-
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 -
Transplantation and Cellular Therapy Jun 2023Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and... (Review)
Review
Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3,100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.
Topics: Adult; Humans; Young Adult; Middle Aged; Aged; Adolescent; Foscarnet; Herpesvirus 6, Human; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; DNA, Viral
PubMed: 36878429
DOI: 10.1016/j.jtct.2023.02.022 -
BioRxiv : the Preprint Server For... Jan 2023The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses EBV and KSHV and the...
UNLABELLED
The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses EBV and KSHV and the alpha-herpesviruses HSV-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting involvement of an immediate early or early (IE-E) viral protein. In support of this mechanism, cycloheximide treatment of HCMV-infected cells prevents the expression of viral proteins and simultaneously blocks APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which is a viral DNA synthesis inhibitor affecting late protein expression, still permits A3B relocalization. These results combine to show that the beta-herpesvirus HCMV uses a fundamentally different, RNR-independent molecular mechanism to antagonize APOBEC3B.
IMPORTANCE
Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses in order to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.
PubMed: 36778493
DOI: 10.1101/2023.01.30.526383 -
Retinal Cases & Brief Reports Mar 2024To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
PURPOSE
To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
METHODS
Retrospective case report of a lung-transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs.
RESULTS
A 72-year-old lung-transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the uninjected eye.
CONCLUSION
This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.
Topics: Humans; Aged; Cytomegalovirus Retinitis; Valganciclovir; Foscarnet; Retrospective Studies; Ganciclovir; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 36730596
DOI: 10.1097/ICB.0000000000001372 -
Zhonghua Nei Ke Za Zhi Jan 2023To evaluate and compare the efficacies of ganciclovir plus foscarnet and a single agent for the treatment of cytomegalovirus (CMV) infection after haploidentical... (Clinical Trial)
Clinical Trial
[Clinical analysis of the efficacies of ganciclovir plus foscarnet and a single antiviral drug for the treatment of cytomegalovirus infection after haploidentical stem cell transplantation].
To evaluate and compare the efficacies of ganciclovir plus foscarnet and a single agent for the treatment of cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation. This study was a non-randomized clinical controlled trial. The data of patients who underwent haploidentical transplantation and developed CMV infection between January 1, 2021, and June 30, 2021, were retrospectively analyzed. Follow-up was conducted through telephone, inpatient consultations, and the review of outpatient medical records. The observed indicators included the incidence of CMV infection (including CMV disease), rate of recurrence of CMV infection, overall survival (OS), and disease-free survival (DFS). A total of 242 patients were diagnosed with post-transplantation CMV infection; 116 patients tested positive for CMV DNA for more than 14 days (=0.011). Of the 242 patients with CMV infection, 65 were treated with ganciclovir plus foscarnet, and 156 patients were treated with a single antiviral drug; the median durations of CMV seroconversion were 21 (3-60) and 14 (3-32) days for the combination and single-drug groups, respectively. There were no significant differences between their incidence of CMV infections and 1-year OS and DFS. Of the patients with refractory CMV infections, 53 (45.7%) were treated with ganciclovir plus foscarnet, and 63 (54.3%) were treated with a single antiviral agent. The median durations of CMV seroconversion for the combination and single-drug groups were 21 (15-60) days and 20 (15-45) days, respectively (=0.472). Two patients in each group progressed to CMV disease (=0.860). During follow-up, 12 patients (22.6%) in the combination group and 8 patients (12.7%) in the single-drug group experienced recurrent episode(s) of CMV infection (=0.158). The 1-year OS of the combination and single-drug groups were 92.0% and 87.1%, respectively (=0.543); the 1-year DFS were 90.3% and 85.7%, respectively (=0.665). Univariate analysis revealed no associations between the antiviral agents used and OS and DFS (OS: =0.644, =0.547; DFS: =0.757, =0.666). There were no significant differences in the duration of CMV infection, incidence of CMV disease, rate of recurrence of CMV infection, and survival of the patients treated with the combination of antiviral drugs and a single antiviral drug.
Topics: Humans; Antiviral Agents; Foscarnet; Ganciclovir; Retrospective Studies; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation
PubMed: 36631041
DOI: 10.3760/cma.j.cn112138-20220118-00058 -
Biochemistry Jan 2023The Gram-positive pathogen is a leading cause of antimicrobial resistance related deaths worldwide. Like many pathogens with multidrug-resistant strains, contains...
The Gram-positive pathogen is a leading cause of antimicrobial resistance related deaths worldwide. Like many pathogens with multidrug-resistant strains, contains enzymes that confer resistance through antibiotic modification(s). One such enzyme present in is FosB, a Mn-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. gene knockout experiments show that the minimum inhibitory concentration (MIC) of fosfomycin is significantly reduced when the FosB enzyme is not present. This suggests that inhibition of FosB could be an effective method to restore fosfomycin activity. We used high-throughput -based screening to identify small-molecule analogues of fosfomycin that inhibited thiol transferase activity. Phosphonoformate (PPF) was a top hit from our approach. Herein, we have characterized PPF as a competitive inhibitor of FosB from (FosB) and (FosB). In addition, we have determined a crystal structure of FosB with PPF bound in the active site. Our results will be useful for future structure-based development of FosB inhibitors that can be delivered in combination with fosfomycin in order to increase the efficacy of this antibiotic.
Topics: Anti-Bacterial Agents; Foscarnet; Fosfomycin; Microbial Sensitivity Tests; Staphylococcus aureus; Transferases; Drug Resistance, Bacterial; Bacterial Proteins
PubMed: 36525630
DOI: 10.1021/acs.biochem.2c00566 -
Voprosy Virusologii Nov 2022The review provides information on the mechanisms of the emergence of resistance to antiviral drugs in human viruses from the subfamily Betaherpesvirinae. Data on the...
The review provides information on the mechanisms of the emergence of resistance to antiviral drugs in human viruses from the subfamily Betaherpesvirinae. Data on the principles of action of antiviral drugs and their characteristics are given. The occurrence rates of viral resistance in various groups of patients is described and information about the possible consequences of the emergence of resistance to antiviral drugs is given. Information is provided regarding the virus genes in which mutations occur that lead to viral resistance, and a list of such mutations that have described so far is given. The significance of the study of mutations leading to the resistance of the virus to antiviral drugs for medical practice is discussed.
Topics: Humans; Antiviral Agents; Ganciclovir; Cytomegalovirus; Drug Resistance, Viral; DNA-Directed DNA Polymerase; Betaherpesvirinae; Foscarnet; Cytosine
PubMed: 36515284
DOI: 10.36233/0507-4088-136 -
Transplant Immunology Feb 2023Long-term neurocognitive deficits after human herpesvirus-6 (HHV-6) infection are common in stem-cell transplant recipients, but SIADH (Syndrome of inappropriate...
Long-term neurocognitive deficits after human herpesvirus-6 (HHV-6) infection are common in stem-cell transplant recipients, but SIADH (Syndrome of inappropriate antidiuretic hormone secretion) with persistent hyponatremia is rare. A 51-year-old woman presented with somnolence, hyponatremia (121 mmol/L) and HHV-6 viremia (80,330 copies/ml) on day +22 post umbilical cord blood transplant (UCBT). With waterrestriction, tolvaptan and combination of foscarnet and ganciclovir, patient's hyponatremia and HHV-6 viremia improved. On day +94 UCBT, hyponatremia and HHV-6 viremia recurred. Foscarnet was restarted and continued until day +269 UCBT due to multiple HHV-6 recurrences with persistent hyponatremia. At day +712, patient remains on water-restriction, tolvaptan for continuous hyponatremia from SIADH.
Topics: Female; Humans; Middle Aged; Hyponatremia; Foscarnet; Herpesvirus 6, Human; Tolvaptan; Inappropriate ADH Syndrome; Transplant Recipients; Cord Blood Stem Cell Transplantation; Viremia; Roseolovirus Infections
PubMed: 36372142
DOI: 10.1016/j.trim.2022.101742 -
European Journal of Ophthalmology Sep 2023To report a case of cytomegalovirus (CMV) retinitis improved by treatment with ganciclovir in a patient with ganciclovir-resistant CMV infection associated with Good...
PURPOSE
To report a case of cytomegalovirus (CMV) retinitis improved by treatment with ganciclovir in a patient with ganciclovir-resistant CMV infection associated with Good syndrome.
STUDY DESIGN
Case report.
RESULT
A 52-year-old gentleman with Good syndrome presented with visual disturbance in his right eye. He had a history of receiving intravitreal ganciclovir treatment with CMV retinitis a year ago. During treatment for CMV colitis three months ago, in systemic blood, UL97 mutation was identified and improved after changing treatment from ganciclovir to foscarnet. CMV retinitis recurred, and intravitreal ganciclovir injection was performed but there was no improvement. Therefore, the treatment was changed to foscarnet, but retinal infiltration progressed. Accordingly, it was changed to ganciclovir again and as a result, the progression of retinitis could be stopped.
CONCLUSIONS
Even in the case of CMV retinitis, which has been genetically confirmed to be ganciclovir resistance in systemic blood, ganciclovir treatment can be considered if other anti-CMV agents are not effective.
Topics: Humans; Male; Middle Aged; Cytomegalovirus Retinitis; Ganciclovir; Antiviral Agents; Foscarnet; Treatment Outcome
PubMed: 36314436
DOI: 10.1177/11206721221136316 -
Chemical & Pharmaceutical Bulletin Dec 2022Quantitative H-NMR (H-qNMR) is useful for determining the absolute purity of organic molecules; however, it is sometimes difficult to identify the target signal(s) for...
Quantitative H-NMR (H-qNMR) is useful for determining the absolute purity of organic molecules; however, it is sometimes difficult to identify the target signal(s) for quantitation because of their overlap and complexity. Therefore, we focused on the P nucleus because of the simplicity of its signals and previously reported P-qNMR in DO. Here we report P-qNMR of an organophosphorus compound, sofosbuvir (SOF), which is soluble in organic solvents. Phosphonoacetic acid (PAA) and 1,4-bis(trimethylsilyl)benzene-d (1,4-BTMSB-d) were used as reference standards for P-qNMR and H-qNMR, respectively, in methanol-d. The purity of SOF determined by P-qNMR was 100.63 ± 0.95%, whereas that determined by H-qNMR was 99.07 ± 0.50%. The average half bandwidths of the P signal of PAA and SOF were 3.38 ± 2.39 and 2.22 ± 0.19 Hz, respectively, suggesting that the T relaxation time of the PAA signal was shorter than that of SOF and varied among test laboratories. This difference most likely arose from the instability in the chemical shift due to the deuterium exchange of the acidic protons of PAA, which decreased the integrated intensity of the PAA signal. Next, an aprotic solvent, dimethyl sulfoxide-d (DMSO-d), was used as the dissolving solvent with PAA and sodium 4,4-dimethyl-4-silapentanesulfonate-d (DSS-d) as reference standards for P-qNMR and H-qNMR, respectively. SOF purities determined by P-qNMR and H-qNMR were 99.10 ± 0.30 and 99.44 ± 0.29%, respectively. SOF purities determined by P-qNMR agreed with the established H-qNMR values, suggesting that an aprotic solvent is preferable for P-qNMR because it is unnecessary to consider the effect of deuterium exchange.
Topics: Deuterium; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Reference Standards; Sofosbuvir; Solvents
PubMed: 36223954
DOI: 10.1248/cpb.c22-00639