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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 -
The Annals of Pharmacotherapy May 2023To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients. (Review)
Review
OBJECTIVE
To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients.
DATA SOURCES
A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: , and .
STUDY SELECTION AND DATA EXTRACTION
All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials.
DATA SYNTHESIS
Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
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.
CONCLUSION
Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.
Topics: Adult; Humans; Cytomegalovirus; Transplant Recipients; Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Benzimidazoles
PubMed: 36003036
DOI: 10.1177/10600280221118959 -
Transplant Infectious Disease : An... Jun 2023Cytomegalovirus (CMV), a common post-transplant infection, is associated with increased healthcare resource utilization. In the Phase 3 SOLSTICE trial, maribavir was... (Randomized Controlled Trial)
Randomized Controlled Trial
Healthcare resource utilization of maribavir versus investigator-assigned therapy in transplant recipients with cytomegalovirus infection refractory (with or without genotypic resistance) to prior treatment: Exploratory analysis of the Phase 3 SOLSTICE trial.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSION
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: Humans; Antiviral Agents; Transplant Recipients; Cytomegalovirus Infections; Ganciclovir; Cytomegalovirus; Delivery of Health Care
PubMed: 37154528
DOI: 10.1111/tid.14064 -
Current Opinion in Infectious Diseases Dec 2014To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow... (Review)
Review
PURPOSE OF REVIEW
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.
RECENT FINDINGS
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.
SUMMARY
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
PubMed: 25304390
DOI: 10.1097/QCO.0000000000000107 -
Infectious Disease Reports Jan 2024Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to... (Review)
Review
Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the gene under letermovir than low-grade resistance mutations. Some mutations emerging in the gene under maribavir can be cross-resistant with ganciclovir. Thus, letermovir and maribavir now extend the drug arsenal available for the management of CMV infections and their respective niches are currently defined.
PubMed: 38247977
DOI: 10.3390/idr16010005 -
Medecine Et Maladies Infectieuses Dec 2018Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation.... (Review)
Review
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
PubMed: 29650261
DOI: 10.1016/j.medmal.2018.03.006 -
Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance.Antiviral Research Mar 2019The 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... (Review)
Review
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 for prophylaxis of HCMV infection in adult seropositive recipients of an allogeneic HSCT. Amino acid substitutions conferring resistance to LMV selected in vitro map primarily to the pUL56 and rarely to the pUL89 and pUL51 subunits of the HCMV terminase complex. MBV is an inhibitor of the viral pUL97 kinase activity and interferes with the morphogenesis and nuclear egress of nascent viral particles. MBV is safe and well tolerated and has an excellent oral bioavailability. MBV was effective for the treatment of HCMV infections (including those that are refractory or drug-resistant) in transplant recipients in two phase II studies and is further evaluated in two phase III trials. Mutations conferring resistance to MBV map to the UL97 gene and can cause cross-resistance to ganciclovir. MBV-resistant mutations also emerged in the UL27 gene in vitro and could compensate for the inhibition of pUL97 kinase activity by MBV. Thus, LMV and probably MBV will broaden the armamentarium of antiviral drugs available for the prevention and treatment of HCMV infections.
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
PubMed: 30690043
DOI: 10.1016/j.antiviral.2019.01.011 -
Journal of Clinical Microbiology Feb 2021
PubMed: 33826526
DOI: 10.1128/JCM.00119-20 -
Antiviral Research Sep 2021Because ganciclovir resistance mutations in the cytomegalovirus UL97 gene most commonly occur at codons 460, 520 and 590-607, diagnostic genotyping for drug resistance...
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
PubMed: 34273445
DOI: 10.1016/j.antiviral.2021.105139 -
Journal of Clinical Pharmacology Feb 2023Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is primarily metabolized in the liver. This open-label, single-center study evaluated the effect of hepatic impairment on the pharmacokinetics of maribavir in nontransplant participants. A single 200-mg dose of maribavir was administered orally under fasting conditions to participants with moderate hepatic impairment (Child-Pugh class B) (n = 10) and healthy controls (n = 10) matched for age, weight, sex, and smoking status. Compared with participants with normal hepatic function, maximum plasma concentration (C ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity values for maribavir in participants with moderate hepatic impairment were 1.346-fold (90%CI of geometric mean ratio, 1.091-1.660) and 1.261-fold (0.889-1.787) higher, respectively. However, C and AUC values for unbound maribavir were comparable. For VP 44469, the main metabolite of maribavir, the C and AUC from time 0 to infinity values were 1.190-fold (0.836-1.693) and 1.309-fold (1.007-1.702) higher, respectively, in participants with moderate hepatic impairment. In total, 7 mild treatment-emergent adverse events were reported, all in the moderate hepatic impairment group. Dysgeusia was the most frequently reported treatment-emergent adverse event, at a frequency of 50%. These results indicated that total maribavir concentrations were mildly increased in participants with moderate hepatic impairment, while unbound concentrations were unaffected. Similar maribavir pharmacokinetics in participants with moderate hepatic impairment and normal hepatic function suggest that dose adjustment may not be required for patients with moderate hepatic impairment.
Topics: Humans; Area Under Curve; Liver Diseases; Benzimidazoles; Ribonucleosides
PubMed: 36089648
DOI: 10.1002/jcph.2155