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Therapeutics and Clinical Risk... 2022Cytomegalovirus (CMV) infections are a common complication in solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients, leading to increased morbidity... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) infections are a common complication in solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients, leading to increased morbidity and mortality. Currently available treatment options have reduced the burden of infection, but utilization of these agents can be limited by toxicities such as nephrotoxicity and/or myelosuppression as well as emergence of resistance. The expansion of our current armamentarium towards CMV infection is crucial. Here, we review an emerging therapy, maribavir, and the safety and efficacy of this potential new agent for the prophylaxis and treatment of CMV infections including resistant/refractory disease.
RECENT FINDINGS
Maribavir is a novel agent with CMV activity approved by Federal Food and Drug Administration (FDA) in December 2021 for resistant/refractory disease. Compared to currently available treatment for CMV infection, maribavir has a unique mechanism of action, retains activity against most (val)ganciclovir resistant strains, provides a more predictable pharmacokinetic profile, and fewer severe toxicities. Maribavir has been studied in phase 2 and 3 studies with ongoing phase 3 studies. While maribavir failed to meet the primary endpoints in the initial phase 3 study for prophylaxis therapy in allogeneic-HSCT and liver transplant recipients, results from the phase 2 study when used for pre-emptive therapy after HSCT show similar efficacy to valganciclovir, and results from the phase 3 study examining resistant/refractory disease demonstrate superiority to investigator-initiated therapy of (val)ganciclovir, foscarnet, or cidofovir.
SUMMARY
Maribavir provides a new agent for the management of resistant/refractory CMV infection. Results of the recently published phase 3 study provide further insight into the role of this novel therapy.
PubMed: 35308097
DOI: 10.2147/TCRM.S303052 -
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 -
Frontiers in Microbiology 2023Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs... (Review)
Review
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.
PubMed: 38053548
DOI: 10.3389/fmicb.2023.1321116 -
Clinical Infectious Diseases : An... Mar 2024Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.
BACKGROUND
Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir.
METHODS
In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS
Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%).
CONCLUSIONS
Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Hematopoietic Stem Cell Transplantation; Neutropenia; Valganciclovir; Viremia
PubMed: 38036487
DOI: 10.1093/cid/ciad709 -
Infectious Disease Clinics of North... Nov 2023The authors summarize recent updates in the prevention and management of cytomegalovirus (CMV) in solid organ transplant (SOT) recipients with a focus on CMV... (Review)
Review
The authors summarize recent updates in the prevention and management of cytomegalovirus (CMV) in solid organ transplant (SOT) recipients with a focus on CMV seronegative recipients of organs from seropositive donors (CMV D+/R-) who are at highest risk of CMV infection and disease. They discuss advantages of preemptive therapy for CMV disease prevention in CMV D+/R- liver transplant recipients, letermovir for CMV prophylaxis, and updates in the development of monoclonal antibodies and vaccines as immune-based preventative strategies. They review the roles of maribavir and virus-specific T cells for management of resistant or refractory CMV infection in SOT recipients.
PubMed: 37989636
DOI: 10.1016/j.idc.2023.10.001 -
Expert Opinion on Pharmacotherapy Apr 2024Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV... (Review)
Review Comparative Study
INTRODUCTION
Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV drugs are limited by toxicities and the development of resistance. Letermovir and maribavir are newly approved antivirals for the prevention and treatment of CMV.
AREAS COVERED
Prior reviews have discussed use of letermovir for prevention of CMV after HCT and maribavir for resistant or refractory (R/R) CMV post HCT or SOT. Subsequent data have expanded their use including letermovir for primary CMV prophylaxis in high-risk renal transplant recipients and new recommendations for extending prophylaxis through day + 200 in certain HCT patients. Data on the use of maribavir for first asymptomatic CMV infection post-HCT has also been published. This review compares the pharmacology of anti-CMV agents and discusses the updated literature of these new drugs in the prevention and treatment of CMV.
EXPERT OPINION
Letermovir and maribavir are much needed tools that spare toxicities of ganciclovir, foscarnet, and cidofovir. High cost is a challenge preventing their integration into clinical practice in resource-limited countries. Transplant centers need to exercise restraint in overuse to avoid resistance, particularly in the setting of high viral loads.
Topics: Humans; Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Opportunistic Infections; Organ Transplantation; Quinazolines; Ribonucleosides; Viral Load
PubMed: 38717943
DOI: 10.1080/14656566.2024.2353627 -
Clinical and Translational Science Jan 2024Maribavir is an oral benzimidazole riboside for treatment of post-transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment... (Review)
Review
Maribavir is an oral benzimidazole riboside for treatment of post-transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment (with or without resistance). Through competitive inhibition of adenosine triphosphate, maribavir prevents the phosphorylation actions of UL97 to inhibit CMV DNA replication, encapsidation, and nuclear egress. Maribavir is active against CMV strains with viral DNA polymerase mutations that confer resistance to other CMV antivirals. After oral administration, maribavir is rapidly and highly absorbed (fraction absorbed >90%). The approved dose of 400 mg twice daily (b.i.d.) achieves a steady-state area under the curve per dosing interval of 128 h*μg/mL and trough concentration of 4.90 μg/mL (13.0 μM). Maribavir is highly bound to human plasma proteins (98%) with a small apparent volume of distribution of 27.3 L. Maribavir is primarily cleared by hepatic CYP3A4 metabolism; its major metabolite, VP44669 (pharmacologically inactive), is excreted in the urine and feces. There is no clinically relevant impact on maribavir pharmacokinetics by age, sex, race/ethnicity, body weight, transplant type, or hepatic/renal impairment status. In phase II dose-ranging studies, maribavir showed similar rates of CMV viral clearance across 400, 800, or 1200 mg b.i.d. groups, ranging from 62.5-70% in study 202 (NCT01611974) and 74-83% in study 203 (EudraCT 2010-024247-32). In the phase III SOLSTICE trial (NCT02931539), maribavir 400 mg b.i.d. demonstrated superior CMV viremia clearance at week 8 versus investigator-assigned treatments, with lower treatment discontinuation rates. Dysgeusia, nausea, vomiting, and diarrhea were commonly experienced adverse events among patients treated with maribavir in clinical trials.
Topics: Humans; Antiviral Agents; Translational Science, Biomedical; Cytomegalovirus Infections; Benzimidazoles; Dichlororibofuranosylbenzimidazole
PubMed: 38071422
DOI: 10.1111/cts.13696 -
Tropical Medicine and Infectious Disease Dec 2022Human cytomegalovirus (HCMV) is ubiquitous worldwide and elicits global health problems. The diseases associated with HCMV are a serious threat to humans, especially for... (Review)
Review
Human cytomegalovirus (HCMV) is ubiquitous worldwide and elicits global health problems. The diseases associated with HCMV are a serious threat to humans, especially for the sick, infant, elderly and immunocompromised/immunodeficient individuals. Although traditional antiviral drugs (e.g., ganciclovir, valganciclovir, cidofovir, foscarnet) can be used to treat or prevent acute HCMV infections, their efficacy is limited because of toxicity, resistance issues, side effects and other problems. Fortunately, novel drugs (e.g., letermovir and maribavir) with less toxicity and drug/cross-resistance have been approved and put on the market in recent years. The nucleic acid-based gene-targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPRs-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) have been investigated to remove both lytic and latent CMV in vitro and/or in vivo. Cell therapy including the adoptive T cell therapy (ACT) and immunotherapy have been tried against drug-resistant and recurrent HCMV in patients receiving hematopoietic stem cell transplantation (HSCT) or solid organ transplant (SOT), and they have also been used to treat glioblastoma (GBM) associated with HCMV infections. These newly developed antiviral strategies are expected to yield fruitful results and make a significant contribution to the treatment of HCMV infections. Despite this progress, the nucleic acid-based gene-targeting approaches are still under study for basic research, and cell therapy is adopted in a small study population size or only successful in case reports. Additionally, no current drugs have been approved to be indicated for latent infections. Therefore, the next strategy is to develop antiviral strategies to elevate efficacy against acute and/or latent infections and overcome challenges such as toxicity, resistance issues, and side effects. In this review, we would explore the challenges, recent advances and perspectives in the treatment of HCMV infections. Furthermore, the suitable therapeutic strategies as well as the possibility for compassionate use would be evaluated.
PubMed: 36548694
DOI: 10.3390/tropicalmed7120439 -
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