gw-257406x and Cytomegalovirus-Infections

To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients.. A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms:. All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials.. The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear.. Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Transplant Recipients

Topics: Adult; Antiviral Agents; Benzimidazoles; Child; Cytomegalovirus Infections; Drug Resistance, Viral; Humans; Ribonucleosides

Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies. Maribavir was initially studied as an agent for CMV prophylaxis in solid organ and hematopoietic stem cell recipients, but initial phase III trials failed to meet clinical efficacy endpoints. It has been more recently studied as a therapeutic agent at higher doses for refractory-resistant (R-R) CMV infections with favorable outcomes. After an overview of maribavir's chemistry and clinical pharmacology, this review will summarize clinical efficacy, safety, tolerability, and resistance data associated with maribavir therapy.

Topics: Adult; Anti-Infective Agents; Antiviral Agents; Benzimidazoles; Child; Cidofovir; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Valganciclovir

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

Topics: Acetates; Animals; Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Development; Drug Resistance, Viral; Humans; Quinazolines; Ribonucleosides; Viral Proteins; Virus Replication

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.

Topics: Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Practice Guidelines as Topic; Ribonucleosides

Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation. Therapeutic antiviral options [(val)ganciclovir, foscarnet, cidofovir] are still limited and can expose to severe toxicities. Moreover, prolonged antiviral drug exposure and ongoing viral replication are key factors in the development of antiviral drug resistance. After many years of few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period characterized by a series of phase III clinical trials incorporating three novel agents: maribavir, brincidofovir, and letermovir. This article summarizes the current state of the prevention and treatment of CMV infections as well as data of investigational drugs in clinical development.

Topics: Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Cytosine; Ganciclovir; Humans; Organophosphonates; Quinazolines; Ribonucleosides

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.

Topics: Acetates; Acyclovir; Allografts; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Male; Quinazolines; Ribonucleosides; Risk Factors; Valacyclovir

Topics: Administration, Oral; Antiviral Agents; Benzimidazoles; Blood; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Ribonucleosides; Sputum; Time Factors

Human cytomegalovirus (HCMV) represents the major viral complication after hematopoietic stem cell transplantation. HCMV infection may be controlled by the reconstituting immune system and remain subclinical or can lead to severe systemic and/or organ disease (mainly pneumonia and gastroenteritis) when immune reconstitution is delayed or impaired. In order to prevent the occurrence of HCMV disease, a prompt diagnosis of HCMV infection is mandatory. The adoption of pre-emptive therapy strategies guided by virological monitoring dramatically reduced the occurrence of HCMV disease. However, late-onset end-organ disease may occur in some patients with apparent immune reconstitution. In the near future, introduction of immunological monitoring and immunotherapies could markedly improve management of HCMV infection.

Topics: Acetates; Adult; Animals; Antiviral Agents; Asymptomatic Diseases; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Disease Management; Gastroenteritis; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Monitoring, Immunologic; Organophosphonates; Pneumonia; Postoperative Complications; Quinazolines; Ribonucleosides

The 2015 Tandem American Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Meetings provide an opportunity to review the current status and future perspectives on therapy for cytomegalovirus (CMV) infection in the setting of hematopoietic stem cell transplantation (HSCT). After many years during which we have seen few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period of late-stage drug development, characterized by a series of phase III trials incorporating a variety of novel agents. These trials have the potential to shift our current standard therapeutic strategies, which generally involve pre-emptive therapy based on sensitive molecular surveillance, towards the prophylactic approaches we see more generally with other herpes viruses such as herpes simplex and varicella zoster. This comes at a time when the promise of extensive preclinical research has been translated into encouraging clinical responses with several cellular immunotherapy strategies, which have also been moved towards definitive late-stage clinical trials. How these approaches will be integrated with the new wave of antiviral drugs remains open to conjecture. Although most of the focus of these cellular immunotherapy studies has been on adaptive immunity, and in particular T cells, an increasing awareness of the possible role of other cellular subsets in controlling CMV infection has developed. In particular, the role of natural killer (NK) cells is being revisited, along with that of γδ T cells. Depletion of NK cells in mice results in higher titers of murine CMV in tissues and increased mortality, whereas NK cell deficiency in humans has been linked to severe CMV disease. We will review recent progress in these areas.

Topics: Acetates; Adoptive Transfer; Animals; Antiviral Agents; Benzimidazoles; Cell- and Tissue-Based Therapy; Clinical Trials, Phase III as Topic; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Hematopoietic Stem Cell Transplantation; Humans; Isoxazoles; Killer Cells, Natural; Leflunomide; Mice; Organophosphonates; Quinazolines; Ribonucleosides; T-Lymphocytes

Cytomegalovirus (CMV) remains a significant cause of morbidity and mortality in immunocompromised patients, particularly following allogeneic haematopoietic transplantation. One of the principal factors leading to this increased risk is the loss of T-cell immunity.. In a recent review, we assessed the treatment strategies for prophylaxis and pre-emptive treatment of CMV, particularly where relevant to the high-risk patient populations following allogeneic haematopoietic transplantation. This review is a focused update to our previous article and presents a more detailed analysis of the developments in drugs, vaccines and adoptive T-cell therapies since that time. Relevant studies were selected from PubMed and clinicaltrials.gov. The search terms include allogeneic transplant, cytomegalovirus, multidrug-resistant virus and adoptive T-cell therapy.. The current randomised controlled studies evaluating pharmacological agents for CMV should inform as to whether these provide significant clinical benefits. Adoptive cell therapy provides a more physiological approach to the problem of lack of CMV-specific immunity. Recent reports add to the evidence that culture-based techniques can create cellular products that are safe and efficacious, although without Phase III data to definitively support their routine application and the difficulty of satisfying GMP standards.

Topics: Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Organophosphonates; Quinazolines; Ribonucleosides; T-Lymphocytes; Transplant Recipients; Transplantation, Homologous

To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow transplantation, congenital infection, and intervention during pregnancy.. Three double-blind randomized placebo-controlled phase 2 proof-of-concept studies have each identified a novel antiviral drug with activity against CMV infection in bone marrow transplant patients. One of these (brincidofovir) inhibits the DNA polymerase that is the target of the currently licensed drug ganciclovir. Another new drug (maribavir) inhibits a protein kinase which, coincidentally, is the enzyme responsible for activating ganciclovir through phosphorylation. The third drug (letermovir) inhibits the terminase enzyme complex responsible for packaging unit length DNA into assembling virions.In addition, in a double-blind randomized placebo-controlled trial in neonates with symptomatic congenital CMV infection, a 6-month course of valganciclovir was superior to the standard 6-week course of the same drug. In pregnant women with primary CMV infection, administration of hyperimmune immunoglobulin did not significantly reduce transmission of CMV across the placenta.. The ability to diagnose CMV infections reliably in different clinical settings through application of molecular laboratory methods has ushered in new ways of evaluating potential new treatments for CMV. Several of these may help control the diseases caused by this important human pathogen.

Topics: Acetates; Antiviral Agents; Benzimidazoles; Bone Marrow Transplantation; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Disease Transmission, Infectious; Double-Blind Method; Female; Ganciclovir; Humans; Male; Organ Transplantation; Organophosphonates; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Infectious; Quinazolines; Randomized Controlled Trials as Topic; Ribonucleosides

We summarize the history of the clinical drug development of maribavir for its use as prophylaxis in stem-cell transplant recipients. We highlight key aspects in the design and interpretation of the results of the dose escalation phase II maribavir study that may have contributed to the negative findings on the phase III trials. We discuss key aspects of study design that should be considered in the study of new interventions needed to advance the prevention and treatment of CMV in transplant recipients.

Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cytomegalovirus; Cytomegalovirus Infections; Humans; Randomized Controlled Trials as Topic; Ribonucleosides; Stem Cell Transplantation

The serine/threonine kinase expressed by human cytomegalovirus from gene UL97 phosphorylates the antiviral drug ganciclovir, but its biological function is the phosphorylation of its natural viral and cellular protein substrates which affect viral replication at many levels. The UL97 kinase null phenotype is therefore complex, as is the mechanism of action of maribavir, a highly specific inhibitor of its enzymatic activity. Studies that utilise the drug corroborate results from genetic approaches and together have elucidated many functions of the UL97 kinase that are critical for viral replication. The kinase phosphorylates eukaryotic elongation factor 1delta, the carboxyl terminal domain of the large subunit of RNA polymerase II, the retinoblastoma tumour suppressor and lamins A and C. Each of these is also phosphorylated and regulated by cdc2/cyclin-dependent kinase 1, suggesting that the viral kinase may perform a similar function. These and other activities of the UL97 kinase appear to stimulate the cell cycle to support viral DNA synthesis, enhance the expression of viral genes, promote virion morphogenesis and facilitate the egress of mature capsids from the nucleus. In the absence of UL97 kinase activity, viral DNA synthesis is inefficient and structural proteins are sequestered in nuclear aggresomes, reducing the efficiency of virion morphogenesis. Mature capsids that do form fail to egress the nucleus as the nuclear lamina are not dispersed by the kinase. The critical functions performed by the UL97 kinase illustrate its importance in viral replication and confirm that the kinase is a target for the development of antiviral therapies.

Topics: Amino Acid Sequence; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; DNA Replication; DNA, Viral; Humans; Molecular Sequence Data; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Viral Proteins; Virus Replication

Antiviral prophylaxis is commonly prescribed to haematological cancer patients. We conducted a systematic review and meta-analysis to quantify its overall benefit in specific clinical scenarios.. Randomised controlled trials assessing antiviral prophylaxis versus placebo, no treatment, pre-emptive treatment or another antiviral drug were included. Patients undergoing haematopoietic stem cell transplantation (HSCT) or intensive chemotherapy for acute leukaemia or high-grade lymphoma were included. No restrictions on language, year or publication status were applied. Overall mortality, herpes simplex virus (HSV) and cytomegalovirus (CMV) diseases were assessed as primary outcomes. Pooled relative risks (RRs) and numbers needed to treat (NNT) with 95% confidence intervals (CI) are reported.. HSCT was the condition assessed in 22 trials and intensive chemotherapy in 5 trials. In the pre-engraftment setting of autologous or allogeneic HSCT, antiviral prophylaxis (mainly acyclovir for HSV seropositive recipients) significantly reduced HSV (NNT 2, 2-2, control event rate (CER) 61.9%) and CMV disease, with no effect on overall mortality. In the allogeneic post-engraftment setting (mainly CMV-seropositive recipients/donors), antiviral prophylaxis resulted in a significant reduction in overall mortality, RR 0.79 (0.65-0.95), NNT 12 (7-50, CER 39.4%) and all viral-related outcomes. In this setting, acyclovir significantly reduced overall mortality (RR 0.71, 0.53-0.96, 4 trials) and ganciclovir/maribavir significantly reduced CMV disease (RR 0.26, 0.14-0.48, 5 trials). During chemotherapy, acyclovir significantly decreased HSV disease (NNT 3, 2-4, CER 37.4%) and infection rates, with no effect on mortality.. Antiviral prophylaxis reduced mortality with a small NNT in the post-engraftment setting of allogeneic HSCT. In the pre-engraftment phase and during chemotherapy only viral-related morbidity was reduced.

Topics: Acyclovir; Antineoplastic Agents; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Ganciclovir; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Oral Ulcer; Randomized Controlled Trials as Topic; Ribonucleosides; Treatment Outcome

To review the pharmacology, pharmacokinetics, efficacy, and safety of maribavir, a novel antiviral agent in the benzimidazole drug class.. Articles were identified through searches of MEDLINE (January 1998-July 2008). Abstracts from recent scientific meetings and the manufacturer were also included.. All English-language in vitro and in vivo studies and abstracts evaluating maribavir were reviewed and considered for inclusion. All human studies were included.. Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses. Unlike ganciclovir, which needs to be phosphorylated by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase. UL 97 kinase is an early viral gene product involved in viral DNA elongation, DNA packaging, and egress or shedding of capsids from viral nuclei. Maribavir has also been found to be effective against ganciclovir-resistant CMV strains. Maribavir differs from current CMV antiviral agents in its adverse event profile. Maribavir is not associated with nephrotoxicity or hematologic toxicities, but has been associated with taste disturbances. In February 2007, maribavir was granted Food and Drug Administration orphan drug status for prevention of CMV viremia and diseases in at-risk populations. Maribavir Phase 2 trials in stem-cell transplant recipients have been completed, and there are ongoing Phase 3 trials in stem-cell and organ transplant recipients.. Maribavir may be an option for treatment of ganciclovir-resistant CMV infections. Its bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir. No differences in pharmacokinetics were seen in renally impaired patients, although dialysis-dependent patients were not evaluated. Maribavir is not associated with hematologic toxicities; however, the high prevalence of taste disturbances may limit its tolerability.

Topics: Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease

Topics: Acyclovir; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Graft Rejection; Humans; Immunity, Cellular; Immunity, Innate; Immunosuppressive Agents; Liver Transplantation; Ribonucleosides; Risk Factors; Treatment Outcome; Valganciclovir; Virus Replication

A leading complication of leukemia therapy and stem cell transplantation is opportunistic viral infections. Infections caused by cytomegalovirus, herpes simplex, varicella-zoster, Epstein-Barr, and the community respiratory viruses are associated with significant morbidity and mortality in this highly immunosuppressed population. Fortunately, a growing armamentarium is allowing more effective prophylaxis of these pathogens. This article reviews the epidemiology and prophylactic strategies available for these common opportunistic viral pathogens.

Topics: Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Foscarnet; Ganciclovir; Herpes Zoster; Humans; Immune Sera; Immunization, Passive; Immunocompromised Host; Leukemia; Opportunistic Infections; Ribonucleosides; Stem Cell Transplantation; Virus Diseases

Maribavir is a novel benzimidazole riboside compound that is currently in clinical development with ViroPharma for the prevention of cytomegalovirus (CMV) infections in transplant patients. Maribavir is thought to inhibit viral DNA assembly and inhibit egress of viral capsids from infected cell nuclei. This mechanism is different to other available CMV treatments that inhibit CMV DNA polymerase. Maribavir, originally developed by GlaxoSmithKline, was licensed to ViroPharma in August 2003. Glaxo was conducting phase I/II clinical studies in the EU and the US in 2001, but discontinued development because the company felt that there was no longer a significant clinical need for maribavir as advances in the treatment of HIV have lead to improved immune systems in patients, resulting in a reduction in the incidence of CMV and CMV retinitis. In August 2003, ViroPharma acquired exclusive worldwide rights (excluding Japan) to develop and commercialise maribavir for the prevention and treatment of CMV infections related to transplant and congenital transmission and in patients with HIV infection. ViroPharma paid GlaxoSmithKline a $US3.5 million upfront licensing fee and will pay additional milestones based on defined clinical development and regulatory events. The company will also pay royalties on product sales in the US and the rest of the world, excluding Japan.A phase III study with maribavir as a prophylactic agent in patients undergoing allogeneic stem cell transplant who are CMV seropositive has been initiated and another phase III trial in solid organ transplant patients is planned. The stem cell transplant trial will take approximately 18 months to complete enrolment and the solid organ transplant trial, which won't be as large as the stem cell transplant trial, will be completed within this time-frame also. ViroPharma hopes to file an NDA for maribavir in 2009. Maribavir was granted fast-track status by the US FDA in February 2006 for the prevention of CMV infection in allogeneic bone marrow and solid organ transplant patients. Maribavir has received orphan drug status in the US for the prevention of CMV viraemia and disease in at-risk populations. ViroPharma has conducted a dose-ranging phase II clinical study designed to evaluate the antiviral activity, safety and pharmacokinetic profile of maribavir for the prevention of CMV infection in patients who have undergone allogeneic stem cell transplantation. The randomised, double-blind, placebo-controlled,

Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; HIV Infections; Humans; Ribonucleosides

ViroPharma, under license from GlaxoSmithKline, is developing maribavir, a DNA synthesis inhibitor for the potential prevention and treatment of human cytomegalovirus infections related to transplants (including solid organ and hematopoietic stem cells), congenital transmission, and in patients with HIV infection. In July 2004, a phase II trial was initiated.

Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytomegalovirus Infections; Humans; Nucleic Acid Synthesis Inhibitors; Patents as Topic; Randomized Controlled Trials as Topic; Ribonucleosides; Structure-Activity Relationship

Benzimidazole ribosides are a new class of compounds with novel mechanisms of action against CMV. One compound in this series, BDCRB, inhibits CMV DNA processing by the UL89 gene product (putative terminase), but rapid metabolism to an inactive compound makes it unsuitable for development as a medicine. Another benzimidazole analogue, 1263W94, has many characteristics that make it an attractive candidate for development, including high potency in vitro, selectivity, good oral bioavailability, and lower toxicity than therapies currently available for treatment of CMV disease. Initial clinical trials have provided encouraging results, including good tolerability and linear pharmacokinetics over a wide dose range. Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease.

Topics: Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Drug Design; Humans; Ribonucleosides

Cytomegalovirus (CMV), a common post-transplant infection, is associated with increased healthcare resource utilization. In the Phase 3 SOLSTICE trial, maribavir was superior to investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, and cidofovir) for CMV viremia clearance at Week 8 in transplant recipients with confirmed refractory CMV infection with/without resistance. This exploratory analysis evaluated hospital admissions of patients during the SOLSTICE trial.. Patients were randomized to maribavir (400 mg twice daily) or IAT for an 8-week treatment phase with a 12-week follow-up. After ≥3 weeks of treatment, patients on IAT who met pre-specified criteria could enter a maribavir rescue arm (8-week maribavir treatment, 12-week follow-up). Adjusted hospitalization rates and length of hospital stay (LOS) were estimated using negative binomial models adjusting for the time in the relevant study phase. Subgroup analysis for the maribavir rescue arm was conducted.. Overall, 352 patients were randomized (maribavir: 235; IAT: 117); 22 entered the maribavir rescue arm. After adjusting for treatment exposure, patients on maribavir had a 34.8% reduction in hospitalization rate and 53.8% reduced LOS (days/person/year) versus IAT during the treatment phase. No significant differences between treatments were observed during the follow-up phase, although in both arms, hospitalization rates were lower than in the treatment phase. In the maribavir rescue arm, hospitalizations were 60.6% lower on/after maribavir rescue versus pre-rescue treatment (p = 0.008).. In patients requiring post-transplant CMV treatment, hospitalization rate and LOS were lower for maribavir than IAT, and hospitalization rates were lower on/after maribavir rescue than pre-rescue. Reducing hospitalizations can alleviate the burden on patients and healthcare systems.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Delivery of Health Care; Ganciclovir; Humans; Transplant Recipients

Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.. In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.. 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.. Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Valganciclovir; Viremia

Topics: Adult; Antiviral Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Cytochrome P-450 CYP2D6; Cytomegalovirus Infections; Dextromethorphan; Digoxin; Drug Interactions; Female; Genotype; Healthy Volunteers; Humans; Male; Middle Aged; Ribonucleosides; Young Adult

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.).

Topics: Adult; Aged; Allografts; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Dysgeusia; Female; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Intention to Treat Analysis; Male; Middle Aged; Neutropenia; Organ Transplantation; Ribonucleosides; Valganciclovir; Viremia; Virus Activation

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.

Topics: Benzimidazoles; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Genes, Viral; Genotyping Techniques; Humans; Inhibitory Concentration 50; Mutation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

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.. 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).. 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 <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.. Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.. NCT01611974.

Topics: Adolescent; Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Ribonucleosides; Transplant Recipients; Young Adult

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

Topics: Acyclovir; Administration, Oral; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Liver Transplantation; Male; Postoperative Complications; Prospective Studies; Ribonucleosides; Risk Assessment; Treatment Outcome

Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients.. In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645.. Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0.95), but not when measured by plasma cytomegalovirus DNA PCR (27.8%vs 30.4%; OR 0·88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6%vs 37.4%; OR 0.73, 0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo).. Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials.. ViroPharma Incorporated.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; Benzimidazoles; Canada; Chemoprevention; Cytomegalovirus Infections; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; Placebos; Ribonucleosides; Stem Cell Transplantation; Transplantation; Treatment Outcome; United States; Young Adult

The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Ribonucleosides; Stem Cell Transplantation; Taste Disorders; Transplantation, Homologous; Vomiting

The effect of renal function on the pharmacokinetics of maribavir, a novel anticytomegalovirus agent, was evaluated in 12 adults with normal renal function (creatinine clearance [CrCl] >80 mL/min) and 19 adults with renal impairment classified as mild (n = 5), moderate (n = 5), or severe (n = 9), as measured by CrCl 50-80, 30-49, and <30 mL/min, respectively. After a single oral dose of maribavir 400 mg, the pharmacokinetics of maribavir, based on total and unbound plasma concentrations, showed no statistically significant difference between subjects with normal renal function and subjects with mild/moderate or severe renal impairment. Renal impairment was associated with an increase in area under the plasma concentration-time curve (AUC) values for an inactive metabolite of maribavir, VP 44469. Results were consistent with those of previous studies, which showed that very little maribavir was excreted unchanged in urine, whereas about 22% of an oral dose of maribavir is recovered in urine as VP 44469.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Creatinine; Cytomegalovirus Infections; Female; Humans; Kidney Diseases; Male; Middle Aged; Ribonucleosides

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,beta-L-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log(10) PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.

Topics: Adult; Area Under Curve; Benzimidazoles; Cells, Cultured; Culture Media; Cytomegalovirus Infections; DNA, Viral; Dose-Response Relationship, Drug; HIV Infections; Humans; Male; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleosides; Semen; Urine; Viral Plaque Assay; Virus Shedding

Topics: Cytomegalovirus; Cytomegalovirus Infections; Humans; Renal Insufficiency

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Humans; Organ Transplantation; Transplant Recipients

Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory (with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.

Topics: Adolescent; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Ribonucleosides; United States

Topics: Antiviral Agents; Cytomegalovirus Infections; Humans

Topics: Antiviral Agents; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Transplant Recipients

Management of pan-resistant cytomegalovirus infection (CMVi) requires a multifaceted approach, including host defence optimization by reducing immunosuppression, and standard or experimental antiviral therapy.. A 36-year-old man with anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma, who underwent allogeneic haematopoietic stem cell transplant (alloHCT) with resultant graft-versus-host disease treated with immunosuppressive therapy, developed pan-resistant CMVi. He was successfully treated with combination therapy of maribavir and letermovir.. Combination therapy, used for other infections to prevent cross-resistant, may apply for CMVi.

Topics: Acetates; Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Quinazolines; Ribonucleosides

Topics: Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Humans

In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks.. 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.. 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.. 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.. NCT01611974 and EudraCT 2010-024247-32.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Mutation; Phenotype; Phosphotransferases (Alcohol Group Acceptor)

Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of these drugs is limited by toxicity and the development of resistance. The 2017 approval of letermovir for prevention of CMV after stem cell transplant marked the first approval of an anti-CMV agent since 2003. The role of letermovir in treatment of established CMV infection or disease remains largely unstudied, although early reports suggest that a low barrier to resistance will likely limit efficacy as primary therapy for patients with refractory or resistant disease. The investigational agent maribavir has shown promise as preemptive treatment; in patients with refractory or resistant disease the emergence of resistance while on treatment has been observed and ongoing studies will define efficacy in this population. Both agents have unique mechanisms of action limiting cross resistance, and neither exhibit myelotoxicity or nephrotoxicity.

Topics: Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Humans; Quinazolines; Ribonucleosides; Transplant Recipients

Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs' antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.

Topics: Aminopyridines; Animals; Antiviral Agents; Benzimidazoles; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Combinations; Drug Resistance, Viral; Ganciclovir; Humans; Mice; Protein Kinase Inhibitors; Pyrazoles; Ribonucleosides; Triazines; Virus Replication

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.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Female; Ganciclovir; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kidney Transplantation; Mutation; Organ Transplantation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Transplant Recipients; Treatment Outcome

Because ganciclovir resistance mutations in the cytomegalovirus UL97 gene most commonly occur at codons 460, 520 and 590-607, diagnostic genotyping for drug resistance has often omitted the analysis of codons below 440. However, the UL97 kinase inhibitor maribavir selects for distinctive resistance mutations at codons 409 and 411, and ganciclovir/maribavir resistance mutations have also been described in the ATP binding region starting at codon 335. Expanded genotypic testing of UL97 codons 335-440 in 1535 clinical specimens disclosed 10 uncharacterized sequence variants that were phenotyped for ganciclovir and maribavir susceptibility. Notable findings included low-grade ganciclovir resistance conferred by amino acid substitutions K359N and E362D, decreased maribavir susceptibility of L348V, and maribavir hypersensitivity of V345I and E362D. Recently published substitutions F342Y and K359E/Q were also confirmed. The data indicate that mutations in the UL97 ATP binding region may arise in clinical specimens to affect the interpretation of ganciclovir and maribavir resistance. This region should now be included in the standard diagnostic genotyping of UL97, especially with the introduction of maribavir into therapeutic use.

Topics: Adenosine Triphosphate; Amino Acid Substitution; Antiviral Agents; Benzimidazoles; Codon; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Genotyping Techniques; Humans; Mutation; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

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.. 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)).. 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.. Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.

Topics: Acetates; Adult; Antiviral Agents; Benzimidazoles; Chromatography, Liquid; Cytomegalovirus Infections; Female; Humans; Kinetics; Maternal-Fetal Exchange; Models, Biological; Perfusion; Placenta; Pregnancy; Quinazolines; Ribonucleosides; Tandem Mass Spectrometry

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.

Topics: Acetates; Antiviral Agents; Artemisinins; Benzimidazoles; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Drug Interactions; Drug Synergism; Drugs, Investigational; Female; Ganciclovir; Humans; Organ Culture Techniques; Organophosphonates; Placenta; Pregnancy; Quinazolines; Ribonucleosides

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.

Topics: Benzimidazoles; Calcium Signaling; Cell Differentiation; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Organ Culture Techniques; Organoids; Receptors, Purinergic; Ribonucleosides; Virus Replication; Voltage-Gated Sodium Channels

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.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Cidofovir; Cyclopropanes; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; DNA-Directed DNA Polymerase; Drug Antagonism; Drug Combinations; Drug Resistance, Viral; Drug Synergism; Drug Therapy, Combination; Endodeoxyribonucleases; Fibroblasts; Foscarnet; Ganciclovir; Guanine; Humans; Nucleic Acid Synthesis Inhibitors; Organophosphonates; Ribonucleosides; Viral Proteins; Virus Replication

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.. The objective of this study was to evaluate the potential effect of maribavir on CMV-specific T cell function in comparison to ganciclovir.. 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.. 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.. 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.

Topics: Antiviral Agents; Benzimidazoles; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Immunity, Cellular; Immunocompetence; Immunologic Tests; Ribonucleosides

Congenital human cytomegalovirus (HCMV) infection is a major public health problem due to severe sequelae in the fetus and newborns. Currently, due to their toxicity anti-CMV treatments cannot be administered to pregnant women. We thus developed an ex vivo model of 1(st) trimester placental CMV infection to observe the route of infection across the placenta and to test the efficacy of various new drugs targeting different stages of viral cycle.. After validation of the viability of floating villi explants by ELISA β-HCG, the kinetics of placental infection were determined by immunochemistry and qPCR in this ex vivo model. Antiviral susceptibility was determined in vitro using focus reduction assay and by qPCR in the ex vivo model.. The ex vivo model showed viral infection in trophoblasts and mesenchymal space of floating villi. In vitro, antiviral combinations of maribavir with baïcalein or artesunate inhibited viral infection by more than 90%. On the other hand, in ex vivo model, infection was reduced by 40% in presence of maribavir and artesunate. The synergistic effect observed in vitro was not observed ex vivo.. This model allowed us to understand the CMV spread in 1(st) trimester floating villi better and to analyze the anti-CMV efficacy and toxicity of new drugs that could be administered to pregnant women, either alone or in combination.. Such an ex vivo model could be applied to other viruses such as rubella or parvovirus B19 and in new drug development.

Topics: Adult; Antiviral Agents; Artemisinins; Artesunate; Benzimidazoles; Cytomegalovirus Infections; Female; Flavanones; Humans; Pregnancy; Pregnancy Complications, Infectious; Ribonucleosides; Trophoblasts

Topics: Benzimidazoles; Colitis; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Heart Transplantation; Humans; Male; Middle Aged; Ribonucleosides; Transplant Recipients

Human cytomegalovirus UL97 kinase mutations that commonly confer ganciclovir resistance cluster in different parts of the gene than those conferring resistance to maribavir, an experimental UL97 kinase inhibitor. The drug resistance, growth, and autophosphorylation phenotypes of several unusual UL97 mutations in the kinase catalytic domain were characterized. Mutations V466G and P521L, described in clinical specimens from ganciclovir-treated subjects, conferred a UL97 kinase knockout phenotype with no autophosphorylation, a severe growth defect, and high-level ganciclovir, cyclopropavir, and maribavir resistance, similar to mutations at the catalytic lysine residue K355. Mutations F342S and V356G, observed after propagation under cyclopropavir in vitro, showed much less growth attenuation and moderate- to high-level resistance to all three drugs while maintaining UL97 autophosphorylation competence and normal cytopathic effect in cell culture, a novel phenotype. F342S is located in the ATP-binding P-loop and is homologous to a c-Abl kinase mutation conferring resistance to imatinib. UL97 mutants with relatively preserved growth fitness and multidrug resistance are of greater concern in antiviral therapy than the severely growth-impaired UL97 knockout mutants. Current diagnostic genotyping assays are unlikely to detect F342S and V356G, and the frequency of their appearance in clinical specimens remains undefined.

Topics: Antiviral Agents; Benzimidazoles; Catalytic Domain; Cell Line; Cyclopropanes; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple; Drug Resistance, Viral; Ganciclovir; Genotype; Guanine; Humans; Mutation; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

Maribavir (MBV), a UL97 inhibitor, shows good oral bioavailability, low host cell toxicity, and theoretical benefits to inhibit cross-resistant viruses. We herein examined clinical and virological outcomes of 12 patients, including 3 bone marrow recipients and 9 organ recipients infected with resistant cytomegalovirus (CMV) and treated with MBV during 2011-2012. All received at least 800-mg daily doses. They had developed clinical (12/12) and/or virological (11/12) resistance to CMV infection. Based on a decrease of viral load in blood >1.5 log copies/mL half of them responded to MBV treatment. The individual changes varied from a rapid decrease in viral load (n = 4) to no response (n = 3) with some late response slowly decreasing viremia (n = 3). In 2 cases MBV was used as secondary prophylaxis. No clear parameter emerged as a clinical surrogate for nonresponse to MBV. These results contrast with the lack of efficacy in phase III trials of MBV prophylaxis among stem cell recipients, which were possibly due to low doses or inadequate timing of drug initiation in the study. Additional clinical and surrogate laboratory markers are needed to determine antiviral responses to guide MBV use. Dosage ranging studies might benefit future MBV use.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; France; Genotype; Humans; Microbial Sensitivity Tests; Middle Aged; Organ Transplantation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

Human cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients. The use of antiviral agents is limited by toxicity and evolving resistance in immunocompromised patients with ongoing viral replication during therapy. Here, we present the first documented case of genotypic resistance against maribavir in a bone marrow transplant (BMT) recipient.. The female 13-year-old patient was suffering from a refractory cytopenia. Ganciclovir, foscarnet, cidofovir, leflunomide and maribavir, an inhibitor of the cytomegalovirus UL97 protein, were administered to treat a therapy-resistant cytomegalovirus infection. Viral mutations conferring resistance against nucleotide and pyrophosphate analogs as well as maribavir (MBV) have evolved sequentially. Particularly, impressive was the fast emergence of multiple mutations T409M, H411Y and H411N conferring maribavir resistance after less than 6 weeks.. We describe the fast emergence of cytomegalovirus variants with different maribavir resistance associated mutations in a bone marrow transplant recipient treated with MBV 400 mg p.o. twice per day. The results suggest that a high virus load permitted a selection of several but distinct therapy-resistant HCMV mutants. Since a phase II study with MBV is intended for the treatment of resistant or refractory HCMV infections in transplant recipients this has to be kept in mind in patients with high viral loads during therapy (NCT01611974).

Topics: Adolescent; Antiviral Agents; Benzimidazoles; Bone Marrow Transplantation; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Female; Humans; Ribonucleosides

Resistance to the experimental human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir has been mapped to UL97 mutations at codons 353, 397, 409 and 411, in the kinase ATP-binding region, and to mutations in the UL27 gene. We studied the maribavir susceptibility phenotypes of additional UL97 mutations observed in vitro and in clinical trials, and the effect of simultaneous mutation in both UL97 and UL27. In vitro selection under maribavir identified a new locus of UL97 mutation within the conserved kinase p-loop (L337M), which conferred low grade maribavir resistance (3.5-fold increased EC50) without ganciclovir cross-resistance. During maribavir Phase III CMV prevention clinical trials, three previously unknown UL97 sequence variants were detected in plasma samples after 27-98 days of drug exposure (I324V, S334G and S386L). These variants did not confer any drug resistance despite proximity to mutations that confer maribavir resistance. The UL27 resistance mutation R233S, when added to strains containing UL97 mutations L337M or V353A, doubled their maribavir EC50s. These results expand the range of UL97 maribavir-resistance mutations into another part of the kinase ATP-binding region, but offer no genotypic evidence that development of drug resistance affected the outcomes of Phase III maribavir clinical trials after drug exposure of up to 14 weeks. There is a potential for increased maribavir resistance in UL27-UL97 double mutants.

Topics: Antiviral Agents; Benzimidazoles; Clinical Trials, Phase III as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Humans; Mutation, Missense; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides

Infection with the β-herpesvirus human cytomegalovirus (HCMV) is lifelong, causing limited disease in healthy adults, but life threatening in immunocompromised individuals. The viral kinase pUL97, a functional ortholog of cellular cyclin-dependent kinases (CDKs), is critical for HCMV replication and a target for antiviral drug development. Upon kinase inhibition, drug-resistant strains emerge with mutations in UL27, an HCMV gene of unknown function. Using a proteomics approach, we discovered that pUL27 is necessary and sufficient to degrade Tip60, a host acetyltransferase and interacting partner of HIV Tat. Consistent with this, the expression of Tat restored antiviral inhibition of an otherwise resistant HCMV strain. The functional consequence of Tip60 degradation was the induction of the CDK inhibitor p21(Waf1/Cip1) and cell-cycle arrest, representing changes necessary for the antiviral effects of pUL97 inhibition. Consequently, either increasing p21(Waf1/Cip1) expression or decreasing Tip60 levels improved the antiviral activity of the HCMV kinase inhibitor maribavir.

Topics: Antiviral Agents; Benzimidazoles; Cell Cycle; Cell Line; Cyclin-Dependent Kinase Inhibitor p21; Cytomegalovirus; Cytomegalovirus Infections; Down-Regulation; Histone Acetyltransferases; Humans; Lysine Acetyltransferase 5; Phosphotransferases (Alcohol Group Acceptor); Protein Binding; Protein Kinase Inhibitors; Ribonucleosides

Topics: Antiviral Agents; Benzimidazoles; Chemoprevention; Cytomegalovirus Infections; Humans; Randomized Controlled Trials as Topic; Ribonucleosides; Stem Cell Transplantation; Transplantation; Treatment Failure

The molecular mechanisms of human cytomegalovirus (CMV) resistance to both ganciclovir and maribavir reported so far rely predominantly on the presence of mutations within UL97 phosphotransferase. The accurate interpretation of genotypic antiviral resistance assay results requires the clear distinction between resistance mutations and natural interstrain sequence variations. The objective of this work was to extend the catalog of CMV UL97 phosphotransferase natural polymorphisms. The full-length UL97 gene sequence analysis from 4 laboratory strains and 35 clinical samples from patients who had not received any previous anti-CMV treatment was performed. At the nucleotide level, the interstrain identity was >98%. At the amino acid level, ten natural polymorphisms never previously described were identified. Together with all previous results reported in the literature, a new map of UL97 phosphotransferase natural polymorphism could be settled in the era of ganciclovir and maribavir.

Topics: Amino Acid Sequence; Antiviral Agents; Base Sequence; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Genotype; Humans; Molecular Sequence Data; Mutation; Phosphotransferases (Alcohol Group Acceptor); Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Ribonucleosides; Sequence Analysis, DNA

Select mutations in the human cytomegalovirus (HCMV) gene UL27 confer low-grade resistance to the HCMV UL97 kinase inhibitor maribavir (MBV). It has been reported that the 608-amino acid UL27 gene product (pUL27) normally localizes to cell nuclei and nucleoli, whereas its truncation at codon 415, as found in a MBV-resistant mutant, results in cytoplasmic localization. We now show that in the context of full-length pUL27, diverse single amino acid substitutions associated with MBV resistance result in loss of its nucleolar localization when visualized after transient transfection, whereas substitutions representing normal interstrain polymorphism had no such effect. The same differences in localization were observed during a complete infection cycle with recombinant HCMV strains over-expressing full-length fluorescent pUL27 variants. Nested UL27 C-terminal truncation expression plasmids showed that amino acids 596-599 were required for the nucleolar localization of pUL27. These results indicate that the loss of a nucleolar function of pUL27 may contribute to MBV resistance, and that the nucleolar localization of pUL27 during HCMV infection depends not only on a carboxy-terminal domain but also on a property of pUL27 that is affected by MBV-resistant mutations, such as an interaction with component(s) of the nucleolus.

Topics: Antiviral Agents; Benzimidazoles; Cell Nucleus; Cytomegalovirus; Cytomegalovirus Infections; Cytoplasm; Drug Resistance, Viral; Humans; Mutation, Missense; Ribonucleosides; Viral Proteins; Virus Replication

The experimental cytomegalovirus UL97 kinase inhibitor maribavir was used to treat 2 cases of infection in which viral mutations that conferred ganciclovir and foscarnet resistance had evolved sequentially. In one case, viral shedding was cleared without evidence of maribavir resistance in an isolate obtained after therapy. In the other case, a high-grade viremia was initially reduced 50-fold but rebounded 2 months later, coincident with the emergence of viral UL97 mutations T409M and H411Y, which confer maribavir resistance. The relatively rapid onset of maribavir resistance probably resulted from incomplete viral suppression in an immunosuppressed host with a high viral load.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Female; Heart Transplantation; Humans; Lung Transplantation; Male; Mutation; Ribonucleosides; Viral Load; Viremia

Topics: Algorithms; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Isoxazoles; Leflunomide; Ribonucleosides; Stem Cell Transplantation; Transplantation Immunology

Despite advances in cytomegalovirus (CMV) prophylaxis and therapy, some transplant recipients still develop refractory CMV infections. Maribavir (MBV), an investigational benzimidazole antiviral agent, acts by a mechanism different from that of existing anti-CMV drugs. Previous Phase I and II studies have demonstrated a favorable safety profile for MBV, but its utility in treatment of complex CMV syndromes is unknown.. Between June and December 2008, MBV was released for use under individual emergency investigational new drug applications requested by treating physicians and approved by the US Food and Drug Administration and local institutional review boards. Six patients (5 solid organ transplant recipients and 1 hematopoietic stem cell transplant recipient) who had failed to respond to other therapies and/or had known ganciclovir-resistant CMV were treated with MBV at a starting oral dose of 400 mg twice daily.. Patients were treated for a median of 207 days (range, 15-376). Four of 6 patients had no detectable CMV DNAemia within 6 weeks of starting MBV therapy. One patient, who had an initial viral load of 1.8 million copies/mL, developed MBV resistance mutations. One patient, who had low serum levels of MBV, had persistent CMV DNAemia and viruria without developing genotypic or phenotypic resistance to MBV. One patient cleared CMV DNAemia, but died of pneumonia and multiorgan failure. No significant adverse effects attributable to MBV were observed.. MBV deserves further systematic evaluation as treatment for CMV infection that is resistant and/or refractory to standard therapies, but its optimal dose, duration of therapy, and use in combinations versus as a single agent have yet to be determined.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Female; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Organ Transplantation; Ribonucleosides; Treatment Outcome

The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/cyclin-dependent kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser(22)). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser(22) is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitotic host cell kinase activity promotes nuclear egress while accommodating viral arrest of the cell cycle.

Topics: Benzimidazoles; CDC2 Protein Kinase; Cell Line; Cell Nucleus; Cytomegalovirus; Cytomegalovirus Infections; Humans; Lamin Type A; Molecular Mimicry; Nuclear Lamina; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Virus Replication

A human cytomegalovirus (CMV) UL54 pol exonuclease domain II mutation, D413A, found in a clinical specimen, conferred ganciclovir (GCV) and cidofovir resistance but not foscarnet resistance when incorporated into laboratory strain T2294. After several passages without drug, mutation was observed in five of eight plaques of T2294, and its plating efficiency under foscarnet was increased approximately 30-fold over that of a control strain. When T2294 was serially passed under maribavir (MBV), phenotypic changes and viral UL97 mutations were detected by passage 5, much earlier than previously reported for other CMV strains. By passage 15, mutations included two cases of H411Y, one each of H411L and H411N, three of T409M, five of V353A, and one of L397R. Five instances of codon 409 or 411 mutations evolved into double mutations including V353A. Marker transfer experiments showed H411N/Y/L to confer 9- to 70-fold-increased MBV resistance and combinations of H411L/Y and V353A to confer >150-fold-increased MBV resistance, but no GCV resistance. These findings are consistent with defective exonuclease activity of the pol D413A mutant T2294, leading to the accelerated evolution of UL97 mutations under MBV. This recapitulated the known resistance mutations V353A, L397R, and T409M; suggested their relative frequency; and identified new ones at codon 411. These UL97 mutations predict an MBV binding region overlapping the kinase ATP binding site and located upstream of known GCV resistance mutations. The existence of viable pol D413A mutants may facilitate the selection of additional drug resistance mutations in vivo and the study of these mutations in vitro.

Topics: Amino Acid Sequence; Amino Acid Substitution; Antiviral Agents; Benzimidazoles; Cells, Cultured; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Models, Molecular; Molecular Sequence Data; Mutant Proteins; Organophosphonates; Phosphotransferases (Alcohol Group Acceptor); Protein Structure, Tertiary; Ribonucleosides; Sequence Alignment; Viral Proteins

The cytomegalovirus (CMV) UL97 kinase inhibitor maribavir antagonized the anti-CMV effect of ganciclovir, increasing the ganciclovir 50% inhibitory concentration against a sensitive strain by up to 13-fold. Antiviral activities of foscarnet and cidofovir were unaffected by maribavir.

Topics: Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Antagonism; Drug Resistance, Viral; Drug Therapy, Combination; Ganciclovir; Humans; Microbial Sensitivity Tests; Ribonucleosides

Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were implanted with human fetal tissue that was subsequently infected with HCMV. In one model, human fetal retinal tissue was implanted into the anterior chamber of the SCID mouse eye, and in the second, human fetal thymus and liver (thy/liv) tissues were implanted under the kidney capsule. After the implants were established, they were infected with 2,000 to 9,000 PFU of HCMV. To determine the efficacy of three benzimidazole nucleosides, 2-bromo-5,6-dichloro-(1-beta-D-ribofuranosyl)benzimidazole (BDCRB), GW275175X (175X), and GW257406X (1263W94, maribavir [MBV]) treatment was initiated 24 h after infection of the implants and continued for 28 days. Treatment consisted of either placebo, 25 mg of ganciclovir (GCV)/kg of body weight administered intraperitoneally (i.p.) twice daily, 33 or 100 mg of BDCRB/kg administered i.p. twice daily, or 75 mg of either MBV or 175X/kg administered orally twice daily. GCV was effective in both models, inhibiting HCMV infection by 5- to 3,000-fold. In the retinal tissue model, MBV and BDCRB reduced HCMV replication about fourfold through 21 days postinfection compared with results for the vehicle control. In the thy/liv tissue model, all three benzimidazole nucleosides were effective in inhibiting HCMV replication by approximately 30- to 3,000-fold in comparison to the vehicle control. These data indicate that the benzimidazole nucleosides were efficacious in these animal models and suggest that this class of compounds should be active against the various HCMV infections that occur in the immunocompromised host.

Topics: Animals; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Disease Models, Animal; Humans; Injections, Intraperitoneal; Male; Mice; Mice, SCID; Retina; Ribonucleosides; Viral Plaque Assay; Virus Replication

Topics: Animals; Anti-HIV Agents; Benzimidazoles; Biological Availability; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Microbial; Drugs, Investigational; Haplorhini; HIV Infections; Humans; Rats; Ribonucleosides