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Journal of Pediatric Hematology/oncology Apr 2024Resistant and refractory cytomegalovirus (CMV) viremia can limit the provision of chemotherapy due to myelosuppression and end-organ dysfunction. Few therapies are...
Resistant and refractory cytomegalovirus (CMV) viremia can limit the provision of chemotherapy due to myelosuppression and end-organ dysfunction. Few therapies are available for children with clinically significant CMV viremia. We successfully used maribavir for a 4-year-old patient with lymphoma to complete his chemotherapy course. Resistance to maribavir did result after many months of therapy.
Topics: Child, Preschool; Humans; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Neoplasms; Ribonucleosides; Viremia
PubMed: 38447094
DOI: 10.1097/MPH.0000000000002841 -
Transplant Infectious Disease : An... Apr 2024
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antiviral Agents; Drug Resistance, Viral; Dichlororibofuranosylbenzimidazole
PubMed: 38430481
DOI: 10.1111/tid.14259 -
Journal of the Pediatric Infectious... Feb 2024Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a...
Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a significant cause of morbidity and mortality. Newer antiviral medications are reshaping the landscape for prevention and treatment of CMV DNAemia, infection, and disease. Letermovir is approved for CMV prevention in adult HCT patients and is attractive due to the absence of marrow suppression seen with ganciclovir/valganciclovir. Letermovir should not be routinely used for CMV treatment due to its low threshold for resistance. Maribavir is approved for the treatment of refractory or resistant CMV disease in HCT and SOT recipients ≥12 years of age, though it has no current role in CMV prevention. More research is needed to fully elucidate the roles, efficacy, and safety of these newer agents in prevention and treatment of CMV in pediatric transplant recipients.
Topics: Adult; Humans; Child; Cytomegalovirus; Antiviral Agents; Transplant Recipients; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Acetates; Quinazolines
PubMed: 38417084
DOI: 10.1093/jpids/piad059 -
Current Opinion in Pulmonary Medicine Jul 2024Infections in lung transplant recipients remain a major challenge and can affect lung allograft function and cause significant morbidity and mortality. New strategies... (Review)
Review
PURPOSE OF REVIEW
Infections in lung transplant recipients remain a major challenge and can affect lung allograft function and cause significant morbidity and mortality. New strategies for the prevention and treatment of infection in lung transplantation have emerged and are reviewed.
RECENT FINDINGS
For important vaccine preventable infections (VPIs), guidance has been updated for at risk solid organ transplant (SOT) recipients. However, data on the efficacy of newer vaccines in lung transplant, including the respiratory syncytial virus (RSV) vaccine, are limited. Studies demonstrate improved vaccination rate with Infectious Diseases consultation during pretransplant evaluation. Two new antiviral agents for the treatment and prevention of cytomegalovirus (CMV) in SOT, letermovir and maribavir, are being incorporated into clinical care. CMV-specific cell-mediated immune function assays are more widely available. Antibiotics for the management of multidrug resistant pathogens and Burkholderia cepacia complex have been described in case series and case reports in lung transplant.
SUMMARY
Although new vaccines and novel therapies for preventing and treating infections are available, larger studies evaluating efficacy in lung transplant recipients are needed.
Topics: Humans; Lung Transplantation; Antiviral Agents; Transplant Recipients; Cytomegalovirus Infections; Anti-Bacterial Agents
PubMed: 38411211
DOI: 10.1097/MCP.0000000000001060 -
Pharmaceutics Jan 2024The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include...
The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors.
PubMed: 38399219
DOI: 10.3390/pharmaceutics16020158 -
Tropical Medicine and Infectious Disease Feb 2024Human cytomegalovirus (HCMV) is a pathogen with high prevalence in the general population that is responsible for high morbidity and mortality in immunocompromised... (Review)
Review
Human cytomegalovirus (HCMV) is a pathogen with high prevalence in the general population that is responsible for high morbidity and mortality in immunocompromised individuals and newborns, while remaining mainly asymptomatic in healthy individuals. The HCMV genome is 236,000 nucleotides long and encodes approximately 200 genes in more than 170 open reading frames, with the highest rate of genetic polymorphisms occurring in the envelope glycoproteins. HCMV infection is treated with antiviral drugs such as ganciclovir, valganciclovir, cidofovir, foscarnet, letermovir and maribavir targeting viral enzymes, DNA polymerase, kinase and the terminase complex. One of the obstacles to successful therapy is the emergence of drug resistance, which can be tested phenotypically or by genotyping using Sanger sequencing, which is a widely available but less sensitive method, or next-generation sequencing performed in samples with a lower viral load to detect minority variants, those representing approximately 1% of the population. The prevalence of drug resistance depends on the population tested, as well as the drug, and ranges from no mutations detected to up to almost 50%. A high prevalence of resistance emphasizes the importance of testing the patient whenever resistance is suspected, which requires the development of more sensitive and rapid tests while also highlighting the need for alternative therapeutic targets, strategies and the development of an effective vaccine.
PubMed: 38393138
DOI: 10.3390/tropicalmed9020049 -
Transplantation Proceedings Mar 2024Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are...
BACKGROUND
Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT.
METHODS
This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC.
RESULTS
Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV.
CONCLUSION AND RELEVANCE
In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.
Topics: Adult; Humans; Cytomegalovirus; Foscarnet; Antiviral Agents; Ganciclovir; Cytomegalovirus Infections; Organ Transplantation; Transplant Recipients
PubMed: 38355369
DOI: 10.1016/j.transproceed.2024.01.052 -
Transplant International : Official... 2024
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Kidney Transplantation; Transplant Recipients; Valganciclovir
PubMed: 38314399
DOI: 10.3389/ti.2024.11985 -
Current Opinion in Organ Transplantation Apr 2024Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT). (Review)
Review
PURPOSE OF REVIEW
Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT).
RECENT FINDINGS
Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients.
SUMMARY
Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT.
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Valganciclovir; Transplant Recipients; Organ Transplantation; Acetates; Quinazolines
PubMed: 38288947
DOI: 10.1097/MOT.0000000000001139 -
Infectious Disease Reports Jan 2024Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to... (Review)
Review
Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the gene under letermovir than low-grade resistance mutations. Some mutations emerging in the gene under maribavir can be cross-resistant with ganciclovir. Thus, letermovir and maribavir now extend the drug arsenal available for the management of CMV infections and their respective niches are currently defined.
PubMed: 38247977
DOI: 10.3390/idr16010005