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Viruses Sep 2023A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C...
A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, = 1; death, = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.
Topics: Adult; Humans; Sofosbuvir; Ribavirin; Hepacivirus; Antiviral Agents; Treatment Outcome; Hepatitis C; Hepatitis C, Chronic; Genotype; Drug Therapy, Combination
PubMed: 37896803
DOI: 10.3390/v15102026 -
Viruses Sep 2023The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection... (Review)
Review
The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection and fulminant hepatitis necessitate the administration of anti-HEV medications. However, there is a lack of specific antiviral drugs designed for HEV, and the currently available drug (ribavirin) has been associated with significant adverse effects. The development of innovative antiviral drugs involves targeting distinct steps within the viral life cycle: the early step (attachment and internalization), middle step (translation and RNA replication), and late step (virus particle formation and virion release). We recently established three HEV reporter systems, each covering one or two of these steps. Using these reporter systems, we identified various potential drug candidates that target different steps of the HEV life cycle. Through rigorous in vitro testing using our robust cell culture system with the genotype 3 HEV strain (JE03-1760F/P10), we confirmed the efficacy of these drugs, when used alone or in combination with existing anti-HEV drugs. This underscores their significance in the quest for an effective anti-HEV treatment. In the present review, we discuss the development of the three reporter systems, their applications in drug screening, and their potential to advance our understanding of the incompletely elucidated HEV life cycle.
Topics: Humans; Hepatitis E virus; Drug Evaluation, Preclinical; Hepatitis E; Antiviral Agents; Ribavirin; Virus Replication
PubMed: 37896767
DOI: 10.3390/v15101989 -
Current Issues in Molecular Biology Oct 2023Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent... (Review)
Review
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
PubMed: 37886964
DOI: 10.3390/cimb45100521 -
ACS Omega Oct 2023Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated ()-eIF4E overexpression. Once -eIF4E binds to the cap...
Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated ()-eIF4E overexpression. Once -eIF4E binds to the cap structure of mRNA, it advocates a nonstop translation process. In this regard, 15 new-based GMP analogs were synthesized to target eIF4E and restrain its binding to cap mRNA. The compounds were tested against three types of cancer cell lines: Caco-2, HepG-2, MCF-7, and normal kidney cells (Vero cells). Most of the compounds showed high potency against breast cancer cells (MCF-7), characterized by the highest cancer type for overexpression of -eIF4E. Compound was found to be the most active against three cell lines, colon (Caco-2), hepatic (HepG-2), and breast (MCF-7), with positive IC values of 31.40, 27.15, and 21.71 μM, respectively. Then, chitosan-coated niosomes loaded with compound (Cs/-NSs) were developed (as kinetically enhanced molecules) to improve the anticancer effects further. The prepared Cs/-NSs showed pronounced cytotoxicity compared to the free against Caco2, Hepg2, and MCF-7 with IC values of 16.15, 26.66, and 6.90 μM, respectively. Then, the expression of both the phosphorylated and nonphosphorylated western blot techniques was conducted on MCF-7 cells treated with the most active compounds (based on the obtained IC values) to determine the total protein expression of both eIF4E and -eIF4e. Interestingly, the selected most active compounds displayed 35.8-40.7% inhibition of -eIF4E expression when evaluated on MCF-7 compared to Ribavirin (positive control). CS/-NSs showed the best inhibition (40.7%). The findings of the present joint molecular docking, simulation dynamic studies, and experimental investigation suggest the potential use of niosomal nanovesicles as a promising nanocarrier for the targeted delivery of the newly synthesized compound to eukaryotic initiation factor 4E. These outcomes support the possible use of Cs/-NSs in targeted cancer therapy.
PubMed: 37867723
DOI: 10.1021/acsomega.3c02991 -
Open Veterinary Journal Sep 2023Nipah Virus (NiV) is a highly virulent pathogen that poses a significant threat to human and animal populations. This review provides a comprehensive overview of the... (Review)
Review
Nipah Virus (NiV) is a highly virulent pathogen that poses a significant threat to human and animal populations. This review provides a comprehensive overview of the latest control and prevention strategies against NiV, focusing on vaccine development, antiviral drug discovery, early diagnosis, surveillance, and high-level biosecurity measures. Advancements in vaccine research, including live-attenuated vaccines, virus-like particles, and mRNA-based vaccines, hold promise for preventing NiV infections. In addition, antiviral drugs, such as remdesivir, ribavirin, and favipiravir, have the potential to inhibit NiV replication. Early diagnosis through molecular and serological assays, immunohistochemistry, and real-time reverse transcription polymerase chain reaction plays a crucial role in timely detection. Surveillance efforts encompassing cluster-based and case-based systems enhance outbreak identification and provide valuable insights into transmission dynamics. Furthermore, the implementation of high-level biosecurity measures in agriculture, livestock practices, and healthcare settings is essential to minimize transmission risks. Collaboration among researchers, public health agencies, and policymakers is pivotal in refining and implementing these strategies to effectively control and prevent NiV outbreaks and safeguard public health on a global scale.
Topics: Humans; Animals; Nipah Virus; Disease Outbreaks; Henipavirus Infections
PubMed: 37842102
DOI: 10.5455/OVJ.2023.v13.i9.1 -
Frontiers in Public Health 2023Hepatitis C virus (HCV) infection is an independent risk factor associated with adverse outcomes in patients with end-stage renal disease (ESRD). Due to the wide variety... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hepatitis C virus (HCV) infection is an independent risk factor associated with adverse outcomes in patients with end-stage renal disease (ESRD). Due to the wide variety of direct-acting antiviral regimens (DAAs) and the factor of renal insufficiency, careless selection of anti-hepatitis C treatment can lead to treatment failure and safety problems. The integrated evidence for optimized therapies for these patients is lacking. This study would conduct comparisons of different DAAs and facilitate clinical decision-making.
METHODS
We conducted a systematic literature search in multiple databases (PubMed, Ovid, Embase, Cochrane Library, and Web of Science) up to 7 August 2023. Study data that contained patient characteristics, study design, treatment regimens, intention-to-treat sustained virologic response (SVR), and adverse event (AE) data per regimen were extracted into a structured electronic database and analyzed. The network meta-analysis of the estimation was performed by the Bayesian Markov Chain Monte Carlo methods.
RESULTS
Our search identified 5,278 articles; removing the studies with duplicates and ineligible criteria, a total of 62 studies (comprising 4,554 patients) were included. Overall, the analyses contained more than 2,489 male individuals, at least 202 patients with cirrhosis, and no less than 2,377 patients under hemodialysis. Network meta-analyses of the DAAs found that receiving ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (R) plus dasabuvir (DSV), glecaprevir (G)/pibrentasvir (P), and sofosbuvir (SOF)/ledipasvir (LDV) ranked as the top three efficacy factors for the HCV-infected ESRD patients. Stratified by genotype, the G/P would prioritize genotype 1 and 2 patients with 98.9%-100% SVR, the SOF/DCV regimen had the greatest SVR rates (98.7%; 95% CI, 93.0%-100.0%) in genotype 3, and the OBV/PTV/R regimen was the best choice for genotype 4, with the highest SVR of 98.1% (95% CI, 94.4%-99.9%). In the pan-genotypic DAAs comparison, the G/P regimen showed the best pooled SVR of 99.4% (95% CI, 98.6%-100%). DAA regimens without Ribavirin or SOF showed the lowest rates of AEs (49.9%; 95% CI, 38.4%-61.5%) in HCV-infected ESRD patients.
CONCLUSION
The G/P could be recommended as the best option for the treatment of pan-genotypic HCV-infected ESRD patients. The OBV/PTV/R plus DSV, SOF/Velpatasvir (VEL), SOF/Ledipasvir (LDV), and SOF/DCV would be reliable alternatives for HCV treatment with comparable efficacy and safety profiles.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/#searchadvanced, PROSPERO: CRD42021242359.
Topics: Humans; Male; Antiviral Agents; Network Meta-Analysis; Hepacivirus; Bayes Theorem; Hepatitis C, Chronic; Treatment Outcome; Ritonavir; Hepatitis C; Kidney Failure, Chronic
PubMed: 37841743
DOI: 10.3389/fpubh.2023.1179531 -
Annals of Saudi Medicine 2023Hepatitis C virus (HCV) can cause chronic liver disease, hepatic cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Early diagnosis and treatment are... (Observational Study)
Observational Study
BACKGROUND
Hepatitis C virus (HCV) can cause chronic liver disease, hepatic cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Early diagnosis and treatment are thus vital.
OBJECTIVES
We aimed to investigate the sustained virological response (SVR) rates in chronic hepatitis C patients infected with different genotypes, receiving different direct-acting antiviral treatments (DAAs).
DESIGN
Retrospective, observational SETTING: Clinic for infectious diseases and clinical microbiology PATIENTS AND METHODS: Patients diagnosed with chronic hepatitis C who applied to our outpatient clinic between January 2016 and November 2022 and were treated with a DAA were included in the study. Treatment responses were evaluated after each patient was treated with either ledipasvir plus sofosbuvir (LDV/SOF), LDV/SOF + ribavirin (RBV), SOF+RBV, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r±DSV) ±RBV, or glecaprevir plus pibrentasvir (GLE/PIB).
MAIN OUTCOME MEASURES
Sustained virological response (SVR) rates at 12 weeks (SVR12) post-treatment.
SAMPLE SIZE
360 patients.
RESULTS
Of 360 patients who met the inclusion criteria, 218 (60.6%) were male and 142 (39.4%) were female with no statistically significant differences in SVR between sexes (=.252). Nearly all had a SVR (n=353, 98.1%). The median (IQR) age of the patients was 56 (30.3) years. There were 42 (11.7%), 199 (55.3%), 4 (1.1%), 106 (29.4%), 8 (2.2%) and 1 (0.3%) patient with genotypes 1a, 1b, 2, 3, 4 and 5, respectively, and SVR12 did not differ significantly between genotypes (=.066). SVR12 response was higher in 246 (68.3%) non-injecting drug users compared to 114 (31.7%) injecting drug users (=.005). The SVR12 response was achieved in 100% of patients with genotypes 1a, 2, 4, and 5. SVR12 response could not be obtained in 1 of 199 genotype 1b patients and 6 of 106 genotype 3 patients. The common feature of 6 reinfection patients with genotype 3 was that they were using intravenous drugs. These 6 patients were reinfected due to their continued intravenous drug use.
CONCLUSION
In conclusion, DAAs provide high SVR12 rates in cirrhotic/non-cirrhotic, pegylated interferon-naive/experienced patient groups and in patients infected with all genotypes. DAAs have a high SVR12 rate in patients with chronic hepatitis C.
LIMITATIONS
Retrospective, single-center.
Topics: Humans; Male; Female; Middle Aged; Antiviral Agents; Hepatitis C, Chronic; Retrospective Studies; Turkey; Drug Therapy, Combination; Ribavirin; Ritonavir; Hepacivirus; Liver Neoplasms; Genotype; Treatment Outcome
PubMed: 37805816
DOI: 10.5144/0256-4947.2023.308 -
Nature Medicine Nov 2023Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41 .
Topics: Child; Adolescent; Humans; Diabetes Mellitus, Type 1; Ribavirin; C-Peptide; Double-Blind Method; Antiviral Agents
PubMed: 37789144
DOI: 10.1038/s41591-023-02576-1 -
Virus Research Nov 2023Hemorrhagic fever with renal syndrome (HFRS) represents a serious zoonotic disease caused by orthohantaviruses in Eurasia. A specific antiviral therapy is not available....
Hemorrhagic fever with renal syndrome (HFRS) represents a serious zoonotic disease caused by orthohantaviruses in Eurasia. A specific antiviral therapy is not available. HFRS is characterized by acute kidney injury (AKI) with often massive proteinuria. Infection of kidney cells may contribute to the clinical picture. However, orthohantaviral replication in kidney cells is not well characterized. Therefore, we aimed to perform a reliable high-throughput assay that allows the quantification of infection rates and testing of antiviral compounds in different cell types. We quantified relative infection rates of Eurasian pathogenic Puumala virus (PUUV) by staining of nucleocapsid protein (N protein) in an in-cell Western (ICW) assay. Vero E6 cells, derived from the African green monkey and commonly used in viral cell culture studies, and the human podocyte cell line CIHP (conditionally immortalized human podocytes) were used to test the ICW assay for replication kinetics and antiviral drug testing. Quantification of infection by ICW revealed reliable results for both cell types, as shown by their correlation with immunofluorescence quantification results by counting infected cells. Evaluation of antiviral efficacy of ribavirin by ICW assay revealed differences in the toxicity (TC) and inhibitory concentrations (IC) between Vero E6 cells and podocytes. IC5O of ribavirin in podocytes is about 12-fold lower than in Vero E6 cells. In summary, ICW assay together with relevant human target cells represents an important tool for the study of hantaviral replication and drug testing.
Topics: Animals; Humans; Chlorocebus aethiops; Puumala virus; Hemorrhagic Fever with Renal Syndrome; Ribavirin; Orthohantavirus; Vero Cells; Antiviral Agents; Virus Replication
PubMed: 37777116
DOI: 10.1016/j.virusres.2023.199230 -
Saudi Pharmaceutical Journal : SPJ :... Oct 2023The development of thermosensitive systems has become widespread and prospective due to the optimal parameters of the phase transition - in the temperature range from...
INTRODUCTION
The development of thermosensitive systems has become widespread and prospective due to the optimal parameters of the phase transition - in the temperature range from room to physiological. Those properties can provide thermosensitive polymers, for example, poloxamers - as the most common.It is worth noting that the addition of active pharmaceutical ingredients (APIs) changes the parameters of systems, but no systematic study of the effect of APIs has been conducted. was to develop a systematic approach to studying the effect of APIs on the rheological properties of poloxamer compositions.
MATERIALS AND METHODS
The biopharmaceutical classification system (BCS) was chosen as the basis. Accordingly, the following APIs were selected for the experiment: BCS class I - lidocaine hydrochloride and ketorolac tromethamine, class II - ibuprofen and diclofenac, class III - pyridoxine hydrochloride and ribavirin, class IV - furosemide and abiraterone. To create thermoreversible compositions, previously studied for stability combinations of poloxamer 407, poloxamer 188 and PEG 1500 were used.At the stage of preparation of experimental samples formulations with APIs of classes II and IV of BCS were excluded, since the solubilizing ability of poloxamers is not enough to obtain stable combined complexes.
RESULTS
In the course of the work, the following results were obtained: BCS class I APIs significantly reduced the phase transition temperature of the matrix of poloxamers 407 and 188, while the addition of PEG 1500 eliminated the effect of APIs on gels; BCS class III APIs practically did not affect the rheological properties of the studied combinations; the phase transition temperature of the gel based on poloxamer 407 did not change with the addition of Class I and Class III APIs.Nevertheless, the obtained results made it possible to reveal the regular behavior of complexes of poloxamer matrices depending on the class of BCS of the API. Further research is required.
PubMed: 37766821
DOI: 10.1016/j.jsps.2023.101780