letermovir and Opportunistic-Infections

Cytomegalovirus (CMV) is a common opportunistic infection that causes significant morbidity and preventable mortality after solid-organ and allogeneic hematopoietic stem cell transplantation. Areas covered: Current strategies of pharmacological treatment of CMV in solid-organ and hematologic stem cell transplantation are reviewed. The role of the newly approved drug, letermovir, and other novel investigational compounds is discussed. The complementary role of viral and immunologic monitoring in guiding the optimal role of pharmacologic agents on the management of CMV after transplantation is highlighted. Advances in immunotherapeutics are highlighted. Expert commentary: With advances in therapeutic and diagnostic modalities, the management of CMV infection and disease after transplantation continues to evolve. The authors provide a succinct yet comprehensive review of the current prevention and treatment for CMV infection and disease in transplant recipients. The role of the newly approved drug, letermovir, for CMV prevention is highlighted in the context of current prevention strategies after allogeneic hematopoietic stem cell transplantation. The emerging role of cell-mediated immunologic monitoring, which complements the established function of viral load testing, is emphasized. Finally, the integration of novel antiviral therapies, standardized molecular tests, immunologic assays, and immunotherapeutics are discussed.

Topics: Acetates; Antiviral Agents; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Opportunistic Infections; Organ Transplantation; Quinazolines; Viral Load

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become one of the standard treatment for hematological diseases. Although the clinical outcome has improved significantly during the last decades, the morbidity and mortality after allo-HSCT are still obstacles to cure. Out of major morbidities, opportunistic virus infections such as cytomegalovirus (CMV) infection are important complications, in particular in patients who received human leukocyte antigen-mismatched HSCT. Here, we aim to summarize information about current and future therapeutic options in CMV disease after allo-HSCT.. Recently, not only new drugs but also adoptive T-cell therapy are tested in the setting of clinical trials. CMV prophylaxis using letermovir significantly reduced the incidence of CMV disease in comparison to placebo in a phase III clinical trial. Meanwhile, adoptive T-cell therapies which are fully adapted to good manufacturing practice (GMP) conditions are now available. A recent multicenter study in Germany showed a promising result using Streptamer-isolated T-cell therapy.. With the recent development of CMV-targeted therapy, treatment strategies of CMV infection would be further sophisticated in the near future. VIDEO ABSTRACT: http://links.lww.com/COID/A19.

Topics: Acetates; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Opportunistic Infections; Postoperative Complications; Quinazolines; Transplant Recipients

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-of-concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.

Topics: Acetates; Adult; Aged; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Kidney Transplantation; Male; Middle Aged; Opportunistic Infections; Quinazolines; Viral Load; Viremia

Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance.. In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection.. The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.. Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

Topics: Acetates; Adult; Antiviral Agents; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Incidence; Kaplan-Meier Estimate; Opportunistic Infections; Quinazolines; Transplantation, Homologous; Treatment Failure

Little information on the efficacy and pharmacokinetics of letermovir among immunocompromised children is currently available. We describe here the use of letermovir in a 2-year-old immunocompromised child with ganciclovir-resistant cytomegalovirus disease who required extracorporeal membrane oxygenation. Detailed information on therapeutic-drug-monitoring measures and dosage adjustments for letermovir is provided.

Topics: Acetates; Antiviral Agents; Child, Preschool; Compassionate Use Trials; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Dose-Response Relationship, Drug; Drug Monitoring; Extracorporeal Membrane Oxygenation; Fatal Outcome; Female; Ganciclovir; Hepatitis, Viral, Human; Humans; Immunocompromised Host; Opportunistic Infections; Pneumonia, Viral; Polymerase Chain Reaction; Quinazolines; Treatment Failure; Viral Load

Topics: Acetates; Antiviral Agents; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Opportunistic Infections; Quinazolines