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La Revue Du Praticien Mar 2019Cytomegalovirus infections. Cytomegalovirus (CMV) infections, which are common in children and adolescents, are often asymptomatic or with little specific signs. When...
Cytomegalovirus infections. Cytomegalovirus (CMV) infections, which are common in children and adolescents, are often asymptomatic or with little specific signs. When they occur in adults, clinical forms may be more severe even in the immunocompetent. CMV is responsible for significant morbidity and mortality in transplant patients. In pregnant women, congenital CMV infection can lead to neurosensory damages requiring diagnosis and early management. The diagnosis of primary infection is based on serology, whereas the monitoring of infection in immunocompromised patients requires the use of polymerase chain reaction. As screening for congenital infection by serology is not recommended so far, it will be realized in an evocative context. Therapeutic options are still limited and expose to haematological or renal toxicity, but new antivirals (maribavir, letermovir) should be available soon to optimize therapeutic management.
Topics: Adolescent; Adult; Antiviral Agents; Child; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Immunocompromised Host; Infant, Newborn; Pregnancy
PubMed: 30983259
DOI: No ID Found -
Clinical Pharmacology in Drug... Jun 2023This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants....
This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants. Under fasting conditions, 12 healthy adult participants of Japanese descent and 12 matched White participants received a single 400-mg dose of maribavir. Japanese participants received 2 further doses of maribavir: 200 mg and 800 mg, or 800 mg and 200 mg, separated by a ≥72-hour washout period. Serial blood samples were collected up to 24 hours after dosing for pharmacokinetic assessments. Following the 400-mg dose, the geometric mean ratios (90% confidence interval) of Japanese versus White participants were 110% (91.7%-133%) for maximum plasma concentration, 122% (96.8%-155%) for area under the plasma concentration-time curve (AUC) from time of dosing to the last measurable concentration, and 125% (98.0%-160%) for AUC extrapolated to infinity. In Japanese participants, maribavir AUC extrapolated to infinity and AUC from time of dosing to the last measurable concentration increased in a dose-proportional fashion over 200-800 mg; maximum plasma concentration increased less than dose proportionally. Seven participants reported treatment-emergent adverse events (TEAEs; Japanese participants, 400 mg: 2 [16.7%], 200 mg: 1 [8.3%]; White participants, 400 mg: 4 [33.3%]), all mild and most commonly dysgeusia. No serious TEAEs or TEAEs leading to discontinuation were reported. This study demonstrated higher maribavir systemic exposure in Japanese than White participants and similar safety outcomes. This difference in exposure is not considered clinically important and its significance remains to be determined.
Topics: Adult; Humans; Area Under Curve; East Asian People; White People; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 37036111
DOI: 10.1002/cpdd.1247 -
Clinical Transplantation Apr 2023
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antiviral Agents; Transplant Recipients; Organ Transplantation
PubMed: 36740886
DOI: 10.1111/ctr.14929 -
Journal of Clinical Pharmacy and... May 2022Management of pan-resistant cytomegalovirus infection (CMVi) requires a multifaceted approach, including host defence optimization by reducing immunosuppression, and...
WHAT IS KNOWN AND OBJECTIVE
Management of pan-resistant cytomegalovirus infection (CMVi) requires a multifaceted approach, including host defence optimization by reducing immunosuppression, and standard or experimental antiviral therapy.
CASE DESCRIPTION
A 36-year-old man with anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma, who underwent allogeneic haematopoietic stem cell transplant (alloHCT) with resultant graft-versus-host disease treated with immunosuppressive therapy, developed pan-resistant CMVi. He was successfully treated with combination therapy of maribavir and letermovir.
WHAT IS NEW AND CONCLUSION
Combination therapy, used for other infections to prevent cross-resistant, may apply for CMVi.
Topics: Acetates; Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Quinazolines; Ribonucleosides
PubMed: 35023177
DOI: 10.1111/jcpt.13585 -
Ugeskrift For Laeger Apr 2024Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for...
Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.
Topics: Humans; Cytomegalovirus Infections; Liver Transplantation; Antiviral Agents; Ribonucleosides; Benzimidazoles; Male; Middle Aged; Cytomegalovirus; Dichlororibofuranosylbenzimidazole
PubMed: 38708697
DOI: 10.61409/V11230726 -
Journal of Virology May 2013Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV...
Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus.
Topics: Antiviral Agents; Benzimidazoles; Cell Line; Down-Regulation; Epstein-Barr Virus Infections; Gene Expression Regulation, Viral; Genome, Viral; Herpesvirus 4, Human; Humans; Protein Serine-Threonine Kinases; Ribonucleosides; Viral Proteins; Virus Replication
PubMed: 23449792
DOI: 10.1128/JVI.03505-12 -
Antiviral Research Aug 2012Resistance to the experimental human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir has been mapped to UL97 mutations at codons 353, 397, 409 and 411, in the...
Resistance to the experimental human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir has been mapped to UL97 mutations at codons 353, 397, 409 and 411, in the kinase ATP-binding region, and to mutations in the UL27 gene. We studied the maribavir susceptibility phenotypes of additional UL97 mutations observed in vitro and in clinical trials, and the effect of simultaneous mutation in both UL97 and UL27. In vitro selection under maribavir identified a new locus of UL97 mutation within the conserved kinase p-loop (L337M), which conferred low grade maribavir resistance (3.5-fold increased EC50) without ganciclovir cross-resistance. During maribavir Phase III CMV prevention clinical trials, three previously unknown UL97 sequence variants were detected in plasma samples after 27-98 days of drug exposure (I324V, S334G and S386L). These variants did not confer any drug resistance despite proximity to mutations that confer maribavir resistance. The UL27 resistance mutation R233S, when added to strains containing UL97 mutations L337M or V353A, doubled their maribavir EC50s. These results expand the range of UL97 maribavir-resistance mutations into another part of the kinase ATP-binding region, but offer no genotypic evidence that development of drug resistance affected the outcomes of Phase III maribavir clinical trials after drug exposure of up to 14 weeks. There is a potential for increased maribavir resistance in UL27-UL97 double mutants.
Topics: Antiviral Agents; Benzimidazoles; Clinical Trials, Phase III as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Humans; Mutation, Missense; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides
PubMed: 22664236
DOI: 10.1016/j.antiviral.2012.05.013 -
Antimicrobial Agents and Chemotherapy May 2008Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis following stem cell or solid organ transplantation. The main objective of this study was to assess the effects of oral ketoconazole, a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study with 20 healthy adults. Subjects were administered a single dose of maribavir at 400 mg. After a washout period, subjects received a single dose of ketoconazole at 400 mg followed by a single dose of maribavir. Blood samples were collected for each drug sequence, and pharmacokinetic parameters for maribavir and its principal metabolite, VP 44469, were determined. Safety was evaluated by physical examination, clinical laboratory testing, 12-lead electrocardiogram, and monitoring for adverse events. Ketoconazole moderately reduced the clearance of both maribavir and VP 44469; oral clearance values were 35% and 13% lower, respectively, for maribavir-plus-ketoconazole treatment than for maribavir alone. Based on the assumption of complete inhibition of CYP3A4 activity, CYP3A4 is responsible for 35% of the overall clearance of maribavir. Treatment was generally well tolerated. The most-common adverse event was dysgeusia (taste disturbance), reported by nine (47%) and seven (35%) subjects in the maribavir alone and maribavir-plus-ketoconazole groups, respectively. The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and maribavir-plus-ketoconazole treatment groups, suggest that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors or substrates.
Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Benzimidazoles; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Ketoconazole; Middle Aged; Ribonucleosides
PubMed: 18316526
DOI: 10.1128/AAC.00951-07 -
Clinical Infectious Diseases : An... Jul 2021Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of...
Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of these drugs is limited by toxicity and the development of resistance. The 2017 approval of letermovir for prevention of CMV after stem cell transplant marked the first approval of an anti-CMV agent since 2003. The role of letermovir in treatment of established CMV infection or disease remains largely unstudied, although early reports suggest that a low barrier to resistance will likely limit efficacy as primary therapy for patients with refractory or resistant disease. The investigational agent maribavir has shown promise as preemptive treatment; in patients with refractory or resistant disease the emergence of resistance while on treatment has been observed and ongoing studies will define efficacy in this population. Both agents have unique mechanisms of action limiting cross resistance, and neither exhibit myelotoxicity or nephrotoxicity.
Topics: Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Humans; Quinazolines; Ribonucleosides; Transplant Recipients
PubMed: 33197929
DOI: 10.1093/cid/ciaa1713 -
Journal of Medical Virology Apr 2024This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for... (Comparative Study)
Comparative Study
Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.
This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.
Topics: Humans; Cost-Benefit Analysis; Cytomegalovirus Infections; Antiviral Agents; Ribonucleosides; Benzimidazoles; Quality-Adjusted Life Years; United States; Cytomegalovirus; Drug Resistance, Viral; Male; Female; Middle Aged; Adult; Genotype; Transplant Recipients; Dichlororibofuranosylbenzimidazole
PubMed: 38647051
DOI: 10.1002/jmv.29609