Kathleen M Mullane; Janice Brown; Horst Nowak; Katrin Kölling; Hans P Stobernack; Peter Lischka; Holger Zimmermann; Helga Rübsamen-Schaeff; Richard E Champlin; Gerhard Ehninger Journal: N Engl J Med Date: 2014-05-08 Impact factor: 91.245
Authors: Jennifer L Saullo; Arthur W Baker; Laurie D Snyder; John M Reynolds; Lorenzo Zaffiri; Emily M Eichenberger; Alana Ferrari; Julie M Steinbrink; Eileen K Maziarz; Melissa Bacchus; Holly Berry; Stylianos A Kakoullis; Cameron R Wolfe Journal: J Heart Lung Transplant Date: 2021-12-22 Impact factor: 13.569
Authors: Beatrice Mercorelli; Anna Luganini; Marta Celegato; Giorgio Palù; Giorgio Gribaudo; Galina I Lepesheva; Arianna Loregian Journal: Antimicrob Agents Chemother Date: 2020-09-21 Impact factor: 5.191
Authors: Beatrice Mercorelli; Marta Celegato; Anna Luganini; Giorgio Gribaudo; Galina I Lepesheva; Arianna Loregian Journal: Antiviral Res Date: 2021-03-13 Impact factor: 5.970