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Infectious Diseases and Therapy Feb 2023Cytomegalovirus (CMV) infection can have both direct and indirect effects after solid-organ transplantation, with a significant impact on transplant outcomes. Prevention... (Review)
Review
Cytomegalovirus (CMV) infection can have both direct and indirect effects after solid-organ transplantation, with a significant impact on transplant outcomes. Prevention strategies decrease the risk of CMV disease, although CMV still occurs in up to 50% of high-risk patients. Ganciclovir (GCV) and valganciclovir (VGCV) are the main drugs currently used for preventing and treating CMV. Emerging data suggest that letermovir is as effective as VGCV with fewer hematological side effects. Refractory and resistant CMV also still occur in solid-organ-transplant patients. Maribavir has been shown to be effective and have less toxicity in the treatment of refractory and resistant CMV. In this review paper, we discuss prevention strategies, refractory and resistant CMV, and drug-related side effects and their impact, as well as optimal use of novel anti-CMV therapies.
PubMed: 36583845
DOI: 10.1007/s40121-022-00746-1 -
Journal of Clinical Pharmacology Jan 2020Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined...
Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin C , AUC , and AUC with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUC and AUC ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Antiviral Agents; Benzimidazoles; Cytochrome P-450 CYP2D6; Cytomegalovirus Infections; Dextromethorphan; Digoxin; Drug Interactions; Female; Genotype; Healthy Volunteers; Humans; Male; Middle Aged; Ribonucleosides; Young Adult
PubMed: 31385617
DOI: 10.1002/jcph.1504 -
The Journal of Infectious Diseases Mar 2020This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy.... (Review)
Review
This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.
Topics: Antiviral Agents; Clinical Decision-Making; Cytomegalovirus; Cytomegalovirus Infections; Disease Management; Disease Susceptibility; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Organ Transplantation; Pre-Exposure Prophylaxis; Time Factors; Tissue Donors; Transplant Recipients; Viral Vaccines
PubMed: 32134486
DOI: 10.1093/infdis/jiz454 -
Nature Reviews. Drug Discovery Jan 2022
PubMed: 34873323
DOI: 10.1038/d41573-021-00208-2 -
Open Forum Infectious Diseases Jan 2023
PubMed: 36632422
DOI: 10.1093/ofid/ofac686 -
Clinical Microbiology and Infection :... Jan 2023The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have... (Review)
Review
BACKGROUND
The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have successfully been used for prevention and treatment of CMV infections, although with serious side effects such as leucopenia and some development of resistance. Until recently, available therapies for ganciclovir-resistant CMV have significant toxicities. Although advances have been made in the field, the unmet medical needs for effective and well-tolerated therapies are significant.
OBJECTIVES
This review aims to summarise the current and emerging CMV antiviral drugs and discusses future perspectives in the field.
SOURCES
We searched for relevant articles with pertinent keywords: "Cytomegalovirus OR CMV", "Transplant" and "Antiviral". Articles published after 2019 were given preference. Articles were reviewed by the authors for relevance and impact to the subject of interest.
CONTENT
We outline in this review current advances in prophylaxis of CMV infection with letermovir, breakthrough CMV infections while on or after prophylaxis, the development of resistant and refractory CMV infections, and the newly approved anti-CMV agent, maribavir, in haematopoietic and solid-organ transplant recipients.
IMPLICATIONS
Prevention of CMV infections after transplant has improved greatly over the past few years. Despite major advancements, breakthrough CMV infections and development of refractory and resistant CMV infections remain major complications post transplantation. We highlight emerging therapeutics that tolerably and effectively prevent and treat CMV infections, especially refractory and resistant cases.
Topics: Humans; Transplant Recipients; Cytomegalovirus Infections; Antiviral Agents; Ganciclovir; Cytomegalovirus
PubMed: 35843567
DOI: 10.1016/j.cmi.2022.07.001 -
The Journal of Infectious Diseases Mar 2020The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV)... (Review)
Review
The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others. The development of monoclonal antibodies, sirtuins, and cyclopropovir may provide new treatment options.
Topics: Acetates; Antiviral Agents; Biomarkers; Clinical Studies as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Development; Drug Resistance, Viral; Humans; Infectious Disease Transmission, Vertical; Quinazolines; Research Design; Sirtuins; Stem Cell Transplantation; Treatment Outcome; Viral Load
PubMed: 32134483
DOI: 10.1093/infdis/jiz493 -
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 -
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 -
Transplant Infectious Disease : An... Aug 2022
Topics: Benzimidazoles; Dichlororibofuranosylbenzimidazole; Humans; Immunosuppressive Agents; Organ Transplantation; Ribonucleosides; Tacrolimus; Transplant Recipients
PubMed: 35598322
DOI: 10.1111/tid.13869