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Antiviral Research Sep 2021Because ganciclovir resistance mutations in the cytomegalovirus UL97 gene most commonly occur at codons 460, 520 and 590-607, diagnostic genotyping for drug resistance...
Because ganciclovir resistance mutations in the cytomegalovirus UL97 gene most commonly occur at codons 460, 520 and 590-607, diagnostic genotyping for drug resistance has often omitted the analysis of codons below 440. However, the UL97 kinase inhibitor maribavir selects for distinctive resistance mutations at codons 409 and 411, and ganciclovir/maribavir resistance mutations have also been described in the ATP binding region starting at codon 335. Expanded genotypic testing of UL97 codons 335-440 in 1535 clinical specimens disclosed 10 uncharacterized sequence variants that were phenotyped for ganciclovir and maribavir susceptibility. Notable findings included low-grade ganciclovir resistance conferred by amino acid substitutions K359N and E362D, decreased maribavir susceptibility of L348V, and maribavir hypersensitivity of V345I and E362D. Recently published substitutions F342Y and K359E/Q were also confirmed. The data indicate that mutations in the UL97 ATP binding region may arise in clinical specimens to affect the interpretation of ganciclovir and maribavir resistance. This region should now be included in the standard diagnostic genotyping of UL97, especially with the introduction of maribavir into therapeutic use.
Topics: Adenosine Triphosphate; Amino Acid Substitution; Antiviral Agents; Benzimidazoles; Codon; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Genotyping Techniques; Humans; Mutation; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides
PubMed: 34273445
DOI: 10.1016/j.antiviral.2021.105139 -
Nature Reviews. Microbiology Dec 2021Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by... (Review)
Review
Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by a vigorous immune response so that infections are asymptomatic or symptoms are mild. However, if the immune system is compromised, HCMV can replicate to high levels and cause serious end organ disease. Substantial progress is being made in understanding the natural history and pathogenesis of HCMV infection and disease in the immunocompromised host. Serial measures of viral load defined the dynamics of HCMV replication and are now used routinely to allow intervention with antiviral drugs in individual patients. They are also used as pharmacodynamic read-outs to evaluate prototype vaccines that may protect against HCMV replication and to define immune correlates of this protection. This novel information is informing the design of randomized controlled trials of new antiviral drugs and vaccines currently under evaluation. In this Review, we discuss immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Humans; Immunity; Immunocompromised Host; Randomized Controlled Trials as Topic; Viral Load; Virus Replication
PubMed: 34168328
DOI: 10.1038/s41579-021-00582-z -
Journal of Clinical Microbiology Feb 2021
PubMed: 33826526
DOI: 10.1128/JCM.00119-20 -
Journal of Clinical Microbiology Feb 2021
PubMed: 33826525
DOI: 10.1128/JCM.00118-20 -
International Journal of Molecular... Jan 2021Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that...
Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs' antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.
Topics: Aminopyridines; Animals; Antiviral Agents; Benzimidazoles; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Combinations; Drug Resistance, Viral; Ganciclovir; Humans; Mice; Protein Kinase Inhibitors; Pyrazoles; Ribonucleosides; Triazines; Virus Replication
PubMed: 33430060
DOI: 10.3390/ijms22020575 -
Antimicrobial Agents and Chemotherapy Dec 2020Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation, lifelong disease, and, in severe cases, fetal or neonatal death. Placental...
Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation, lifelong disease, and, in severe cases, fetal or neonatal death. Placental infection with HCMV is the major mechanism of mother-to-child transmission (MTCT) and fetal injury. Thus, any pharmaceutical antiviral interference to reduce viral load may reduce placental damage, MTCT, and fetal disease. However, there is currently no licensed HCMV antiviral for use during pregnancy. In this study, aciclovir and the HCMV-specific antivirals letermovir, maribavir, and cidofovir were compared with ganciclovir for antiviral effects in model systems of pregnancy, including first-trimester TEV-1 trophoblast cell cultures and third-trimester placental explant histocultures. HCMV-infected trophoblasts at 7 days postinfection (dpi) showed an EC of 21 μM for aciclovir, 0.0007 μM for letermovir, 0.11 μM for maribavir, and 0.29 μM for cidofovir, relative to 0.42 μM for ganciclovir. Antivirals added at 10 μM showed no cytotoxic effects and did not affect trophoblast cell proliferation ( > 0.9999). Multiple-round HCMV replication measured at 7 dpi showed letermovir, maribavir, and cidofovir treatment inhibited immediate early, early, and true late viral protein expression as assayed on Western blots. Antiviral treatment of HCMV-infected placental explants showed significant inhibition ( 0.05) of viral replication with letermovir (83.3%), maribavir (83.6%), cidofovir (89.3%), and ganciclovir (82.4%), but not aciclovir ( > 0.9999). In model systems, recently trialed HCMV antivirals letermovir and maribavir were effective at inhibiting HCMV replication. They partly fulfil requirements for use as safe and effective therapeutics during pregnancy to control congenital HCMV. Clinical trials of these newer agents would assist assessment of their utility in pregnancy.
Topics: Antiviral Agents; Child; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Placenta; Pregnancy; Virus Replication
PubMed: 33077661
DOI: 10.1128/AAC.01627-20 -
Molecules (Basel, Switzerland) Oct 2020The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the...
The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure-activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.
Topics: Antiviral Agents; Benzimidazoles; Cell Line; Cytomegalovirus; Glycosylation; Humans; Imidazoles; Nucleosides; Pyridines; Ribonucleosides
PubMed: 33022923
DOI: 10.3390/molecules25194531 -
The Journal of Infectious Diseases Sep 2022In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for...
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.
Topics: Humans; Cytomegalovirus; Drug Resistance, Viral; Antiviral Agents; Phosphotransferases (Alcohol Group Acceptor); Cytomegalovirus Infections; Ganciclovir; Mutation; Phenotype
PubMed: 32726419
DOI: 10.1093/infdis/jiaa462 -
Clinical and Translational Science Nov 2020Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation....
Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline-adjusted and placebo-adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo-controlled, four-period crossover study in healthy participants (men and women ages 18-50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study's ability to detect QT prolongation. Digital 12-lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia's, and Bazett's QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100-mg and 1200-mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two-sided 90% confidence interval was below the 10-ms threshold at all time points. The concentration-effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.
Topics: Administration, Oral; Adolescent; Adult; Antiviral Agents; Benzimidazoles; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dysgeusia; Electrocardiography; Female; Healthy Volunteers; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Moxifloxacin; Ribonucleosides; Young Adult
PubMed: 32506738
DOI: 10.1111/cts.12814 -
PloS One 2020Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome....
Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection.
BACKGROUND
Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment.
METHODS
The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)).
RESULTS
For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively.
CONCLUSIONS
Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.
Topics: Acetates; Adult; Antiviral Agents; Benzimidazoles; Chromatography, Liquid; Cytomegalovirus Infections; Female; Humans; Kinetics; Maternal-Fetal Exchange; Models, Biological; Perfusion; Placenta; Pregnancy; Quinazolines; Ribonucleosides; Tandem Mass Spectrometry
PubMed: 32353010
DOI: 10.1371/journal.pone.0232140