-
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 -
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 -
Microbiology Spectrum Jun 2016Human roseoloviruses include three different species, human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7), genetically related to human cytomegalovirus. They... (Review)
Review
Human roseoloviruses include three different species, human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7), genetically related to human cytomegalovirus. They exhibit a wide cell tropism in vivo and, like other herpesviruses, induce a lifelong latent infection in humans. In about 1% of the general population, HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6). Many active infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. They also may cause serious diseases, particularly in immunocompromised individuals, including hematopoietic stem-cell transplant (HSCT) and solid-organ transplant recipients, and acquired immunodeficiency syndrome (AIDS) patients. This opportunistic pathogenic role is formally established for HHV-6 infection and less clear for HHV-7. It mainly concerns the central-nervous system, bone marrow, lungs, gastrointestinal tract, skin, and liver. As the best example, HHV-6 causes both exanthema subitum, a benign disease associated with primary infection, and severe encephalitis associated with virus reactivations in HSCT recipients. Diagnosis using serologic and direct antigen-detection methods currently exhibits limitations. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time polymerase-chain reaction (PCR). The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active infections, but there is currently no consensus regarding the indications of treatment or specifics of drug administration. Numerous questions about HHV-6A, HHV-6B, HHV-7 are still pending, concerning in particular clinical impact and therapeutic options in immunocompromised patients.
Topics: Antiviral Agents; Cidofovir; Cytosine; DNA, Viral; Foscarnet; Ganciclovir; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunocompromised Host; Organophosphonates; Roseolovirus Infections; Transplant Recipients; Virus Latency
PubMed: 27337451
DOI: 10.1128/microbiolspec.DMIH2-0007-2015 -
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 Feb 2023Herpes simplex virus (HSV) and varicella zoster virus (VZV) are alpha herpesviruses that establish life-long latent infection in neuronal ganglia after primary... (Review)
Review
Herpes simplex virus (HSV) and varicella zoster virus (VZV) are alpha herpesviruses that establish life-long latent infection in neuronal ganglia after primary infection. Periodic reactivation of these viruses results in recurrent infections that can have significant impact on patients' quality of life. HSV commonly causes oral and genital mucocutaneous infections whereas VZV is responsible for varicella/chickenpox and herpes zoster/shingles, but cancer patients are at particularly higher risk of complications including disseminated and visceral infections due to impaired cell-mediated immunity. While diagnosis of more common HSV and/or VZV infections is frequently clinically based, immunocompromised hosts may have atypical skin presentation or visceral involvement. Thus, diagnostic confirmation using virus-specific tests such as polymerase chain reaction or immunohistochemical staining is crucial in some cases. Oral acyclovir, valacyclovir and famciclovir are usually used for mild to moderate infections and intravenous acyclovir is the drug of choice for severe or disseminated infections. Foscarnet can be used when acyclovir-resistance is confirmed or suspected. Pharmaceutical prophylaxis against HSV and/or VZV should be considered in high-risk cancers patients. Currently, there is no commercially available vaccine against HSV, but VZV vaccines are available to prevent varicella and zoster.
Topics: Humans; Chickenpox; Herpesvirus 3, Human; Simplexvirus; Quality of Life; Herpes Zoster; Varicella Zoster Virus Infection; Acyclovir; Neoplasms
PubMed: 36851652
DOI: 10.3390/v15020439 -
Current Treatment Options in Infectious... 2014In treating cytomegalovirus (CMV) infection, it is crucial to decide whether one is treating pre-emptively or if one is treating established disease. Disease may be... (Review)
Review
In treating cytomegalovirus (CMV) infection, it is crucial to decide whether one is treating pre-emptively or if one is treating established disease. Disease may be further divided into viral syndrome and tissue-invasive disease. Generally, mild disease in immunosuppressed patients may be treated with oral valganciclovir. Treatment may also be started with valganciclovir for CMV retinitis in AIDS patients. In other tissue-invasive syndromes, starting with intravenous ganciclovir or foscarnet at full doses (adjusted for renal function) is preferred. Treatment at full doses should be continued until symptom resolution and until blood antigenemia (or DNAemia) is cleared. Patients receiving treatment must be closely monitored for side effects to the drugs, as well as for response. Drug-resistant CMV is a therapeutic challenge; combination therapy with both ganciclovir and foscarnet may be tried. In extreme cases, resorting to unconventional agents like leflunomide or maribavir may be necessary. Immune reconstitution, through reduction in immunosuppression, or the introduction of anti-retroviral therapy, should be attempted. CMX001 is a novel agent active against double-stranded viruses; thus far, resistance to CMX001 does not confer resistance to ganciclovir or foscarnet. Hence, prophylaxis or pre-emptive treatment with CMX001 may allow the use of ganciclovir or foscarnet for treatment.
PubMed: 25999800
DOI: 10.1007/s40506-014-0021-5 -
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 -
Clinical Infectious Diseases : An... Apr 2019Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study.
BACKGROUND
Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
METHODS
Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
RESULTS
From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
CONCLUSIONS
Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
CLINICAL TRIALS REGISTRATION
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
PubMed: 30329038
DOI: 10.1093/cid/ciy706