-
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 -
Clinical Microbiology and Infection :... Sep 2023Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation.... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation. Treatment of CMV disease involves a two-pronged approach with antiviral drug treatment coupled with strategies to minimize the intensity of immune suppression.
OBJECTIVES
This narrative review examines the evidence for the current treatment of CMV disease in transplant recipients, including the use of oral antiviral drugs.
SOURCES
Literature search was performed on PubMed with keywords cytomegalovirus, transplantation, ganciclovir, valganciclovir, maribavir, letermovir, cidofovir, and foscarnet.
CONTENT
Intravenous and oral valganciclovir are the standard first-line treatment of cytomegalovirus disease after transplantation. Oral maribavir has demonstrated superior efficacy and safety over CMV DNA polymerase inhibitors for the treatment of refractory or resistant CMV infection. Transplant patients with severe and life-threatening CMV disease, those with very high viral load, and patients with impaired gastrointestinal absorption should still be treated initially with intravenous antiviral drugs, including ganciclovir and foscarnet. Criteria for the safe transition from intravenous therapies to oral antiviral drugs include achieving clinical improvement and satisfactory decline in viral load. Recurrence of CMV viremia and disease is common, particularly among transplant patients who are lymphopenic and have impaired CMV-specific immunity.
IMPLICATIONS
Oral antiviral drugs for the treatment of CMV infection and disease in transplant recipients have improved the CMV landscape, because they reduce the cost and mitigate the inconvenience and risks related to prolonged hospitalization and the need for long-term intravascular access. However, their antiviral efficacy should be complemented by an intentional strategy of reducing the degree of immune suppression to allow for immunologic recovery that ensures durable control of CMV infection.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Valganciclovir; Foscarnet; Transplant Recipients; Ganciclovir; Cytomegalovirus Infections
PubMed: 36963566
DOI: 10.1016/j.cmi.2023.03.020 -
Ophthalmology Mar 2017To evaluate the available evidence in peer-reviewed publications about the diagnosis and treatment of acute retinal necrosis (ARN). (Review)
Review
PURPOSE
To evaluate the available evidence in peer-reviewed publications about the diagnosis and treatment of acute retinal necrosis (ARN).
METHODS
Literature searches of the PubMed and Cochrane Library databases were last conducted on July 27, 2016. The searches identified 216 unique citations, and 49 articles of possible clinical relevance were reviewed in full text. Of these 49 articles, 27 were deemed sufficiently relevant or of interest, and they were rated according to strength of evidence. An additional 6 articles were identified from the reference lists of these articles and included. All 33 studies were retrospective.
RESULTS
Polymerase chain reaction (PCR) testing of aqueous or vitreous humor was positive for herpes simplex virus (HSV) or varicella zoster virus (VZV) in 79% to 100% of cases of suspected ARN. Aqueous and vitreous specimens are both sensitive and specific. There is level II and III evidence supporting the use of intravenous and oral antiviral therapy for the treatment of ARN. Data suggest that equivalent plasma drug levels of acyclovir can be achieved after administration of oral valacyclovir or intravenous acyclovir. There is level II and III evidence suggesting that the combination of intravitreal foscarnet and systemic antiviral therapy may have greater therapeutic efficacy than systemic therapy alone. The effectiveness of prophylactic laser or early pars plana vitrectomy (PPV) in preventing retinal detachment (RD) remains unclear.
CONCLUSIONS
Polymerase chain reaction testing of ocular fluid is useful in supporting a clinical diagnosis of ARN, but treatment should not be delayed while awaiting PCR results. Initial oral or intravenous antiviral therapy is effective in treating ARN. The adjunctive use of intravitreal foscarnet may be more effective than systemic therapy alone. The role of prophylactic laser retinopexy or early PPV is unknown at this time.
Topics: Academies and Institutes; Acyclovir; Antiviral Agents; Aqueous Humor; Biomedical Technology; DNA, Viral; Eye Infections, Viral; Foscarnet; Herpes Simplex; Herpes Zoster Ophthalmicus; Herpesvirus 3, Human; Humans; Ophthalmology; Polymerase Chain Reaction; Retinal Necrosis Syndrome, Acute; Retrospective Studies; Simplexvirus; United States; Valacyclovir; Valine; Vitrectomy; Vitreous Body
PubMed: 28094044
DOI: 10.1016/j.ophtha.2016.11.007 -
JAMA Dermatology Oct 2023
Topics: Male; Humans; Foscarnet; Penile Diseases; Antiviral Agents; Ulcer; Skin Diseases; Penis
PubMed: 37647057
DOI: 10.1001/jamadermatol.2023.2592 -
Transplantation and Cellular Therapy Jun 2023Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and... (Review)
Review
Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3,100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.
Topics: Adult; Humans; Young Adult; Middle Aged; Aged; Adolescent; Foscarnet; Herpesvirus 6, Human; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; DNA, Viral
PubMed: 36878429
DOI: 10.1016/j.jtct.2023.02.022 -
Journal of Virology Apr 2021The "omics" revolution of recent years has simplified the study of RNA transcripts produced during viral infection and under specific defined conditions. In the quest to...
The "omics" revolution of recent years has simplified the study of RNA transcripts produced during viral infection and under specific defined conditions. In the quest to find new and differentially expressed transcripts during the course of human Herpesvirus 6B (HHV-6B) infection, we made use of large-scale RNA sequencing to analyze the HHV-6B transcriptome during productive infection of human Molt-3 T-cells. Analyses were performed at different time points following infection and specific inhibitors were used to classify the kinetic class of each open reading frame (ORF) reported in the annotated genome of HHV-6B Z29 strain. The initial search focussed on HHV-6B-specific reads matching new HHV-6B transcripts. Differential expression of new HHV-6B transcripts were observed in all samples analyzed. The presence of many of these new HHV-6B transcripts were confirmed by RT-PCR and Sanger sequencing. Many of these transcripts represented new splice variants of previously reported ORFs, including some transcripts that have yet to be defined. Overall, our work demonstrates the diversity and the complexity of the HHV-6B transcriptome.RNA sequencing (RNA-seq) is an important tool for studying RNA transcripts, particularly during active viral infection. We made use of RNA-seq to study human Herpesvirus 6B (HHV-6B) infection. Using six different time points, we were able to identify the presence of differentially spliced genes at 6, 9, 12, 24, 48 and 72 hours post-infection. Determination of the RNA profiles in the presence of cycloheximide (CHX) or phosphonoacetic acid (PAA) also permitted identification of the kinetic class of each ORF described in the annotated GenBank file. We also identified new spliced transcripts for certain genes and evaluated their relative expression over time. These data and next-generation sequencing (NGS) of the viral DNA have led us to propose a new version of the HHV-6B Z29 GenBank annotated file, without changing ORF names in order to facilitate trace back and correlate our work with previous studies on HHV-6B.
PubMed: 33627386
DOI: 10.1128/JVI.01335-20 -
Journal of Neurovirology Feb 2017The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection... (Review)
Review
The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection is occasionally accompanied by diverse clinical forms of encephalitis. Roseolovirus coinfections with heterologous viruses and delayed primary HHV-7 infection in immunocompetent adults result in very severe neurological and generalized symptoms. Recovery from neurological sequelae is slow and sometimes incomplete. In immunocompromised patients with underlying hematological malignancies and transplantation, frequent single or simultaneous reactivation of roseoloviruses elicit severe, lethal organ dysfunctions, including damages in the limbic system, brain stem, and hippocampus. Most cases have been due to HHV-6B with HHV-6A accounting for 2-3%. The most severe manifestation of HHV-6B reactivation is post-transplantation limbic encephalitis. Seizures, cognitive problems, and abnormal EEG are common. Major risk factors for HHV-6B-associated encephalitis include unrelated cord blood cell transplantation and repeated hematopoietic stem cell transplantation. Rare genetic disorders, male gender, certain HLA constellation, and immune tolerance to replicating HHV-6 in persons carrying chromosomally integrated HHV-6 might also predispose an individual to roseolovirus-associated brain damage. At this time, little is known about the risk factors for HHV-7-associated encephalitis. Intrathecal glial cell destruction due to virus replication, overexpression of proinflammatory cytokines, and viral mimicry of chemokines all contribute to brain dysfunction. High virus load in the cerebrospinal fluid, hippocampal astrogliosis, and viral protein expression in HHV-6B-associated cases and multiple microscopic neuronal degeneration in HHV-7-associated cases are typical laboratory findings. Early empirical therapy with ganciclovir or foscarnet might save the life of a patient with roseolovirus-associated encephalitis.
Topics: Adult; Antiviral Agents; Child; Cord Blood Stem Cell Transplantation; Cytokines; Encephalitis, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans; Immunocompetence; Immunocompromised Host; Limbic Encephalitis; Neuroglia; Risk Factors; Roseolovirus Infections
PubMed: 27538995
DOI: 10.1007/s13365-016-0473-0 -
Biomedicines Mar 2022Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and...
Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and understanding mechanisms of resistance to agents targeting viral DNA polymerases is fundamental for the development of antiviral therapies. We describe here the phenotypic and genotypic characterization of poxvirus DNA polymerase mutants isolated under selective pressure with different acyclic nucleoside phosphonates, including HPMPC (cidofovir), cHPMPC, HPMPA, cHPMPA, HPMPDAP, HPMPO-DAPy, and PMEO-DAPy, and the pyrophosphate analogue phosphonoacetic acid. Vaccinia virus (VACV) and cowpox virus drug-resistant viral clones emerging under drug pressure were characterized phenotypically (drug-susceptibility profile) and genotypically (DNA polymerase sequencing). Different amino acid changes in the polymerase domain and in the 3'-5' exonuclease domain were linked to drug resistance. Changes in the 3'-5' domain emerged earlier than in the polymerase domain when viruses acquired a combination of mutations. Our study highlights the importance of poxvirus DNA polymerase residues 314, 613, 684, 688, and 851, previously linked to drug resistance, and identified several novel mutations in the 3'-5' exonuclease domain (M313I, F354L, D480Y) and in the DNA polymerase domain (A632T, T831I, E856K, L924F) associated with different drug-susceptibility profiles. Furthermore, a combination of mutations resulted in complex patterns of cross-resistance. Modeling of the VACV DNA polymerase bearing the newly described mutations was performed to understand the effects of these mutations on the structure of the viral enzyme. We demonstrated the emergence of drug-resistant DNA polymerase mutations in complex patterns to be considered in case such mutations should eventually arise in the clinic.
PubMed: 35327382
DOI: 10.3390/biomedicines10030580