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Journal of Clinical Microbiology Feb 2021
PubMed: 33826526
DOI: 10.1128/JCM.00119-20 -
The Journal of Infectious Diseases Sep 2022In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for...
BACKGROUND
In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks.
METHODS
Baseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility.
RESULTS
Baseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone.
CONCLUSIONS
After maribavir therapy (400-1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy.
CLINICAL TRIALS REGISTRATION
NCT01611974 and EudraCT 2010-024247-32.
Topics: Humans; Cytomegalovirus; Drug Resistance, Viral; Antiviral Agents; Phosphotransferases (Alcohol Group Acceptor); Cytomegalovirus Infections; Ganciclovir; Mutation; Phenotype
PubMed: 32726419
DOI: 10.1093/infdis/jiaa462 -
The Lancet. Infectious Diseases Apr 2011
Topics: Antiviral Agents; Benzimidazoles; Chemoprevention; Cytomegalovirus Infections; Humans; Randomized Controlled Trials as Topic; Ribonucleosides; Stem Cell Transplantation; Transplantation; Treatment Failure
PubMed: 21414844
DOI: 10.1016/S1473-3099(11)70033-0 -
Antimicrobial Agents and Chemotherapy Oct 2006The cytomegalovirus (CMV) UL97 kinase inhibitor maribavir antagonized the anti-CMV effect of ganciclovir, increasing the ganciclovir 50% inhibitory concentration against...
The cytomegalovirus (CMV) UL97 kinase inhibitor maribavir antagonized the anti-CMV effect of ganciclovir, increasing the ganciclovir 50% inhibitory concentration against a sensitive strain by up to 13-fold. Antiviral activities of foscarnet and cidofovir were unaffected by maribavir.
Topics: Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Drug Antagonism; Drug Resistance, Viral; Drug Therapy, Combination; Ganciclovir; Humans; Microbial Sensitivity Tests; Ribonucleosides
PubMed: 17005835
DOI: 10.1128/AAC.00577-06 -
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 -
Transplantation Proceedings May 2013Maribavir (MBV), a UL97 inhibitor, shows good oral bioavailability, low host cell toxicity, and theoretical benefits to inhibit cross-resistant viruses. We herein...
Maribavir (MBV), a UL97 inhibitor, shows good oral bioavailability, low host cell toxicity, and theoretical benefits to inhibit cross-resistant viruses. We herein examined clinical and virological outcomes of 12 patients, including 3 bone marrow recipients and 9 organ recipients infected with resistant cytomegalovirus (CMV) and treated with MBV during 2011-2012. All received at least 800-mg daily doses. They had developed clinical (12/12) and/or virological (11/12) resistance to CMV infection. Based on a decrease of viral load in blood >1.5 log copies/mL half of them responded to MBV treatment. The individual changes varied from a rapid decrease in viral load (n = 4) to no response (n = 3) with some late response slowly decreasing viremia (n = 3). In 2 cases MBV was used as secondary prophylaxis. No clear parameter emerged as a clinical surrogate for nonresponse to MBV. These results contrast with the lack of efficacy in phase III trials of MBV prophylaxis among stem cell recipients, which were possibly due to low doses or inadequate timing of drug initiation in the study. Additional clinical and surrogate laboratory markers are needed to determine antiviral responses to guide MBV use. Dosage ranging studies might benefit future MBV use.
Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; France; Genotype; Humans; Microbial Sensitivity Tests; Middle Aged; Organ Transplantation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides
PubMed: 23726629
DOI: 10.1016/j.transproceed.2013.01.082 -
Transplant Infectious Disease : An... Apr 2024
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antiviral Agents; Drug Resistance, Viral; Dichlororibofuranosylbenzimidazole
PubMed: 38430481
DOI: 10.1111/tid.14259 -
Transplant Infectious Disease : An... Jun 2024
Topics: Humans; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Lung Transplantation; Antiviral Agents; Ribonucleosides; Benzimidazoles; Treatment Failure; Male; Cytomegalovirus; Middle Aged; Female; Dichlororibofuranosylbenzimidazole
PubMed: 38584587
DOI: 10.1111/tid.14275 -
CPT: Pharmacometrics & Systems... May 2023Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant...
Population pharmacokinetic modeling and simulation of maribavir to support dose selection and regulatory approval in adolescents with posttransplant refractory cytomegalovirus.
Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory (with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.
Topics: United States; Humans; Adolescent; Cytomegalovirus; Antiviral Agents; Ganciclovir; Cytomegalovirus Infections; Benzimidazoles; Ribonucleosides
PubMed: 36789522
DOI: 10.1002/psp4.12943 -
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