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Clinical Infectious Diseases : An... Sep 2022Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 34864943
DOI: 10.1093/cid/ciab988 -
American Journal of Transplantation :... Feb 2013Cytomegalovirus (CMV) is the most common infection after organ transplantation and has a major impact on morbidity, mortality and graft survival. Optimal prevention,... (Review)
Review
Cytomegalovirus (CMV) is the most common infection after organ transplantation and has a major impact on morbidity, mortality and graft survival. Optimal prevention, diagnosis and treatment of active CMV infection enhance transplant outcomes, and are the focus of this section. Methods to prevent CMV include universal prophylaxis and preemptive therapy; each has its merits, and will be compared and contrasted. Diagnostics have improved substantially in recent years, both in type and quality, allowing for more accurate and savvy treatment; advances in diagnostics include the development of an international standard, which should allow comparison of results across different methodologies, and assays for cellular immune function against CMV. Therapy primarily involves ganciclovir, now rendered more versatile by data suggesting oral therapy with valganciclovir is not inferior to intravenous therapy with ganciclovir. Treatment of resistant virus remains problematic, but is enhanced by the availability of multiple novel therapeutic agents.
Topics: Administration, Oral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Graft Survival; Humans; Organ Transplantation; Valganciclovir
PubMed: 23347212
DOI: 10.1111/ajt.12006 -
Clinical Microbiology and Infection :... Jan 2023The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have... (Review)
Review
BACKGROUND
The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have successfully been used for prevention and treatment of CMV infections, although with serious side effects such as leucopenia and some development of resistance. Until recently, available therapies for ganciclovir-resistant CMV have significant toxicities. Although advances have been made in the field, the unmet medical needs for effective and well-tolerated therapies are significant.
OBJECTIVES
This review aims to summarise the current and emerging CMV antiviral drugs and discusses future perspectives in the field.
SOURCES
We searched for relevant articles with pertinent keywords: "Cytomegalovirus OR CMV", "Transplant" and "Antiviral". Articles published after 2019 were given preference. Articles were reviewed by the authors for relevance and impact to the subject of interest.
CONTENT
We outline in this review current advances in prophylaxis of CMV infection with letermovir, breakthrough CMV infections while on or after prophylaxis, the development of resistant and refractory CMV infections, and the newly approved anti-CMV agent, maribavir, in haematopoietic and solid-organ transplant recipients.
IMPLICATIONS
Prevention of CMV infections after transplant has improved greatly over the past few years. Despite major advancements, breakthrough CMV infections and development of refractory and resistant CMV infections remain major complications post transplantation. We highlight emerging therapeutics that tolerably and effectively prevent and treat CMV infections, especially refractory and resistant cases.
Topics: Humans; Transplant Recipients; Cytomegalovirus Infections; Antiviral Agents; Ganciclovir; Cytomegalovirus
PubMed: 35843567
DOI: 10.1016/j.cmi.2022.07.001 -
Antimicrobial Agents and Chemotherapy Sep 2022Maribavir 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... (Review)
Review
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
PubMed: 35916518
DOI: 10.1128/aac.02405-21 -
The New England Journal of Medicine Mar 2015The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time.
METHODS
We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline.
RESULTS
A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64).
CONCLUSIONS
Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).
Topics: Antiviral Agents; Audiometry; Child Development; Cytomegalovirus Infections; Double-Blind Method; Drug Administration Schedule; Evoked Potentials, Auditory, Brain Stem; Ganciclovir; Gestational Age; Hearing Loss, Sensorineural; Humans; Infant, Newborn; Neutropenia; Valganciclovir
PubMed: 25738669
DOI: 10.1056/NEJMoa1404599 -
Transplant International : Official... 2023Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV... (Review)
Review
Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Acetates; Ganciclovir
PubMed: 37901297
DOI: 10.3389/ti.2023.11785 -
Viruses Oct 2022Cytomegalovirus (CMV), a member of the Herpesviridae family, is frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients in absence... (Review)
Review
Cytomegalovirus (CMV), a member of the Herpesviridae family, is frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients in absence of antiviral prophylaxis, and is a major cause of morbidity and mortality in these vulnerable populations. Antivirals such ganciclovir, valganciclovir, and foscarnet are the backbone therapies, however drug toxicity and antiviral resistance may render these agents suboptimal in treatment. Newer therapies such as letermovir and maribavir have offered additional approaches for antiviral prophylaxis as well as treatment of drug resistant CMV infection, though may be limited by cost, drug intolerance, or toxicity. Adoptive immunotherapy, the transfer of viral specific T-cells (VSTs), offers a new approach in treatment of drug-resistant or refractory viral infections, with early clinical trials showing promise with respect to efficacy and safety. In this review, we will discuss some of the encouraging results and challenges of widespread adoption of VSTs in care of immunocompromised patients, with an emphasis on the clinical outcomes for treatment and prophylaxis of CMV infection among high-risk patient populations.
Topics: Humans; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation; Cytomegalovirus Infections; Ganciclovir; Cytomegalovirus; Antiviral Agents; Drug Resistance, Viral
PubMed: 36366468
DOI: 10.3390/v14112370 -
American Journal of Transplantation :... Sep 2007Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative.... (Randomized Controlled Trial)
Randomized Controlled Trial
Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Double-Blind Method; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Injections, Intravenous; Male; Middle Aged; Organ Transplantation; Retrospective Studies; Treatment Outcome; Valganciclovir
PubMed: 17640310
DOI: 10.1111/j.1600-6143.2007.01910.x -
Therapeutic Drug Monitoring Feb 2022Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such... (Review)
Review
BACKGROUND
Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps.
METHODS
For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened.
RESULTS
The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window.
CONCLUSIONS
Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.
Topics: Antiviral Agents; Cytomegalovirus Infections; Drug Monitoring; Ganciclovir; Humans; Valganciclovir
PubMed: 34610621
DOI: 10.1097/FTD.0000000000000925 -
Viruses Apr 2023Human cytomegalovirus (HCMV) exploits host mitochondrial function to promote viral replication. HCMV gene products have been described to directly interact and alter... (Review)
Review
Human cytomegalovirus (HCMV) exploits host mitochondrial function to promote viral replication. HCMV gene products have been described to directly interact and alter functional or structural aspects of host mitochondria. Current antivirals against HCMV, such as ganciclovir and letermovir, are designed against viral targets. Concerns with the current antivirals include toxicity and viral resistance. Targeting host mitochondrial function is a promising alternative or complimentary antiviral approach as (1) drugs targeting host mitochondrial function interact with host targets, minimizing viral resistance, and (2) host mitochondrial metabolism plays key roles in HCMV replication. This review describes how HCMV alters mitochondrial function and highlights pharmacological targets that can be exploited for novel antiviral development.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Virus Replication; Mitochondria
PubMed: 37243170
DOI: 10.3390/v15051083