162 results on '"Maribavir"'
Search Results
2. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies
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Niyati Jakharia, David J. Riedel, and Dianna S. Howard
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Cultural Studies ,Oncology ,Linguistics and Language ,History ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Language and Linguistics ,Letermovir ,Immune system ,Immunity ,Internal medicine ,medicine ,Transplant/Immunocompromised Hosts (M Morales, Section Editor) ,business.industry ,virus diseases ,Maribavir ,Cytomegalovirus ,Clinical trial ,medicine.anatomical_structure ,Anthropology ,business ,CMV infection ,medicine.drug - Abstract
Purpose of Review Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients. Recent Findings The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial. Summary CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.
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- 2021
3. Phenotype and Genotype Study of Novel C480F Maribavir-Ganciclovir Cross-Resistance Mutation Detected in Hematopoietic Stem Cell and Solid Organ Transplant Recipients
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Nuria Fernández, Francesc Fernández Avilés, María del Mar Mosquera Gutiérrez, María Suarez Lledo, Marta Santos Bravo, Nicolas Plault, Montserrat Rovira, Sonsoles Sánchez Palomino, M Ángeles Marcos Maeso, and Sophie Alain
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Adult ,Ganciclovir ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Antiviral Agents ,Drug Resistance, Viral ,Genotype ,medicine ,Humans ,Immunology and Allergy ,Cross-resistance ,Kidney ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Hematopoietic stem cell ,Maribavir ,Organ Transplantation ,Hematopoietic Stem Cells ,medicine.disease ,Kidney Transplantation ,Virology ,Transplant Recipients ,Transplantation ,Phosphotransferases (Alcohol Group Acceptor) ,Treatment Outcome ,Infectious Diseases ,medicine.anatomical_structure ,Cytomegalovirus Infections ,Mutation ,Benzimidazoles ,Female ,Ribonucleosides ,business ,medicine.drug - Abstract
Two transplant recipients (1 kidney and 1 hematopoietic stem cell) received maribavir (MBV) after cytomegalovirus (CMV) infection clinically resistant to standard therapy. Both patients achieved CMV DNA clearance within 30 and 18 days; however, the UL97 C480F variant emerged, causing recurrent CMV infection after a cumulative 2 months of MBV and 15 or 4 weeks of ganciclovir treatment, respectively. C480F was not detected under ganciclovir before MBV treatment. Recombinant phenotyping showed that C480F conferred the highest level of MBV resistance and ganciclovir cross-resistance, with impaired viral growth. Clinical follow-up and genotypic and phenotypic studies are essential for the assessment and optimization of patients with suspected MBV resistance.
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- 2021
4. Advances in drug therapies for cytomegalovirus in transplantation: a focus on maribavir and letermovir
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Raymund R. Razonable and Jackrapong Bruminhent
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Drug ,medicine.medical_specialty ,medicine.medical_treatment ,media_common.quotation_subject ,Congenital cytomegalovirus infection ,Drug resistance ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,medicine ,Pharmacology (medical) ,Intensive care medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,media_common ,business.industry ,Health Policy ,virus diseases ,Maribavir ,Immunosuppression ,medicine.disease ,Cytomegalovirus infection ,Transplantation ,030220 oncology & carcinogenesis ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Cytomegalovirus (CMV) challenges physicians who care for immunocompromised transplant recipients. Antiviral drugs are the cornerstone in the prevention and treatment of CMV disease, but they have t...
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- 2020
5. Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection
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Jingyang Wu, Clyde S. Crumpacker, Kening Song, Sunwen Chou, and Tien Bo
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Congenital cytomegalovirus infection ,Cytomegalovirus ,Drug resistance ,medicine.disease_cause ,Antiviral Agents ,Asymptomatic ,Drug Resistance, Viral ,medicine ,Humans ,Immunology and Allergy ,Ganciclovir ,Genotyping ,Mutation ,business.industry ,Maribavir ,medicine.disease ,Phenotype ,Virology ,Clinical trial ,Phosphotransferases (Alcohol Group Acceptor) ,Infectious Diseases ,Cytomegalovirus Infections ,medicine.symptom ,business - 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 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.
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- 2020
6. Evaluation of the Effect of Maribavir on Cardiac Repolarization in Healthy Participants: Thorough QT/QTc Study
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Katarina Ilic, Ivy H. Song, Patrick Martin, and Jingyang Wu
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Adult ,Male ,030213 general clinical medicine ,medicine.medical_specialty ,Adolescent ,Moxifloxacin ,Administration, Oral ,Blood Pressure ,Dysgeusia ,Antiviral Agents ,030226 pharmacology & pharmacy ,QT interval ,Article ,General Biochemistry, Genetics and Molecular Biology ,Electrocardiography ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Heart Rate ,Internal medicine ,Heart rate ,Humans ,Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Adverse effect ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Research ,General Neuroscience ,Maribavir ,Articles ,General Medicine ,Middle Aged ,Crossover study ,Healthy Volunteers ,Transplantation ,Long QT Syndrome ,Blood pressure ,Tolerability ,Cardiology ,Benzimidazoles ,Female ,Ribonucleosides ,business - Abstract
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.
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- 2020
7. Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence
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Michael Boeckh, Ghady Haidar, and Nina Singh
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0301 basic medicine ,Neutropenia ,Time Factors ,medicine.medical_treatment ,Clinical Decision-Making ,030106 microbiology ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Supplement Articles ,Viremia ,Disease ,Hematopoietic stem cell transplantation ,030230 surgery ,Antiviral Agents ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Disease Management ,virus diseases ,Viral Vaccines ,Maribavir ,Organ Transplantation ,medicine.disease ,Tissue Donors ,Transplant Recipients ,Transplantation ,Infectious Diseases ,Cytomegalovirus Infections ,Immunology ,Pre-Exposure Prophylaxis ,Disease Susceptibility ,business ,Viral load ,medicine.drug - Abstract
This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.
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- 2020
8. New advances in the management of cytomegalovirus in allogeneic haemopoietic stem cell transplantation
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Ashish Bajel, Julian Lindsay, David Gottlieb, Monica A. Slavin, Michelle K Yong, Andrew Grigg, David Ritchie, Jen Kok, and William D. Rawlinson
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Ganciclovir ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Hematopoietic stem cell transplantation ,030204 cardiovascular system & hematology ,Antiviral Agents ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,Valganciclovir ,medicine.disease ,Transplantation ,Cytomegalovirus Infections ,business ,Viral load ,medicine.drug - Abstract
Cytomegalovirus (CMV) viraemia continues to be a frequent complication in the post-haemopoietic stem cell transplantation period despite a low incidence of CMV end-organ disease. Several significant advances in the understanding and management of CMV infection have occurred in the last few years including improved diagnostics, monitoring of CMV immunity, availability of novel anti-CMV drugs, and emerging use of immunotherapies including CMV-specific T-cell infusions. In addition to reviewing these advances we also explore some of the more practical prescribing issues of the older and newer CMV drugs including cost, toxicity and drug interactions to help clinicians navigate this new era of CMV management.
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- 2020
9. Human Cytomegalovirus Prophylaxis and Treatment in Lung Transplantation in the Current Era
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Kathleen M. Mullane
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Human cytomegalovirus ,medicine.medical_specialty ,education.field_of_study ,business.industry ,viruses ,medicine.medical_treatment ,Population ,Pharmaceutical Science ,Maribavir ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Clinical trial ,Letermovir ,Immune system ,Complementary and alternative medicine ,Immunity ,medicine ,Lung transplantation ,Pharmacology (medical) ,Intensive care medicine ,education ,business ,medicine.drug - Abstract
Human cytomegalovirus (HCMV) is an important cause of morbidity and mortality in solid organ transplantation with lung transplant recipients being at highest risk. This article sumarizes recent findings in the pathophysiology of HCMV, especially its effects in lung transplant recipients; the current and new modalities for treatment and prevention of infection; and the latest guidelines for prevention and management of HCMV in lung transplant recipients. Recent findings include moves towards standardization for monitoring and treating HCMV and approval of a new agent, letermovir, for prevention of HCMV reactivation in hematopoietic cell transplant recipients now in clinical trials for solid organ transplant recipients, and updates on the late stage development of maribavir. The newest innovations include promising vaccine candidates as well as adoptive cell-mediated immunity through the use of virus-specific cytotoxic T cells. Finally, assays evaluating HCMV immune function to aid in the evaluation of individual patient’s ability to have a cell-mediated immune response to CMV are being developed. In the past 15 years major advances in diagnosis, prevention, management and risk evaluation in patients with HCMV have occurred, and research continues, which will impact outcomes in the transplant population.
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- 2020
10. Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy
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Morgan Hakki
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Foscarnet ,Ganciclovir ,Cancer Research ,medicine.medical_specialty ,T-Lymphocytes ,Cytomegalovirus ,Opportunistic Infections ,medicine.disease_cause ,Antiviral Agents ,Immunotherapy, Adoptive ,Cytomegalovirus Vaccines ,Immunocompromised Host ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,Immune system ,Risk Factors ,Internal medicine ,Drug Resistance, Viral ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Antiviral ,Hematopoietic cell transplant ,Hematology ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,Virology ,Stem Cell Transplantation (R Maziarz, Section Editor) ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cytomegalovirus Infections ,DNA Polymerase Inhibitor ,Immunotherapy ,business ,Filociclovir ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
Purpose of Review CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection. Recent Findings Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. Summary No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
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- 2020
11. Update on cytomegalovirus in transplant recipients: new agents, prophylaxis, and cell-mediated immunity
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Robin K. Avery and Oriol Manuel
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Microbiology (medical) ,medicine.medical_specialty ,Post hoc ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Antiviral Agents ,law.invention ,Letermovir ,Immune system ,Randomized controlled trial ,law ,medicine ,Humans ,Intensive care medicine ,Immunity, Cellular ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,medicine.disease ,Cell mediated immunity ,Transplant Recipients ,Cytomegalovirus infection ,Infectious Diseases ,Cytomegalovirus Infections ,business ,medicine.drug - Abstract
Purpose of review This review is an overview of recent advances in diagnostics, therapies, and prevention strategies for cytomegalovirus (CMV), focusing on solid-organ transplant and hematopoietic stem cell transplant recipients. Recent findings A randomized trial of prophylaxis vs preemptive therapy in donor-seropositive, recipient-seronegative liver transplant recipients found significantly less CMV disease in the preemptive group. Maribavir has shown promise for the treatment of resistant/refractory CMV and for uncomplicated CMV DNAemia. A post hoc mortality analysis, as well as emerging reports of real-world and off-label use, have expanded the spectrum of clinical experience with letermovir. The first interventional trials using CMV cell-mediated immune assays have been published and showed promising results for delineating antiviral strategies. New data from additional interventional trials are expected soon. Summary The past 1-2 years have seen major developments in the area of CMV management in transplant recipients. Expanding diagnostic and therapeutic capabilities provide a foundation for optimizing strategies in the future, to reduce morbidity and mortality from CMV.
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- 2021
12. Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation
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Marc E. Uknis, Jingyang Wu, Catherine Cordonnier, Xavier Poiré, Peter Jaksch, Faouzi Saliba, Oliver Witzke, Johan Maertens, Anna Wijatyk, and Stephen Villano
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Adult ,Male ,Neutropenia ,Gastrointestinal Diseases ,Medizin ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Viremia ,030204 cardiovascular system & hematology ,Dysgeusia ,Antiviral Agents ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,medicine ,Humans ,Valganciclovir ,030212 general & internal medicine ,Aged ,Intention-to-treat analysis ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,Organ Transplantation ,General Medicine ,Middle Aged ,Allografts ,medicine.disease ,Virology ,Intention to Treat Analysis ,Clinical trial ,Cytomegalovirus Infections ,Benzimidazoles ,Female ,Virus Activation ,Ribonucleosides ,business ,medicine.drug - Abstract
Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).
- Published
- 2019
13. Effects of Maribavir on P‐Glycoprotein and CYP2D6 in Healthy Volunteers
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Patrick Martin, Kenneth C. Lasseter, Katarina Ilic, Joseph Murphy, and Ivy H. Song
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Adult ,Male ,Digoxin ,CYP2D6 ,maribavir ,Genotype ,Cmax ,Pharmacology ,Antiviral Agents ,030226 pharmacology & pharmacy ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Dextrorphan ,P‐glycoprotein ,medicine ,Humans ,Drug Interactions ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,cytochrome P450 2D6 ,dextromethorphan ,business.industry ,Maribavir ,Dextromethorphan ,Middle Aged ,Healthy Volunteers ,Confidence interval ,Cytochrome P-450 CYP2D6 ,030220 oncology & carcinogenesis ,Cytomegalovirus Infections ,Benzimidazoles ,Female ,Ribonucleosides ,business ,pharmacokinetics ,medicine.drug - Abstract
Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug‐drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) activity using probe substrates in healthy volunteers. During this phase 1 open‐label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed‐effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin Cmax, AUClast, and AUC0‐∞ with and without maribavir was 1.257 (1.139‐1.387), 1.187 (1.088‐1.296), and 1.217 (1.110‐1.335), respectively, outside the “no‐effect” window (0.8‐1.25). GMR (90%CI) of dextromethorphan AUClast and AUClast ratio of dextromethorphan/dextrorphan were 0.877 (0.692‐1.112) and 0.901 (0.717‐1.133), respectively, marginally outside the no‐effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P‐gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P‐gp substrates should be evaluated individually, and caution should be exercised with P‐gp substrates with narrow therapeutic windows.
- Published
- 2019
14. New vaccines and antiviral drugs for cytomegalovirus
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Paul D. Griffiths
- Subjects
Ganciclovir ,medicine.drug_class ,Cytomegalovirus ,Brincidofovir ,Antiviral Agents ,Cytomegalovirus Vaccines ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,Virology ,medicine ,Humans ,Clinical Trials as Topic ,Transplantation ,business.industry ,Maribavir ,Valganciclovir ,Viral Load ,Combined Modality Therapy ,3. Good health ,Infectious Diseases ,030220 oncology & carcinogenesis ,Cytomegalovirus Infections ,Immunology ,Antiviral drug ,business ,Viral load ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The natural history of cytomegalovirus (CMV) infection in transplant patients has been well established. This virus may originate from the recipient, the donor or both. When pre-transplant IgG antibodies in the recipient are taken into account, three types of infection are possible: primary, reactivation or reinfection. The risks of high viral load and end-organ disease are highest after primary infection and lowest after reactivation. Serial monitoring of patients by quantitative polymerase chain reaction for CMV DNA allows antiviral drugs to be deployed for pre-emptive therapy or an antiviral drug may be given prophylactically. Both of these strategies are effective, but pre-emptive therapy has the advantage that randomised allocation of a new drug or placebo given prophylactically may show a reduced need for pre-emptive valganciclovir. In this review, I will consider what has been learned from use of ganciclovir and valganciclovir and apply this information to clinical trials that have evaluated maribavir, brincidofovir and letermovir. In addition, pre-emptive therapy has the advantage of facilitating the discovery of vaccines against CMV using a pharmacodynamic approach. Briefly, patients awaiting transplantation are given vaccine or placebo pre-transplant. When they proceed to transplantation, various parameters of viral load can be compared to determine if the vaccine has an effect against CMV when compared to patients randomised to receive placebo. If there is evidence of control of CMV, this can be related to immune responses induced by the vaccine to define a correlate of protection. This review will summarise the published evidence available.
- Published
- 2019
15. MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 2
- Author
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V L Andronova
- Subjects
0301 basic medicine ,Ganciclovir ,Foscarnet ,Drug ,Human cytomegalovirus ,viruses ,medicine.medical_treatment ,media_common.quotation_subject ,030106 microbiology ,Cytomegalovirus ,DNA-Directed DNA Polymerase ,Drug resistance ,Pharmacology ,03 medical and health sciences ,Drug Therapy ,Virology ,Drug Resistance, Viral ,Humans ,Medicine ,Nucleic Acid Synthesis Inhibitors ,media_common ,Chemotherapy ,business.industry ,virus diseases ,Maribavir ,General Medicine ,medicine.disease ,Clinical trial ,Infectious Diseases ,Cytomegalovirus Infections ,DNA, Viral ,Benzimidazoles ,Ribonucleosides ,business ,medicine.drug - Abstract
A number of synthetic compounds, such as the nucleoside analog ganciclovir, its L-valine ester (a metabolic precursor of ganciclovir) and pyrophosphate analog foscarnet, are permitted for the treatment of HCMV-related diseases in the WHO European Region. The viral DNA- polymerase is used by all these drugs as a bio-target. However, the usage of standard anti-CMV therapy is accompanied by severe side effects, as well as the development of drug resistance in the virus, mainly in conditions of immunodeficiency. In this review, we focused on viral proteins of interest as new potential targets and their inhibitors, such as the inhibitor of human CMV terminology, lethermovir, which showed great activity in the third phase of clinical trials, inhibitors of viral cyclin-dependent kinase (maribavir, cyclopropavir ) and a number of compounds exhibiting anti-HCMV-activity, undergoing only preclinical trials in the experiment. Inclusion of new anti-CMV agents that are active against GСV/PFA/CDV-resistant strains of CMV into standard prophylactic and therapeutic regimens, will allow to increase the effectiveness of anti-CMV therapy, including in cases when standard therapy is ineffective. Areas covered: the international databases such as A MEDLINE, PubMed, eLIBRARY.RU, ClinicalTrials.gov., etc. with the purpose of obtaining information on compounds showing selective action against the human cytomegalovirus, the most promising for the development of drugs.
- Published
- 2018
16. Answer to March 2021 Photo Quiz
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Magda Mikhail, Jun Yong, James Cruise, Amit Patel, Michael Beadsworth, Nicholas J. Beeching, and Hugh Adler
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0301 basic medicine ,Microbiology (medical) ,integumentary system ,biology ,business.industry ,viruses ,030106 microbiology ,Varicella zoster virus ,virus diseases ,Photo Quiz ,Maribavir ,biology.organism_classification ,medicine.disease_cause ,Virology ,Virus ,Valaciclovir ,03 medical and health sciences ,0302 clinical medicine ,medicine ,030212 general & internal medicine ,business ,Bacteria ,medicine.drug - Abstract
Answer: Disseminated varicella-zoster virus. The patient was prescribed oral valaciclovir when the lesions first appeared, and after 7 days of treatment, most of lesions resolved. PCR of swabs from the lesions was positive for varicella-zoster virus (VZV) DNA. Stains and culture for bacteria, fungi
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- 2021
17. Photo Quiz: Disseminated Violaceous Skin Lesions following Allogeneic Stem Cell Transplant
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Magda Mikhail, Michael Beadsworth, Nicholas J. Beeching, James Cruise, Amit Patel, Hugh Adler, and Jun Yong
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Microbiology (medical) ,Mutation ,Pathology ,medicine.medical_specialty ,business.industry ,Pseudomonas aeruginosa ,Photo Quiz ,Maribavir ,medicine.disease ,medicine.disease_cause ,Leukemia ,Myelogenous ,Medicine ,Stem cell ,business ,Skin lesion ,Transcription factor - Abstract
A 58-year-old man was admitted for management of Pseudomonas aeruginosa infection of his tunneled central venous catheter. Eleven months previously, he had received an allogeneic bone marrow transplant for acute myelogenous leukemia secondary to a mutation in runt-related transcription factor 1 (
- Published
- 2021
18. Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy
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Manfred Marschall, Stuart T. Hamilton, and William D. Rawlinson
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Ganciclovir ,viruses ,Placenta ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,Pregnancy ,medicine ,Humans ,Pharmacology (medical) ,Aciclovir ,Child ,030304 developmental biology ,Pharmacology ,0303 health sciences ,030306 microbiology ,business.industry ,Infant, Newborn ,virus diseases ,Maribavir ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Virology ,Infectious Disease Transmission, Vertical ,Valaciclovir ,Infectious Diseases ,chemistry ,Cytomegalovirus Infections ,Female ,business ,Viral load ,medicine.drug ,Cidofovir - Abstract
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 ex vivo placental explant histocultures. HCMV-infected trophoblasts at 7 days postinfection (dpi) showed an EC(50) 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 (P > 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 (P 0.9999). In ex vivo 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.
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- 2020
19. Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection
- Author
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Julien Stirnemann, Valentine Faure Bardon, Minh Patrick Lê, Gilles Peytavin, Elisabeth Elefant, Yves Ville, Tiffany Guilleminot, Marianne Leruez-Ville, Fetal Medicine and Obstetric Department [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pharmacology & Toxicology Laboratory [Paris], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Virology Laboratory [Paris], National Reference Laboratory for congenital CMV [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the University Paris Descartes., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord
- Subjects
0301 basic medicine ,Cytomegalovirus Infection ,Embryology ,Viral Diseases ,Placenta ,Acetates ,Toxicology ,Pathology and Laboratory Medicine ,Biochemistry ,Letermovir ,0302 clinical medicine ,Pregnancy ,Tandem Mass Spectrometry ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Medicine and Health Sciences ,Medicine ,Maternal-Fetal Exchange ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,030219 obstetrics & reproductive medicine ,Multidisciplinary ,Antimicrobials ,Pharmaceutics ,Drugs ,Maribavir ,Antivirals ,3. Good health ,Perfusion ,medicine.anatomical_structure ,Infectious Diseases ,In utero ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Cytomegalovirus Infections ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Female ,Anatomy ,medicine.drug ,Research Article ,Adult ,Placental cotyledon ,Science ,030106 microbiology ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Antiviral Agents ,Models, Biological ,Microbiology ,Andrology ,03 medical and health sciences ,Drug Therapy ,Albumins ,Microbial Control ,Virology ,Placental Cotyledon ,Humans ,Serum Albumin ,Pharmacology ,Fetus ,Fetuses ,Toxicity ,business.industry ,Reproductive System ,Biology and Life Sciences ,Proteins ,Kinetics ,[SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Quinazolines ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Benzimidazoles ,Ribonucleosides ,business ,Ex vivo ,Chromatography, Liquid ,Developmental Biology - Abstract
International audience; 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.
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- 2020
20. Viral Infections Post Allogeneic Hematopoietic Cell Transplantation (Allo HCT)
- Author
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Seema Naik
- Subjects
Ganciclovir ,Hematopoietic cell ,business.industry ,Maribavir ,Valganciclovir ,General Medicine ,Antimicrobial ,Transplantation ,Haematopoiesis ,Letermovir ,Immunology ,medicine ,business ,medicine.drug - Abstract
Serious viral infections usually occur within the first six months following allogeneic hematopoietic transplant (AlloHCT) [1]...
- Published
- 2020
21. Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study
- Author
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Fernanda P. Silveira, Robin K. Avery, Stephen Villano, Jingyang Wu, Michael Boeckh, Marc E. Uknis, Genovefa A. Papanicolaou, Marcus R. Pereira, Francisco M. Marty, Amelia Langston, and Anna Wijatyk
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,Ganciclovir ,Foscarnet ,medicine.medical_specialty ,maribavir ,Adolescent ,ganciclovir ,030106 microbiology ,Phases of clinical research ,Antiviral Agents ,Gastroenterology ,Immunocompromised Host ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Drug Resistance, Viral ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Articles and Commentaries ,cytomegalovirus ,Dose-Response Relationship, Drug ,business.industry ,Hematopoietic Stem Cell Transplantation ,foscarnet ,virus diseases ,Maribavir ,Transplant Recipients ,Dysgeusia ,Transplantation ,Infectious Diseases ,chemistry ,Cytomegalovirus Infections ,Benzimidazoles ,Female ,Ribonucleosides ,medicine.symptom ,business ,transplantation ,medicine.drug ,Cidofovir - Abstract
In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of CMV viremia within 6 weeks, with responses maintained for up to 24 weeks., Background Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains. Methods Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs). Results From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts
- Published
- 2018
22. In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus
- Author
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Alexa V. DeVita, Brian G. Gentry, Kylie C. Markovich, Dean Wallace Selleseth, M. Shea O’Brien, and Phiroze Sethna
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Cyclopropanes ,0301 basic medicine ,Ganciclovir ,Foscarnet ,Human cytomegalovirus ,Guanine ,Combination therapy ,viruses ,030106 microbiology ,Organophosphonates ,Cytomegalovirus ,Brincidofovir ,DNA-Directed DNA Polymerase ,Pharmacology ,Virus Replication ,Antiviral Agents ,Cell Line ,Cytosine ,Viral Proteins ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,Nucleic Acid Synthesis Inhibitors ,Endodeoxyribonucleases ,business.industry ,virus diseases ,Drug Synergism ,Maribavir ,Fibroblasts ,medicine.disease ,Drug Combinations ,chemistry ,Cytomegalovirus Infections ,Benzimidazoles ,Drug Therapy, Combination ,Ribonucleosides ,business ,Drug Antagonism ,Cidofovir ,medicine.drug - Abstract
Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient. We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that administration of a viral DNA polymerase inhibitor, MBV, and/or a viral terminase inhibitor in combination has the potential to address the resistance/cross-resistance problems associated with currently available therapeutics.
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- 2018
23. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus
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Ronald J. Ercolani, Sunwen Chou, and Katayoun Derakhchan
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0301 basic medicine ,Human cytomegalovirus ,Foscarnet ,Ganciclovir ,030106 microbiology ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Microbial Sensitivity Tests ,Pharmacology ,Antiviral Agents ,Article ,Cell Line ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,Virology ,medicine ,Humans ,Drug Interactions ,business.industry ,virus diseases ,Maribavir ,medicine.disease ,030104 developmental biology ,chemistry ,Sirolimus ,Benzimidazoles ,Ribonucleosides ,business ,medicine.drug ,Cidofovir - Abstract
The human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir is in Phase III clinical trials as antiviral therapy, including use for infections refractory or resistant to standard therapy. To assess its activity in combination with approved and experimental CMV antivirals, and with the mTor inhibitor rapamycin (sirolimus), drug effects were tested by in vitro checkerboard assays and the data were analyzed using a three dimensional model based on an independent effects definition of additive interactions. Baseline virus and representative drug-resistant mutants were tested. According to the volume of synergy at 95% confidence, maribavir showed additive interactions with foscarnet, cidofovir, letermovir and GW275175X when tested against wild type and mutant viruses, strong antagonism with ganciclovir, and strong synergy with rapamycin, the latter suggesting a potentially useful therapeutic combination.
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- 2018
24. Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation
- Author
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Francisco M. Marty, Matthew P. Cheng, Kaiwen Chen, Sarah P. Hammond, and Hermann Einsele
- Subjects
0301 basic medicine ,Ganciclovir ,medicine.medical_specialty ,medicine.medical_treatment ,030106 microbiology ,Cytomegalovirus ,Brincidofovir ,Review Article ,Hematopoietic stem cell transplantation ,Antiviral Agents ,law.invention ,03 medical and health sciences ,Letermovir ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,business.industry ,Hematopoietic Stem Cell Transplantation ,Maribavir ,Hematology ,Allografts ,Transplantation ,Clinical trial ,Cytomegalovirus Infections ,business ,medicine.drug - Abstract
Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased morbidity and mortality. Although universal antiviral prophylaxis against CMV improves outcomes in solid organ transplant recipients, data have been conflicting regarding such prophylaxis in patients undergoing allogeneic HCT. We conducted a systematic review of randomized trials of prophylactic antivirals against CMV after allogeneic HCT to summarize the evolution of the field over the last 35 years and evaluate the prophylactic potential of antiviral agents against CMV after allogeneic HCT. Electronic databases were queried from database inception through 31 December 2017. For included studies, incidence of CMV infection and all-cause mortality were collected as primary outcomes; CMV disease incidence, use of preemptive therapy, and drug toxicities were collected as secondary outcomes. Nineteen clinical trials conducted between 1981 and 2017 involving a total of 4173 patients were included for review. Prophylactic strategies included use of acyclovir, valacyclovir, ganciclovir, maribavir, brincidofovir, and letermovir compared with placebo or a comparator antiviral. Fourteen trials that compared antiviral prophylaxis with placebo demonstrated overall effectiveness in reducing incidence of CMV infection (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.42-0.58), CMV disease (OR, 0.56; 95% CI, 0.40-0.80), and use of preemptive therapy (OR, 0.51; 95% CI, 0.42-0.62; 6 trials); however, none demonstrated reduction in all-cause mortality (OR, 0.96; 95% CI, 0.78-1.18) except the phase 3 trial of letermovir (week-24 OR, 0.59; 95% CI, 0.38-0.98). Additional research is warranted to determine patient groups most likely to benefit from antiviral prophylaxis and its optimal deployment after allogeneic HCT.
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- 2018
25. CMV Prevention and Treatment in Transplantation: What’s New in 2019
- Author
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Anat Stern and Genovefa A. Papanicolaou
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medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Congenital cytomegalovirus infection ,virus diseases ,Maribavir ,Immune monitoring ,medicine.disease ,Article ,Cell therapy ,Transplantation ,Letermovir ,Infectious Diseases ,Medicine ,business ,Intensive care medicine ,Solid organ transplantation ,education ,medicine.drug - Abstract
PURPOSE OF REVIEW: Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated modalities for prevention and treatment of CMV infection in hematopoietic cell (HCT) and solid organ transplant (SOT) recipients. RECENT FINDINGS: Letermovir was recently approved for CMV prevention in HCT recipients. Data from real world studies support its role to improve outcomes in this population. Letermovir is currently under investigation for broader patient populations and indications. Maribavir is in late stages of development for CMV treatment and may provide a safer alternative to currently available anti-CMV drugs. Promising CMV vaccine candidates and adoptive cell therapy approaches are under evaluation. CMV immune monitoring assays are predicted to play a more central role in our clinical decision making. SUMMARY: In recent years, major advances have been made in CMV prevention and treatment in transplant recipients. Rigorous research is ongoing and is anticipated to further impact our ability to improve outcomes in this population.
- Published
- 2019
26. Thymidine kinase and protein kinase in drug-resistant herpesviruses: Heads of a Lernaean Hydra
- Author
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Graciela Andrei, Sarah Gillemot, Dimitri Topalis, and Robert Snoeck
- Subjects
0301 basic medicine ,Ganciclovir ,Human cytomegalovirus ,Cancer Research ,Protein Conformation ,viruses ,030106 microbiology ,Biology ,medicine.disease_cause ,Antiviral Agents ,Thymidine Kinase ,Virus ,Structure-Activity Relationship ,Viral Proteins ,03 medical and health sciences ,Drug Resistance, Viral ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Protein kinase A ,Herpesviridae ,Pharmacology ,virus diseases ,Maribavir ,Herpesviridae Infections ,medicine.disease ,Virology ,030104 developmental biology ,Infectious Diseases ,Herpes simplex virus ,Oncology ,Thymidine kinase ,Drug Design ,Mutation ,Protein Kinases ,Nucleoside ,medicine.drug - Abstract
Herpesviruses thymidine kinase (TK) and protein kinase (PK) allow the activation of nucleoside analogues used in anti-herpesvirus treatments. Mutations emerging in these two genes often lead to emergence of drug-resistant strains responsible for life-threatening diseases in immunocompromised populations. In this review, we analyze the binding of different nucleoside analogues to the TK active site of the three α-herpesviruses [Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2) and Varicella-Zoster Virus (VZV)] and present the impact of known mutations on the structure of the viral TKs. Furthermore, models of β-herpesviruses [Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6)] PKs allow to link amino acid changes with resistance to ganciclovir and/or maribavir, an investigational chemotherapeutic used in patients with multidrug-resistant HCMV. Finally, we set the basis for the understanding of drug-resistance in γ-herpesviruses [Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV)] TK and PK through the use of animal surrogate models.
- Published
- 2018
27. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation
- Author
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Cyrus Badshah, Kathleen M. Mullane, Andrew J. Ullmann, Shariq Haider, Randi Y. Leavitt, Yoshihiko Murata, Francisco M. Marty, Johan Maertens, Per Ljungman, Hong Wan, Michael Boeckh, Emily A. Blumberg, Sanjeet Dadwal, Yuta Katayama, Roy F. Chemaly, Nicholas A. Kartsonis, David R. Snydman, Hermann Einsele, Yoshinobu Kanda, Mark J. DiNubile, Rafael F. Duarte, Janice M. Brown, and Valerie L Teal
- Subjects
0301 basic medicine ,ACUTE MYOCARDIAL-INFARCTION ,medicine.medical_specialty ,Randomization ,030106 microbiology ,PERCUTANEOUS CORONARY INTERVENTION ,MULTIVESSEL DISEASE ,Placebo ,law.invention ,03 medical and health sciences ,Letermovir ,Medicine, General & Internal ,Randomized controlled trial ,law ,General & Internal Medicine ,Internal medicine ,medicine ,Clinical endpoint ,CULPRIT LESION ,ANGIOPLASTY ,ANGIOGRAPHIC FINDINGS ,Science & Technology ,business.industry ,virus diseases ,Maribavir ,General Medicine ,OPEN-LABEL ,RANDOMIZED-TRIAL ,EARLY REVASCULARIZATION ,Transplantation ,Regimen ,030104 developmental biology ,CARDIOGENIC-SHOCK ,business ,Life Sciences & Biomedicine ,medicine.drug - Abstract
BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex. METHODS: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. RESULTS: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P
- Published
- 2017
28. Ganciclovir and maribavir susceptibility phenotypes of cytomegalovirus UL97 ATP binding region mutations detected by expanded genotypic testing
- Author
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Sunwen Chou, Rohita Sinha, Matthew Watters, and Steven Kleiboeker
- Subjects
Ganciclovir ,Genotyping Techniques ,Cytomegalovirus ,Drug resistance ,Biology ,Antiviral Agents ,Article ,Adenosine Triphosphate ,Virology ,Drug Resistance, Viral ,Genotype ,medicine ,Humans ,Codon ,Genotyping ,Pharmacology ,chemistry.chemical_classification ,Kinase ,Maribavir ,Phenotype ,Amino acid ,Phosphotransferases (Alcohol Group Acceptor) ,Amino Acid Substitution ,chemistry ,Cytomegalovirus Infections ,Mutation ,Benzimidazoles ,Ribonucleosides ,medicine.drug - Abstract
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.
- Published
- 2021
29. First Reported Use of Artesunate Adjunctive Therapy for Severe BK Polyoma Virus Hemorrhagic Cystitis (BKPyV-HC)
- Author
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Cheryl Lynn Nuss-Balczo, Kathleen M. Mullane, Peter A. Riedell, Satyajit Kosuri, and Kenneth Pursell
- Subjects
Transplantation ,medicine.medical_specialty ,business.industry ,viruses ,medicine.medical_treatment ,Interstitial nephritis ,virus diseases ,Immunosuppression ,Maribavir ,Hematology ,medicine.disease ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Artesunate ,Internal medicine ,Medicine ,business ,Busulfan ,Hemorrhagic cystitis ,medicine.drug ,Cidofovir ,Leflunomide - Abstract
BKV is ubiquitous with 80-90% seropositivity. BKV establishes latency in kidney tubular epithelial/urothelial cells but is shed in urine. Reactivation may cause interstitial nephritis (BKV-IN) after renal transplant (Ktxp) and hemorrhagic cystitis (HC) and/or BKV-IN after allo-HSCT. BKV-HC occurs 2-8 wks after HSCT. Diagnosis requires: cystitis, macroscopic hematuria and urine (U) BK VL >7log10 copies/ml. High-level BK viruria occurs in >80% post allo-HSCT but only 5-20% develop HC. Plasma (PL) VLs are elevated in 60% and declining PL-VL correlates with improvement. Re-activation risk factors include young age, male sex; high risk donor; HSCT conditioning with CTX, busulfan, TBI; and grade 2-4 GVHD. Therapy is supportive. There are no FDA approved agents for BKV. Cidofovir (CDV), leflunomide, and FQs have in-vitro BKV activity but clinical use is not supported by rigorous trials. Pooled IVIg contains BKV antibodies. Reduction of immunosuppression improves BKV-IN in Ktxp recipients but is ineffective in allo-HSCT BKV-HC. For >30 years 1st line therapy for malaria has been Artesunate (ART), an artemisinin derivative with a good safety profile. ART has an antiviral spectrum including herpesviruses, HBV, HCV, HIV and BKV. ART inhibits BKV replication in human renal tissue culture via activation of transcription factors NF-κB / Sp-1 and concentration dependent down regulation of phosphorylation by kinase PI3K without cellular cytotoxicity. In-vitro, ATV is synergistic and/or additive with CDV, GCV and Maribavir. Case reports/series of ART use in CMV, HHV6, and resistant HSV-2, are published. CASE: A 22yo M w R/R (see table) T/HRLBCL IIIB underwent a haplo-SCT in PR. At week +8 he developed gross hematuria, cystitis (9-10/10 pain), and urinary outlet obstruction. U-/PL-BK VLs were >100,000,000/ 7.9 mg/dl). PL-BKV VL rose to 196,537copies/ml and both ureters obstructed necessitating bilateral nephrostomy drains. We requested ART via an eIND from the FDA and current US manufacturer. ART load (2.4 mg/kg IV Q 12H x2) followed by 2.4 mg/kg/d administered x 14 d. Cystitis pain fell from 9-10 to 0-2/10 by day 4. U-/PL-BKV VLs fell to 91,980 / There was a strong temporal association between ART treatment and clinical response. CDV and IVIg therapy may also have contributed to the observed improvement. ART therapy may be an emerging option for BKV-IN and HC and further research is warranted.
- Published
- 2020
30. A Phase 3 Active-Controlled Study of Maribavir (MBV) for the Treatment (Tx) of Transplant Recipients with Refractory/Resistant (RR) Cytomegalovirus (CMV): Study Design
- Author
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Jingyang Wu, Sophie Alain, Aimee Sundberg, Camille N. Kotton, Fernanda P. Silveira, Emily A. Blumberg, Robin K. Avery, and Nassim Kamar
- Subjects
Foscarnet ,Ganciclovir ,Transplantation ,medicine.medical_specialty ,business.industry ,virus diseases ,Phases of clinical research ,Retinitis ,Maribavir ,Viremia ,Valganciclovir ,Hematology ,medicine.disease ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business ,medicine.drug ,Cidofovir - Abstract
Introduction In transplant recipients, CMV infection RR to prior antiviral Tx is associated with significant morbidity and mortality. Existing antivirals are not approved for RR CMV infection and are limited by their toxicities. A prior Phase 2 dose-ranging study of MBV for RR CMV (67% of patients [pts] achieved undetectable CMV DNA within 6 wks) motivated initiation of a Phase 3 trial with the concept of an investigator-assigned (IA) Tx comparator arm. Objective To assess the efficacy and safety of MBV compared with IA anti-CMV therapies in HSCT/SOT recipients with RR CMV infection. Methods In this Phase 3, randomized, open-label, multicenter, active-controlled study (NCT02931539), HSCT/SOT recipients (≥12 years old) with RR CMV infection are randomized 2:1 to MBV (400 mg BID) or IA Tx (ganciclovir [GCV], valganciclovir [VGC], foscarnet [FSC], cidofovir [CDV]) for 8 wks. Pts in the IA Tx group discontinuing Tx early (lack of response and/or intolerance; investigator discretion) are assessed Wks 3–7 to enter MBV rescue arm. Pts are followed for 12 wks after the 8-wk Tx period. Inclusion criteria include: documented CMV infection with screening value ≥2730 IU/mL / ≥910 IU/mL (whole blood / plasma) in 2 consecutive tests ≥1 day apart; current refractory CMV infection: documented failure to achieve >1 log10 decrease in CMV DNA after ≥14 days of the same anti-CMV Tx. Pts with ≥1 genetic mutation associated with GCV/VGC, FSC or CDV resistance must also meet refractory criteria. Pts with tissue invasive CMV disease with CNS involvement including the retina, eg CMV retinitis, are excluded. A central specialty laboratory quantifies plasma CMV DNA (COBAS ‘AmpliPrep/TaqMan' CMV test). The primary efficacy endpoint is confirmed CMV viremia clearance (defined as plasma CMV DNA concentrations Results Planned enrollment is 351 pts across ∼140 sites (North America, Europe, Asia Pacific). Study start, Dec 2016; completion ∼Sep 2020. Conclusions The comparator arm of this Phase 3 study is valid for evaluating efficacy and safety of MBV for RR CMV compared with available anti-CMV Tx, whilst allowing for personalized Tx for pts in the comparator group.
- Published
- 2020
31. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients
- Author
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Roy F. Chemaly, Dimpy P. Shah, and Firas El Chaer
- Subjects
Male ,0301 basic medicine ,Ganciclovir ,Foscarnet ,T-Lymphocytes ,030106 microbiology ,Immunology ,Cytomegalovirus ,Brincidofovir ,DNA-Directed DNA Polymerase ,Antiviral Agents ,Biochemistry ,Viral Proteins ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,Drug Resistance, Viral ,medicine ,Humans ,business.industry ,How I Treat ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Valganciclovir ,Maribavir ,Cell Biology ,Hematology ,Transplantation ,Phosphotransferases (Alcohol Group Acceptor) ,chemistry ,Lymphocyte Transfusion ,Cytomegalovirus Infections ,Mutation ,Drug Therapy, Combination ,Female ,business ,medicine.drug ,Cidofovir - Abstract
Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV.
- Published
- 2016
32. Safety considerations with current and emerging antiviral therapies for cytomegalovirus infection in transplantation
- Author
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Guy El Helou and Raymund R. Razonable
- Subjects
Foscarnet ,Ganciclovir ,Human cytomegalovirus ,medicine.medical_specialty ,Congenital cytomegalovirus infection ,030204 cardiovascular system & hematology ,Opportunistic Infections ,Antiviral Agents ,03 medical and health sciences ,chemistry.chemical_compound ,Letermovir ,0302 clinical medicine ,medicine ,Humans ,Pharmacology (medical) ,Intensive care medicine ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,General Medicine ,Organ Transplantation ,medicine.disease ,Transplantation ,chemistry ,030220 oncology & carcinogenesis ,Cytomegalovirus Infections ,business ,Immunosuppressive Agents ,medicine.drug ,Cidofovir - Abstract
Introduction: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell t...
- Published
- 2019
33. Novel UL97 drug resistance mutations identified at baseline in a clinical trial of maribavir for resistant or refractory cytomegalovirus infection
- Author
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Jingyang Wu, Sunwen Chou, Tien Bo, and Kening Song
- Subjects
0301 basic medicine ,Ganciclovir ,Genes, Viral ,Genotyping Techniques ,030106 microbiology ,Congenital cytomegalovirus infection ,Phases of clinical research ,Cytomegalovirus ,Drug resistance ,Article ,Cell Line ,03 medical and health sciences ,Inhibitory Concentration 50 ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,Clinical significance ,Genotyping ,Cross-resistance ,Pharmacology ,business.industry ,Maribavir ,medicine.disease ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Cytomegalovirus Infections ,Mutation ,Benzimidazoles ,Ribonucleosides ,business ,medicine.drug - Abstract
In a Phase 2 clinical trial, 120 subjects with cytomegalovirus (CMV) infection refractory or resistant to standard therapy were randomized equally to 3 doses of oral maribavir treatment, and 70% achieved undetectable plasma CMV DNA within 12 weeks. At study entry, standard diagnostic UL97 genotyping was available for 71 subjects, with 60 (85%) revealing well-characterized ganciclovir resistance mutations that did not preclude a therapeutic response to maribavir. Central laboratory testing of a range of UL97 codons (288-468) not fully covered by standard genotyping was done on 93 subjects at baseline. This detected no previously known maribavir resistance mutations, but identified atypical mutations in 3 subjects, including a P-loop substitution F342Y, and ATP-binding region substitutions K359E/Q. By recombinant phenotyping, K359E and K359Q each conferred a nearly 4-fold increased ganciclovir 50% inhibitory concentration (EC50) without maribavir resistance, whereas F342Y conferred a 6-fold increased ganciclovir EC50 and a 4.5-fold increased maribavir EC50. The subject with F342Y detected at baseline did not achieve plasma CMV DNA clearance after 12 weeks of maribavir therapy and later developed an additional UL97 substitution H411Y known to confer 12- to 20-fold increased MBV EC50 by itself. The combination of F342Y and H411Y was shown to increase the maribavir EC50 by 56-fold. Diagnostic genotyping of UL97 should be expanded to cover the ATP-binding region beginning at codon 335 to enable the detection of atypical resistance mutations and further correlation of their clinical significance.
- Published
- 2019
34. Human Cytomegalovirus Disruption of Calcium Signaling in Neural Progenitor Cells and Organoids
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Emily R Seminary, Scott S. Terhune, Amanda J. Johnson, Allison D. Ebert, Samantha L Sison, and Benjamin S. O’Brien
- Subjects
Human cytomegalovirus ,Immunology ,Population ,Induced Pluripotent Stem Cells ,Cytomegalovirus ,Voltage-Gated Sodium Channels ,Biology ,Virus Replication ,Microbiology ,Calcium in biology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Organ Culture Techniques ,Neural Stem Cells ,Virology ,medicine ,Humans ,Calcium Signaling ,Progenitor cell ,education ,030304 developmental biology ,Calcium signaling ,0303 health sciences ,education.field_of_study ,Receptors, Purinergic ,Maribavir ,Cell Differentiation ,medicine.disease ,Neural stem cell ,Cell biology ,Virus-Cell Interactions ,Organoids ,Insect Science ,Cytomegalovirus Infections ,Benzimidazoles ,Ribonucleosides ,Neural development ,030217 neurology & neurosurgery - Abstract
The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including hepatosplenomegaly, microcephaly, and developmental disabilities. Microcephaly is associated with disruptions in the neural progenitor cell (NPC) population. Here, we defined the impact of HCMV infection on neural tissue development and calcium regulation, a critical activity in neural development. Regulation of intracellular calcium involves purinergic receptors and voltage-gated calcium channels (VGCC). HCMV infection compromised the ability of both pathways in NPCs as well as fibroblasts to respond to stimulation. We observed significant drops in basal calcium levels in infected NPCs which were accompanied by loss in VGCC activity and purinergic receptor responses. However, uninfected cells in the population retained responsiveness. Addition of the HCMV inhibitor maribavir reduced viral spread but failed to restore activity in infected cells. To study neural development, we infected three-dimensional cortical organoids with HCMV. Infection spread to a subset of cells over time and disrupted organoid structure, with alterations in developmental and neural layering markers. Organoid-derived infected neurons and astrocytes were unable to respond to stimulation whereas uninfected cells retained nearly normal responses. Maribavir partially restored structural features, including neural rosette formation, and dampened the impact of infection on neural cellular function. Using a tissue model system, we have demonstrated that HCMV alters cortical neural layering and disrupts calcium regulation in infected cells. IMPORTANCE Human cytomegalovirus (HCMV) replicates in several cell types throughout the body, causing disease in the absence of an effective immune response. Studies on HCMV require cultured human cells and tissues due to species specificity. In these studies, we investigated the impact of infection on developing three-dimensional cortical organoid tissues, with specific emphasis on cell-type-dependent calcium signaling. Calcium signaling is an essential function during neural differentiation and cortical development. We observed that HCMV infects and spreads within these tissues, ultimately disrupting cortical structure. Infected cells exhibited depleted calcium stores and loss of ATP- and KCl-stimulated calcium signaling while uninfected cells in the population maintained nearly normal responses. Some protection was provided by the viral inhibitor maribavir. Overall, our studies provide new insights into the impact of HCMV on cortical tissue development and function.
- Published
- 2019
35. Conserved domains and structure prediction of human cytomegalovirus UL27 protein
- Author
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Gaël Champier, Anthony Couvreux, Laurène Trapes, Sébastien Cotin, Sébastien Hantz, François Denis, Sophie Alain, Serge Bouaziz, Biologie moléculaire et cellulaire des microorganismes (EA3175), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Laboratoire d'informatique Fondamentale de Marseille - UMR 6166 (LIF), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Bouaziz, Serge, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Human cytomegalovirus ,MESH: Sequence Analysis, DNA ,viruses ,Cytomegalovirus ,MESH: Amino Acid Sequence ,medicine.disease_cause ,chemistry.chemical_compound ,MESH: Structure-Activity Relationship ,Pharmacology (medical) ,Peptide sequence ,Conserved Sequence ,Mutation ,MESH: Conserved Sequence ,MESH: Drug Resistance, Viral ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,virus diseases ,Maribavir ,Cell biology ,Phosphotransferases (Alcohol Group Acceptor) ,Infectious Diseases ,MESH: Antiviral Agents ,MESH: Cytomegalovirus ,MESH: Mutation ,[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Sequence analysis ,Molecular Sequence Data ,MESH: Sequence Alignment ,Sequence alignment ,Biology ,Antiviral Agents ,Herpesviridae ,Structure-Activity Relationship ,Drug Resistance, Viral ,medicine ,Humans ,Amino Acid Sequence ,Pharmacology ,MESH: Ribonucleosides ,MESH: Humans ,MESH: Molecular Sequence Data ,Sequence Analysis, DNA ,medicine.disease ,Virology ,MESH: Phosphotransferases (Alcohol Group Acceptor) ,MESH: DNA, Viral ,chemistry ,DNA, Viral ,Benzimidazoles ,Ribonucleosides ,MESH: Benzimidazoles ,Sequence Alignment ,DNA - Abstract
Background The human cytomegalovirus (HCMV) nuclear UL27 protein (pUL27) could be involved at the stage of nuclear egress. Maribavir is a new anti-HCMV drug that targets nuclear egress through direct inhibition of the HCMV serine–threonine kinase, UL97 protein (pUL97). Because maribavir- resistance-related mutations are observed in both proteins, pUL27 is thought to interfere with pUL97 activity; however, its mechanism of action remains unclear. Methods As there is no available crystal structure for pUL27 or any known structures of its homologous proteins, we attempted to identify pUL27 functional domains by sequence analysis, identification of conserved domains, structure prediction and matching with previously known maribavir resistance mutations. Results The UL27 sequence analysis of 20 HCMV wild-type strains and 8 ganciclovir-resistant HCMV strains allowed us to describe four conserved domains, to localize the putative phosphorylation sites and to identify protein–protein interface domains, suggesting that pUL27 could interact with either pUL97 or itself. Conclusions Although the function of pUL27 is still unknown in the HCMV replication cycle, our approach identified target domains that appeared to be essential to the function of pUL27. This work provides a better understanding on the relative importance of each pUL27 mutation and could form the basis of later comparison analyses, when a three-dimensional structure of a pUL27 homologue will be available.
- Published
- 2019
36. Characterization of the dynamics of human cytomegalovirus resistance to antiviral drugs by ultra-deep sequencing
- Author
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Hélène Guermouche, Olivier Rogier, Jean-Michel Pawlotsky, Sonia Burrel, David Boutolleau, Mélanie Mercier-Darty, Christophe Rodriguez, Thomas Kofman, CCSD, Accord Elsevier, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,Human cytomegalovirus ,Foscarnet ,Ultra-deep sequencing ,medicine.drug_class ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Resistance ,Cytomegalovirus ,Microbial Sensitivity Tests ,Antiviral Agents ,03 medical and health sciences ,symbols.namesake ,Immunocompromised Host ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,Variability ,Gene ,Alleles ,Aged ,Pharmacology ,Sanger sequencing ,business.industry ,CMV ,virus diseases ,High-Throughput Nucleotide Sequencing ,Valganciclovir ,Maribavir ,Viral Load ,medicine.disease ,Transplant Recipients ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Amino Acid Substitution ,Cytomegalovirus Infections ,Mutation ,symbols ,Female ,Antiviral drug ,business ,Complication ,medicine.drug - Abstract
International audience; Prophylactic or preemptive treatment strategies are required to prevent human cytomegalovirus (CMV) infections in transplant recipients. However, treatment failure occurs when CMV resistant-associated variants (RAVs) are selected. Although the diversity of CMV is lower than that of RNA viruses, CMV appears to show some genetic instability, with possible minor emerging resistance that may be undetectable by Sanger sequencing. We aimed to examine CMV-resistance mutations over time by ultra-deep sequencing (UDS) and Sanger sequencing in a kidney transplant recipient experiencing CMV infection. This patient showed a transient response to three different antiviral drugs (valganciclovir, foscarnet, and maribavir) and four episodes of CMV resistance over two years. The full-length UL97 (2.3kpb) and partial UL54 (2.4kpb) CMV genes were studied by UDS and Sanger sequencing and linkage mutations calculated to determine RAVs. We detected four major and five minor resistance mutations. Minor resistant variants (2-20%) were detected by UDS, whereas major resistance substitutions (>20%) were identified by both UDS and Sanger method. We detected cross-resistance to three drugs, despite high CMV loads, suggesting that the fitness of the viral mutants was not impaired. In conclusion, CMV showed complex dynamic of resistance under antiviral drug pressure, as described for highly variable viruses. The emergence of successive RAVs constitutes a clinically challenging complication and contributes to the difficulty of therapeutic management of patients.
- Published
- 2019
37. Artemisone demonstrates synergistic antiviral activity in combination with approved and experimental drugs active against human cytomegalovirus
- Author
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Ido Laskov, Amos Panet, Daniel Lantsberg, Dana G. Wolf, Richard K. Haynes, Esther Oiknine-Djian, Shikma Bar-On, and 22966390 - Haynes, Richard Kingston
- Subjects
0301 basic medicine ,Ganciclovir ,Human cytomegalovirus ,medicine.drug_class ,Placenta ,viruses ,030106 microbiology ,Organophosphonates ,Cytomegalovirus ,Brincidofovir ,Pharmacology ,Acetates ,Artemisone ,Antiviral Agents ,Antiviral drug combinations ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,Cytosine ,Organ Culture Techniques ,Pregnancy ,Virology ,medicine ,Humans ,Drug Interactions ,Artemisinin ,business.industry ,Antiviral drugs ,Maribavir ,Drug Synergism ,Drugs, Investigational ,medicine.disease ,Artemisinins ,030104 developmental biology ,chemistry ,Cytomegalovirus Infections ,Quinazolines ,Benzimidazoles ,Female ,Ribonucleosides ,Antiviral drug ,business ,Cidofovir ,medicine.drug - Abstract
We have recently shown that the artemisinin derivative artemisone, which was screened against malaria in human clinical studies, is a potent inhibitor of human cytomegalovirus (HCMV). Here we evaluated the antiviral effect of artemisone when employed in 2-drug combinations with approved and experimental anti-HCMV agents. Using the Chou-Talalay method, we found that in-vitro combination of artemisone with cidofovir, brincidofovir, or with the HCMV UL97 inhibitor maribavir resulted in antiviral synergism and the combination of artemisone with ganciclovir or with the viral terminase inhibitors letermovir and BDCRB resulted in moderate synergism. Importantly, the combination of artemisone with maribavir demonstrated synergistic antiviral activity ex-vivo, in a clinically-relevant multicellular model of human placental tissues maintained in organ culture. Our findings provide the basis for the use of artemisone in synergistically acting drug combinations, to enhance viral control and reduce antiviral drug toxicities.
- Published
- 2019
38. Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance
- Author
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Guy Boivin and Jocelyne Piret
- Subjects
0301 basic medicine ,Ganciclovir ,Human cytomegalovirus ,viruses ,030106 microbiology ,Viral terminase complex ,Cytomegalovirus ,Drug resistance ,Acetates ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,Letermovir ,Viral Proteins ,Drug Development ,Virology ,Drug Resistance, Viral ,medicine ,Animals ,Humans ,Kinase activity ,Polymerase ,Pharmacology ,Clinical Trials as Topic ,biology ,business.industry ,Maribavir ,medicine.disease ,3. Good health ,030104 developmental biology ,Cytomegalovirus Infections ,DNA, Viral ,biology.protein ,Quinazolines ,Benzimidazoles ,Ribonucleosides ,business ,medicine.drug - Abstract
The prevention and treatment of human cytomegalovirus (HCMV) infections is based on the use of antiviral agents that currently target the viral DNA polymerase and that may cause serious side effects. The search for novel inhibitors against HCMV infection led to the discovery of new molecular targets, the viral terminase complex and the viral pUL97 kinase. The most advanced compounds consist of letermovir (LMV) and maribavir (MBV). LMV inhibits the cleavage of viral DNA and its packaging into capsids by targeting the HCMV terminase complex. LMV is safe and well tolerated and exhibits pharmacokinetic properties that allow once daily dosing. LMV showed efficacy in a phase III prophylaxis study in hematopoietic stem cell transplant (HSCT) recipients seropositive for HCMV. LMV was recently approved under the trade name Prevymis™ for prophylaxis of HCMV infection in adult seropositive recipients of an allogeneic HSCT. Amino acid substitutions conferring resistance to LMV selected in vitro map primarily to the pUL56 and rarely to the pUL89 and pUL51 subunits of the HCMV terminase complex. MBV is an inhibitor of the viral pUL97 kinase activity and interferes with the morphogenesis and nuclear egress of nascent viral particles. MBV is safe and well tolerated and has an excellent oral bioavailability. MBV was effective for the treatment of HCMV infections (including those that are refractory or drug-resistant) in transplant recipients in two phase II studies and is further evaluated in two phase III trials. Mutations conferring resistance to MBV map to the UL97 gene and can cause cross-resistance to ganciclovir. MBV-resistant mutations also emerged in the UL27 gene in vitro and could compensate for the inhibition of pUL97 kinase activity by MBV. Thus, LMV and probably MBV will broaden the armamentarium of antiviral drugs available for the prevention and treatment of HCMV infections.
- Published
- 2018
39. Use of Maribavir and Letermovir for Ganciclovir-Resistant Cytomegalovirus Infection in Lung Transplant Recipients
- Author
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A. Cordry, Maher A. Baz, and H.M. Underwood
- Subjects
Pulmonary and Respiratory Medicine ,Ganciclovir ,Transplantation ,medicine.medical_specialty ,Lung ,business.industry ,medicine.medical_treatment ,Congenital cytomegalovirus infection ,Salvage therapy ,Immunosuppression ,Maribavir ,medicine.disease ,Letermovir ,medicine.anatomical_structure ,Internal medicine ,medicine ,Surgery ,Dosing ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Introduction Cytomegalovirus (CMV) infection is a major contributor to morbidity and mortality in solid organ transplant recipients. Ganciclovir-resistant (gan-R) CMV is an emerging concern associated with potent immunosuppression and increased durations of antiviral exposure. Limited data exists regarding efficacy of maribavir and letermovir for treatment and secondary prophylaxis in resistant CMV. Case Report We report a series of 3 lung transplant recipients with gan-R CMV infection treated with maribavir or letermovir between June 1, 2015 and June 1, 2020. Maribavir and letermovir were initiated as monotherapy for CMV treatment in 3 and 1 patients, respectively, with maribavir dosing per institutional study protocol. Patient A was transitioned to letermovir prophylaxis following maribavir treatment. Patient C was transferred to an outside hospital for CMV T-cell therapy and was not discharged on antiviral prophylaxis. Both maribavir and letermovir were well-tolerated by patients. Summary Maribavir 200 mg twice daily resulted in CMV viral suppression in one patient. Patients B and C received much shorter durations of maribavir treatment, which may have been associated with delayed quantitative viral reduction as described in the literature, and subsequent transition to alternative therapy. Further research is needed to evaluate the impact of salvage therapy with maribavir or letermovir on patient outcomes.
- Published
- 2021
40. Human Cytomegalovirus Can Procure Deoxyribonucleotides for Viral DNA Replication in the Absence of Retinoblastoma Protein Phosphorylation
- Author
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Chad V. Kuny and Robert F. Kalejta
- Subjects
0301 basic medicine ,Human cytomegalovirus ,viruses ,Deoxyribonucleotides ,Immunology ,Cytomegalovirus ,Viral Plaque Assay ,Virus Replication ,Retinoblastoma Protein ,Microbiology ,03 medical and health sciences ,Cyclin-dependent kinase ,Virology ,medicine ,Humans ,Phosphorylation ,Cells, Cultured ,DNA synthesis ,biology ,DNA replication ,Retinoblastoma protein ,DNA virus ,Maribavir ,Cell cycle ,medicine.disease ,Molecular biology ,Virus-Cell Interactions ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Insect Science ,DNA, Viral ,biology.protein ,Protein Processing, Post-Translational - Abstract
Viral DNA replication requires deoxyribonucleotide triphosphates (dNTPs). These molecules, which are found at low levels in noncycling cells, are generated either by salvage pathways or through de novo synthesis. Nucleotide synthesis utilizes the activity of a series of nucleotide-biosynthetic enzymes (NBEs) whose expression is repressed in noncycling cells by complexes between the E2F transcription factors and the retinoblastoma (Rb) tumor suppressor. Rb-E2F complexes are dissociated and NBE expression is activated during cell cycle transit by cyclin-dependent kinase (Cdk)-mediated Rb phosphorylation. The DNA virus human cytomegalovirus (HCMV) encodes a viral Cdk (v-Cdk) (the UL97 protein) that phosphorylates Rb, induces the expression of cellular NBEs, and is required for efficient viral DNA synthesis. A long-held hypothesis proposed that viral proteins with Rb-inactivating activities functionally similar to those of UL97 facilitated viral DNA replication in part by inducing the de novo production of dNTPs. However, we found that dNTPs were limiting even in cells infected with wild-type HCMV in which UL97 is expressed and Rb is phosphorylated. Furthermore, we revealed that both de novo and salvage pathway enzymes contribute to viral DNA replication during HCMV infection and that Rb phosphorylation by cellular Cdks does not correct the viral DNA replication defect observed in cells infected with a UL97-deficient virus. We conclude that HCMV can obtain dNTPs in the absence of Rb phosphorylation and that UL97 can contribute to the efficiency of DNA replication in an Rb phosphorylation-independent manner. IMPORTANCE Transforming viral oncoproteins, such as adenovirus E1A and papillomavirus E7, inactivate Rb. The standard hypothesis for how Rb inactivation facilitates infection with these viruses is that it is through an increase in the enzymes required for DNA synthesis, which include nucleotide-biosynthetic enzymes. However, HCMV UL97, which functionally mimics these viral oncoproteins through phosphorylation of Rb, fails to induce the production of nonlimiting amounts of dNTPs. This finding challenges the paradigm of the role of Rb inactivation during DNA virus infection and uncovers the existence of an alternative mechanism by which UL97 contributes to HCMV DNA synthesis. The ineffectiveness of the UL97 inhibitor maribavir in clinical trials might be better explained with a fuller understanding of the role of UL97 during infection. Furthermore, as the nucleoside analog ganciclovir is the current drug of choice for treating HCMV, knowing the provenance of the dNTPs incorporated into viral DNA may help inform antiviral therapeutic regimens.
- Published
- 2016
41. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation
- Author
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Luisa Giaccone, Lucia Brunello, Enrico Maffini, Benedetto Bruno, Alessandro Busca, and Moreno Festuccia
- Subjects
0301 basic medicine ,Ganciclovir ,Foscarnet ,T-Lymphocytes ,medicine.medical_treatment ,Brincidofovir ,Hematopoietic stem cell transplantation ,Antiviral Agents ,Immunotherapy, Adoptive ,immune response ,Cytomegalovirus Vaccines ,03 medical and health sciences ,chemistry.chemical_compound ,Letermovir ,Drug Resistance, Viral ,medicine ,Animals ,Humans ,Transplantation, Homologous ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,hematopoietic stem cell transplantation (HSCT) ,Maribavir ,CMV-vaccine ,Hematology ,Cytomegalovirus (CMV) ,adoptive T-cell therapy (ATCT) ,Transplantation ,Treatment Outcome ,030104 developmental biology ,chemistry ,Cytomegalovirus Infections ,Immunology ,business ,medicine.drug ,Cidofovir - Abstract
Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.
- Published
- 2016
42. In vitro studies of the impact of maribavir on CMV-specific cellular immune responses
- Author
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Michael Boeckh, Terry Stevens-Ayers, and Daniel Stachel
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Ganciclovir ,T cell ,030106 microbiology ,Cytomegalovirus ,Lymphocyte proliferation ,CD8-Positive T-Lymphocytes ,Immunologic Tests ,Biology ,Antiviral Agents ,03 medical and health sciences ,Immune system ,Virology ,medicine ,Humans ,Immunity, Cellular ,Degranulation ,virus diseases ,Maribavir ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Cytomegalovirus Infections ,Immunology ,Benzimidazoles ,Ribonucleosides ,Immunocompetence ,CD8 ,medicine.drug - Abstract
Background Ganciclovir has demonstrated immunosuppressive effects in vitro which may lead to delayed cytomegalovirus (CMV)-specific immune reconstitution when the drug is given prophylactically. Maribavir is a new and more potent anti-CMV drug that is under evaluation for therapeutic use in transplant recipients. Objectives The objective of this study was to evaluate the potential effect of maribavir on CMV-specific T cell function in comparison to ganciclovir. Study design In ten immunocompetent CMV seropositive donors, maribavir and ganciclovir were compared over a broad range of concentrations (0.2–500μM) regarding their effects on lymphoproliferation, CMV-specific CD4+ and CD8+ cytokine expression, T cell multifunctionality, degranulation and apoptosis. Results Maribavir inhibited lymphocyte proliferation at concentrations of 50μM and above, however, cytokine expression, cellular degranulation and multifunctionality of CD4+ and CD8+ T cells in response to CMV lysate and pp65 peptide mix were not impaired except at the highest concentration of 500μM. Ganciclovir inhibited lymphoproliferative responses starting at 10μM. As with maribavir, other cellular responses following stimulation with CMV lysate and pp65 peptide mix were only impaired at the highest concentration of 500μM of ganciclovir. Neither maribavir nor ganciclovir showed induction of lymphocyte apoptosis. Conclusions Maribavir exhibits a low potential to suppress CMV-specific T cell function. This finding supports the use of higher doses in the prophylactic setting than originally proposed.
- Published
- 2016
43. Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance
- Author
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Sunwen Chou
- Subjects
0301 basic medicine ,Genotype ,Genotyping Techniques ,medicine.drug_class ,030106 microbiology ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Drug resistance ,Biology ,Antiviral Agents ,Article ,Deep sequencing ,Viral Proteins ,03 medical and health sciences ,Letermovir ,symbols.namesake ,Drug Resistance, Multiple, Viral ,Virology ,medicine ,Humans ,Pharmacology ,Sanger sequencing ,Clinical Trials as Topic ,High-Throughput Nucleotide Sequencing ,Maribavir ,medicine.disease ,030104 developmental biology ,Cytomegalovirus Infections ,Mutation ,symbols ,Antiviral drug ,medicine.drug - Abstract
Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase inhibitor maribavir. Newly mapped mutations and their phenotypes provide more detail on cross-resistance properties and suggest the need to expand the CMV gene regions covered in diagnostic testing. Next-generation deep sequencing technology offers a more sensitive, higher resolution view of emerging antiviral resistance and is recommended for use in clinical trials. Issues of standardization and diagnostic utility in comparison with traditional Sanger sequencing remain unresolved. Quality control is important for the accurate and reproducible detection of mutant viral populations in clinical specimens.
- Published
- 2020
44. In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review
- Author
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Joshua A. Hill, Karl S. Peggs, Roy F. Chemaly, and Sebastian Voigt
- Subjects
0301 basic medicine ,Foscarnet ,Ganciclovir ,viruses ,030106 microbiology ,Brincidofovir ,medicine.disease_cause ,Antiviral Agents ,Virus ,03 medical and health sciences ,Letermovir ,chemistry.chemical_compound ,In vitro ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,ddc:610 ,Antiviral ,Pharmacology ,business.industry ,DNA Viruses ,virus diseases ,Maribavir ,Drugs, Investigational ,biochemical phenomena, metabolism, and nutrition ,dsDNA virus ,EC50 ,030104 developmental biology ,Herpes simplex virus ,chemistry ,DNA, Viral ,business ,610 Medizin und Gesundheit ,medicine.drug ,Cidofovir - Abstract
Background Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses. Methods A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications. Results Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. Conclusion Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC50 values. These findings could assist clinical practice and developmental research.
- Published
- 2018
45. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)
- Author
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Catherine Cordonnier, Rafael de la Cámara, Petr Hubacek, Hermann Einsele, David Navarro, Christine Robin, Roberto Crocchiolo, Per Ljungman, Joshua A. Hill, and Katherine N. Ward
- Subjects
medicine.medical_specialty ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Antiviral Agents ,Letermovir ,Internal medicine ,medicine ,Humans ,In patient ,Ganciclovir ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Maribavir ,medicine.disease ,Transplantation ,Clinical trial ,Haematopoiesis ,Infectious Diseases ,Hematologic Neoplasms ,Cytomegalovirus Infections ,Practice Guidelines as Topic ,Benzimidazoles ,Ribonucleosides ,Stem cell ,business ,medicine.drug - Abstract
Summary Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.
- Published
- 2018
46. Antiviral Drugs for EBV
- Author
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Joseph S. Pagano, Graciela Andrei, and Christopher B. Whitehurst
- Subjects
0301 basic medicine ,Ganciclovir ,Cancer Research ,maribavir ,Mononucleosis ,ganciclovir ,030106 microbiology ,Population ,Usually asymptomatic ,medicine.disease_cause ,lcsh:RC254-282 ,Virus ,Epstein–Barr virus ,03 medical and health sciences ,hemic and lymphatic diseases ,medicine ,education ,education.field_of_study ,business.industry ,Maribavir ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,antiviral ,Lymphoma ,030104 developmental biology ,Oncology ,Immunology ,Commentary ,acyclovir ,business ,medicine.drug - Abstract
Epstein⁻Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic. However, EBV can cause infectious mononucleosis in approximately 35⁻50% cases when infection occurs during adolescence and early adulthood. Epstein⁻Barr virus is also associated with several B-cell malignancies including Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. A number of antiviral drugs have proven to be effective inhibitors of EBV replication, yet have resulted in limited success clinically, and none of them has been approved for treatment of EBV infections. ispartof: Cancers vol:10 issue:6 pages:197-197 ispartof: location:Switzerland status: published
- Published
- 2018
47. Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis
- Author
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Nicolaus Kröger, Nico Gagelmann, Jan Styczyński, and Per Ljungman
- Subjects
Ganciclovir ,Male ,medicine.medical_specialty ,Acyclovir ,Cytomegalovirus ,Brincidofovir ,Acetates ,Placebo ,Antiviral Agents ,law.invention ,03 medical and health sciences ,Letermovir ,0302 clinical medicine ,Randomized controlled trial ,law ,Risk Factors ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Maribavir ,Hematology ,Allografts ,030220 oncology & carcinogenesis ,Valacyclovir ,Cytomegalovirus Infections ,Quinazolines ,Benzimidazoles ,Female ,Ribonucleosides ,business ,medicine.drug - Abstract
Over the past 25 years, several randomized controlled trials have investigated the efficacy of different antiviral agents for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic cell transplantation. We performed a systematic literature review, conventional meta-analysis, and network meta-analysis using a random-effects model and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) as effect estimates. Fifteen randomized controlled trials were identified, including 7 different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while 3 trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis, with an RR of .66 (95% CI, .48 to .90) and .63 (95% CI, .50 to .79). Across the network, ganciclovir showed the best relative efficacy for CMV disease while letermovir provided first rank of being the best option for CMV infection. The risk for death was not significantly influenced by antiviral prophylaxis in the meta-analysis, with an RR of .92 (95% CI, .78 to 1.08), as well as in the network meta-analysis. In terms of safety, letermovir was at least similar in comparison with placebo and most agents while both letermovir and acyclovir showed significantly reduced risk for serious adverse events compared with ganciclovir, with RRs of .55 (95% CI, .30 to 1.00) for letermovir and .63 (95% CI, .42 to .93) for acyclovir. With a probability of 81%, letermovir appears to be the best option in terms of safety. Future randomized head-to-head comparisons are needed to evaluate the definite efficacy and safety of different prophylactic strategies.
- Published
- 2018
48. Impact of RNA polymerase I inhibitor CX-5461 on viral kinase-dependent and -independent cytomegalovirus replication
- Author
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Kristen N. Westdorp and Scott S. Terhune
- Subjects
0301 basic medicine ,Human cytomegalovirus ,viruses ,030106 microbiology ,Cytomegalovirus ,Microbial Sensitivity Tests ,Biology ,Virus Replication ,Antiviral Agents ,Virus ,Article ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Transcription (biology) ,RNA Polymerase I ,Virology ,Cellular stress response ,RNA polymerase I ,medicine ,Humans ,Benzothiazoles ,Naphthyridines ,Pharmacology ,Kinase ,Maribavir ,Drug Synergism ,Fibroblasts ,medicine.disease ,030104 developmental biology ,chemistry ,Benzimidazoles ,Ribonucleosides ,DNA - Abstract
Human cytomegalovirus (HCMV) infections cause congenital birth defects and disease in immunosuppressed individuals. Antiviral compounds can control infection yet their use is restricted due to concerns of toxicity and the emergence of drug resistant strains. We have evaluated the impact of an RNA Polymerase I (Pol I) inhibitor, CX-5461 on HCMV replication. CX-5461 inhibits Pol I-mediated ribosomal DNA transcription by binding G-quadruplex DNA structures and also activates cellular stress response pathways. The addition of CX-5461 at both early and late stages of the HCMV infection inhibited viral DNA synthesis and virus production. Interestingly, adding CX-5461 after the onset of viral DNA synthesis resulted in a greater reduction compared to continuous treatment starting early during infection. We observed an accompanying increase in cyclin-dependent kinase inhibitor p21 in infected cells treated late but not early which likely explains the differences. Our previous studies demonstrated the importance of p21 in the antiviral activity of the HCMV kinase inhibitor, maribavir. Addition of CX-5461 increased the anti-HCMV activity of maribavir. Our data demonstrate that CX-5461 inhibits HCMV replication and synergizes with maribavir to disrupt infection.
- Published
- 2018
49. Utilizing UL97 Resistant Codon Specificities to Guide Pharmacotherapy Treatment Decisions in Resistant Cytomegalovirus Infections
- Author
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David B Leeser, Tomefa E. Asempa, and Angela Q. Maldonado
- Subjects
Foscarnet ,Ganciclovir ,medicine.medical_specialty ,business.industry ,viruses ,Congenital cytomegalovirus infection ,virus diseases ,Valganciclovir ,Maribavir ,Drug resistance ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business ,Kidney transplantation ,medicine.drug ,Cidofovir - Abstract
The development of cytomegalovirus (CMV) drug resistance has become an emerging clinical challenge. In kidney transplant recipients (KTR), CMV infection is a risk factor for acute rejection, has a detrimental effect on patient survival, and predisposes patients to secondary opportunistic infections. We report here the case of a kidney transplant patient on valganciclovir prophylaxis who developed recurrent CMV infections, complicated by UL97 ganciclovir (GCV) resistance. Our patient underwent unsuccessful treatment courses with high dose GCV, foscarnet and cidofovir. Compassionate use maribavir was initiated and resulted in full recovery. Through this case report and literature review, we highlight potential strategies for the successful management of CMV resistance.
- Published
- 2018
50. Summary of Maribavir (SHP620) Drug–Drug Interactions Based on Accumulated Clinical and Nonclinical Data
- Author
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Patrick Martin, Katarina Ilic, Kefeng Sun, and Ivy Song
- Subjects
Drug ,Voriconazole ,Transplantation ,CYP3A4 ,business.industry ,media_common.quotation_subject ,CYP1A2 ,Maribavir ,Hematology ,Pharmacology ,Tacrolimus ,Discontinuation ,medicine ,Ketoconazole ,business ,medicine.drug ,media_common - Abstract
Introduction Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of cytomegalovirus (CMV) infections in transplant patients. Often numerous concomitant medications are administered to these patients to manage their comorbidities. A thorough evaluation of maribavir potential for drug–drug interactions (DDIs) is warranted and required for the regulatory approval. Objectives To thoroughly evaluate potential DDIs for maribavir. Methods Extensive in vitro studies were conducted to evaluate the potential involvement of cytochrome P450s (CYPs), uridine diphosphate glucuronosyltransferases (UGTs) and transporters on the disposition of maribavir, as well as the inhibitory and induction effect of maribavir on these enzymes and transporters. Clinical Phase 1 studies included a human mass-balance study, two probe-cocktail studies, and five DDI studies with ketoconazole, rifampin, antacid, voriconazole, and tacrolimus. Results Maribavir is metabolized primarily in the liver through CYP3A4 (70–85%) and CYP1A2 (15–30%). Renal clearance is a minor route ( Conclusions Maribavir has low risk for DDI. Inhibitors of CYP3A4 and/or P-gp may increase maribavir exposure, but dose adjustment of maribavir is not necessary. Potent inducers of CYP3A4 and P-gp decrease maribavir exposure, necessitating maribavir dose increase. Maribavir may increase exposure of immunosuppressants, such as tacrolimus. Therefore, monitoring of concomitant immunosuppressants' blood concentration should be considered at initiation, co-administration, and discontinuation of maribavir. Maribavir is not expected to interact with other concurrent medications.
- Published
- 2019
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