Affiliation:
1. Oregon Health and Science University and Veterans Affairs Health Care System, Portland, Oregon, USA
2. Shire Human Genetic Therapies Inc., a Takeda Company, Lexington, Massachusetts, USA
3. Harvard Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA
Abstract
Abstract
Background
In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks.
Methods
Baseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility.
Results
Baseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone.
Conclusions
After maribavir therapy (400–1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy.
Clinical Trials Registration
NCT01611974 and EudraCT 2010-024247-32.
Funder
National Institutes of Health
National Institute of Allergy and Infectious Diseases
Shire Human Genetic Therapies, Inc.
Shire Development LLC
Department of Veterans Affairs
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Immunology and Allergy
Cited by
37 articles.
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