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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 -
International Journal of Molecular... Mar 2022Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the... (Review)
Review
Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation.
Topics: Acyclovir; Antiviral Agents; Cytomegalovirus; Female; HIV Infections; Herpes Genitalis; Herpes Simplex; Herpes Zoster; Herpesviridae Infections; Humans; Infant, Newborn; Pregnancy
PubMed: 35408788
DOI: 10.3390/ijms23073431 -
International Journal of Antimicrobial... Aug 2023Cytomegalovirus (CMV) is a common infection encountered in immunocompromised patients. It is associated with high morbidity and mortality, particularly in patients... (Review)
Review
Cytomegalovirus (CMV) is a common infection encountered in immunocompromised patients. It is associated with high morbidity and mortality, particularly in patients undergoing allogeneic (allo-) haematopoietic stem cell transplantation (HSCT). This review presents the most recent management strategies for CMV infection in allo-HSCT recipients. Pre-emptive treatment (PET) consists of frequent monitoring of CMV polymerase chain reaction (PCR) after HSCT; this has been the standard of care for prevention of CMV for many years, given the potential drug toxicity associated with the traditional drugs used as prophylaxis. However, letermovir, recently approved as a chemoprophylactic agent for prevention of CMV, has shown great efficacy in randomized clinical trials and real-world data. Treatment of CMV disease is becoming increasingly difficult, and must take into account the patient's risk profile and the potential for CMV drug resistance. Different treatment strategies exist for refractory and resistant CMV disease. Maribavir is a new drug that showed promising results in the treatment of refractory and resistant CMV disease. Other alternative treatments, such as cellular adoptive immunotherapy, artesunate and leflunomide, may play an adjunctive role in the treatment of challenging cases; however, further investigation is warranted.
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Cytomegalovirus; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation
PubMed: 37220849
DOI: 10.1016/j.ijantimicag.2023.106860 -
Current Treatment Options in Infectious... 2021Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients.
RECENT FINDINGS
The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial.
SUMMARY
CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.
PubMed: 34305463
DOI: 10.1007/s40506-021-00253-w -
Clinical Infectious Diseases : An... Apr 2019Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study.
BACKGROUND
Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
METHODS
Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
RESULTS
From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
CONCLUSIONS
Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
CLINICAL TRIALS REGISTRATION
NCT01611974.
Topics: Adolescent; Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Ribonucleosides; Transplant Recipients; Young Adult
PubMed: 30329038
DOI: 10.1093/cid/ciy706 -
American Journal of Health-system... Mar 2022
Topics: Antiviral Agents; Benzimidazoles; Humans; Ribonucleosides
PubMed: 35180292
DOI: 10.1093/ajhp/zxab474 -
Drugs Feb 2022Maribavir (LIVTENCITY), a cytomegalovirus (CMV) enzyme pUL97 kinase inhibitor, is being developed by Takeda Pharmaceuticals for the treatment of CMV infections.... (Review)
Review
Maribavir (LIVTENCITY), a cytomegalovirus (CMV) enzyme pUL97 kinase inhibitor, is being developed by Takeda Pharmaceuticals for the treatment of CMV infections. Maribavir was recently approved in the USA for the treatment of post-transplant CMV infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet in adults and paediatric (≥ 12 years of age and weighing ≥ 35 kg) patients. This article summarizes the milestones in the development of maribavir leading to this first approval for CMV infections.
Topics: Adult; Antiviral Agents; Benzimidazoles; Child; Cytomegalovirus Infections; Drug Resistance, Viral; Humans; Ribonucleosides
PubMed: 35147913
DOI: 10.1007/s40265-022-01677-4 -
Hospital Pharmacy Aug 2023Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to... (Review)
Review
Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of publishes selected reviews in this column. For more information about , contact Wolters Kluwer customer service at 866-397-3433.
PubMed: 37360201
DOI: 10.1177/00185787221101480 -
Transplantation Apr 2024Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may... (Review)
Review
Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may be worsening with the proportion of high-risk D+/R- solid organ transplantation recipients increasing in some regions globally. Cohort studies continue to support either universal prophylaxis or preemptive therapy as effective prevention strategies. Letermovir prophylaxis was noninferior to valganciclovir in adult high-risk D+/R- kidney transplant recipients with fewer drug-related adverse events in a recent clinical trial and has now been approved for such use in some regions. Maribavir preemptive therapy failed to demonstrate noninferiority when compared with valganciclovir in hematopoietic stem cell transplant recipients but looked promising for safety. Donor matching could be useful in prevention CMV disease with a survival advantage demonstrated in seronegative recipients waiting up to 30 mo for a seronegative kidney. Immune-guided prophylaxis resulted in fewer CMV infection episodes in lung transplant recipients when compared with fixed-duration prophylaxis in a recent clinical trial. For treatment of refractory or resistant CMV infection, maribavir was more efficacious and better tolerated when compared with investigator-initiated therapy in its registration trial for this condition. Further research regarding best treatment and prophylaxis of resistant or refractory CMV infection is needed to reflect best clinical practice choices. Optimal use of immune globulin or CMV-specific T cells for prevention or treatment of CMV disease remains undefined. Standardized definitions for the design of CMV clinical trials have been developed. In this review, we highlight recent updates in the field from data published since 2018.
Topics: Adult; Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Organ Transplantation; Valganciclovir; Clinical Trials as Topic
PubMed: 37899366
DOI: 10.1097/TP.0000000000004855