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JHEP Reports : Innovation in Hepatology Mar 2024In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV . However, a variant,...
BACKGROUND & AIMS
In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV . However, a variant, A1343V, that is strongly associated with viral relapse impedes treatment success. In this study, we investigated the occurrence of variants during sofosbuvir and ribavirin treatment and assessed the sensitivity of resistance-associated variants to concurrent treatment in cell culture.
METHODS
Two patients with chronic HEV infection that did not clear infection under ribavirin treatment were subsequently treated with a combination of sofosbuvir and ribavirin. We determined response to treatment by measuring liver enzymes and viral load in blood and stool. Moreover, we analyzed viral evolution using polymerase-targeted high-throughput sequencing and assessed replication fitness of resistance-associated variants using a HEV replicon system.
RESULTS
Combination treatment was successful in decreasing viral load towards the limit of quantification. However, during treatment sustained virological response was not achieved. Variants associated with sofosbuvir or ribavirin treatment emerged during treatment, including A1343V and G1634R. Moreover, A1343V, as a single or double mutation with G1634R, was associated with sofosbuvir resistance during concomitant treatment .
CONCLUSIONS
These results highlight the importance of variant profiling during antiviral treatment of patients with chronic infection. Understanding how intra-host viral evolution impedes treatment success will help guide the design of next-generation antivirals.
IMPACT AND IMPLICATIONS
The lack of hepatitis E virus (HEV)-specific antivirals to treat chronic infection remains a serious health burden. Although ribavirin, interferon and sofosbuvir have been reported as anti-HEV drugs, not all patients are eligible for treatment or clear infection, since resistant-associated variants can rapidly emerge. In this study, we analyzed the efficacy of sofosbuvir and ribavirin combination treatment in terms of HEV suppression, the emergence of resistance-associated variants and their ability to escape treatment inhibition . Our results provide novel insights into evolutionary dynamics of HEV during treatment and thus will help guide the design of next-generation antivirals.
PubMed: 38434938
DOI: 10.1016/j.jhepr.2023.100989 -
Frontiers in Physiology 2024Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure...
Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure in society. Symptomatically, both DLU and CLE exhibit delayed healing and excessive inflammation; however, there is little evidence to support a molecular and cellular connection between these two diseases. In this study, we investigated potential common characteristics between DFU and CLE at the molecular level to provide new insights into skin diseases and regeneration, and identify potential targets for the development of new therapies. The gene expression profiles of DFU and CLE were obtained from the Gene Expression Omnibus (GEO) database and used for analysis. A total of 41 common differentially expressed genes (DEGs), 16 upregulated genes and 25 downregulated genes, were identified between DFU and CLE. GO and KEGG analysis showed that abnormalities in epidermal cells and the activation of inflammatory factors were both involved in the occurrence and development of DFU and CLE. Protein-protein interaction network (PPI) and sub-module analysis identified enrichment in seven common key genes which is , , and . Based on these seven key genes, we further identified five miRNAs(has-mir-532-5p, has-mir-324-3p,has-mir-106a-5p,has-mir-20a-5p,has-mir-93-5p) and7 transcription factors including CEBPA, CEBPB, GLI1, EP30D, JUN,SP1, NFE2L2 as potential upstream molecules. Functional immune infiltration assays showed that these genes were related to immune cells. The CIBERSORT algorithm and Pearson method were used to determine the correlations between key genes and immune cells, and reverse key gene-immune cell correlations were found between DFU and CLE. Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions.
PubMed: 38434138
DOI: 10.3389/fphys.2024.1297810 -
Scientific Reports Feb 2024Jatropha variegata and Jatropha spinosa (family: Euphorbiaceae) are utilized in Yemeni traditional medicine to treat respiratory tract infection and in different skin...
Jatropha variegata and Jatropha spinosa (family: Euphorbiaceae) are utilized in Yemeni traditional medicine to treat respiratory tract infection and in different skin conditions such as wound healing, as antibacterial and hemostatic. In this study, we evaluated the cytotoxicity and the antiviral activities of the methanolic J. variegata (leaves: Ext-1, stems: Ext-2, and roots: Ext-3), and J. spinosa extracts (aerial parts: Ext-4 and roots: Ext-5), in addition to their methylene chloride fractions of roots extracts (F-6 and F-7, respectively). All samples were tested against three human cancer cell lines in vitro (MCF-7, HepG2, and A549) and two viruses (HSV-2 and H1N1). Both plants showed significant cytotoxicity, among them, the methylene chloride fractions of roots of J. variegata (F-6) and J. spinosa roots (F-7) showed the highest activity on MCF-7 (IC = 1.4 and 1 μg/mL), HepG2 (IC = 0.64 and 0.24 μg/mL), and A549 (IC = 0.7 and 0.5 μg/mL), respectively, whereas the IC values of the standard doxorubicin were (3.83, 4.73, and 4.57 μg/mL) against MCF-7, HepG2, and A549, respectively. These results revealed that the roots of both plants are potential targets for cytotoxic activities. The in vitro results revealed potential antiviral activity for each of Ext-3, Ext-5, F-6, and F-7 against HVS-2 with IC of 101.23, 68.83, 4.88, 3.24 μg/mL and against H1N1 with IC of 51.29, 27.92, 4.24, and 3.06 μg/mL respectively, whereas the IC value of the standard acyclovir against HVS-2 was 83.19 μg/mL and IC value of the standard ribavirin against H1N1 was 52.40 μg/mL .The methanol extracts of the roots (Ext-3 and Ext-5) of both plants were characterized using UPLC/MS. A total of 73 metabolites were annotated, including fourteen diterpenoids, eleven flavonoids, ten phenolic acid conjugates, twelve fatty acids and their conjugates, five triterpenes and steroids, two sesquiterpenes, and six coumarins. The cytotoxicity and antiviral activities determined in the present work are explained by the existence of flavonoids, coumarins and diterpenes with commonly known cytotoxicity and antiviral activities.
Topics: Humans; Plant Extracts; Jatropha; Influenza A Virus, H1N1 Subtype; Methylene Chloride; Antineoplastic Agents; Flavonoids; Coumarins; Antiviral Agents
PubMed: 38418513
DOI: 10.1038/s41598-024-55196-1 -
Journal of Ayub Medical College,... 2023Recently various combinations of direct acting antivirals (DAAs) have been tried successfully. The Sofosbuvir + Daclatasvir combination has been used with promising...
BACKGROUND
Recently various combinations of direct acting antivirals (DAAs) have been tried successfully. The Sofosbuvir + Daclatasvir combination has been used with promising results. Recently, resistance has been noticed against DAAs. Therefore, polymorphism at particular sites in the interleukin 28B gene are under study to find possible association with resistance. This study was aimed at finding out any association of SNPs rs8099917 and rs12979860 (IL28B gene) with response and resistance to treatment in HCV genotype 3 patients in Khyber Pakhtunkhwa.
METHODS
This cross sectional, Analytical study was conducted at Gastroenterology/hepatology OPD of Prime Teaching Hospital, Peshawar Medical College. Collected Samples were stored at -20o C in PCR Lab of the College. DNA extraction and genotyping was carried out at BJ Molecular Biology Lab in Rawalpindi. Data was analyzed by using SPSS version 21. Chi-Square Test was used to see the statistically significant differences between rs8099917 T/G and rs12979860 T/C model.
RESULTS
In the IL28-B gene, single nucleotide polymorphism at rs12979860 T/C model, we observed that there are 37.5% CC homozygous, 12.5% TT homozygous and 50% CT heterozygous genotypes in resistant patients and 42.85% CC homozygous, 28.57% TT and 28.57% CT genotype in responder group. In rs12979860 T/C model, genotype of IL28-B in the responder and resistant group significantly varies at p-value =0.00572.
CONCLUSION
We conclude that in SNP at rs12979860, CC genotype is associated with clearance of HCV, while CT genotype was more prevalent in the resistant group and associated with chronicity.
Topics: Humans; Antiviral Agents; Carbamates; Cross-Sectional Studies; Genotype; Hepacivirus; Hepatitis C, Chronic; Imidazoles; Interferons; Interleukins; Pyrrolidines; Ribavirin; Sofosbuvir; Treatment Outcome; Valine
PubMed: 38406928
DOI: 10.55519/JAMC-04-11760 -
Experimental and Clinical... Jan 2024Recurrence of hepatitis C virus after organ transplant has dreadful complications. An excellent response has been shown with direct-acting antiviral agents in transplant...
Recurrence Rate of Early Hepatitis C Virus Infection After Renal Transplantation Following Successful Treatment of Patients on Dialysis With Direct-Acting Antiviral Agents.
OBJECTIVES
Recurrence of hepatitis C virus after organ transplant has dreadful complications. An excellent response has been shown with direct-acting antiviral agents in transplant recipients. Although a sustained virological response is considered as the virological cure, it requires patients to be on dialysis for 3 months more before undergoing renal transplant, thus increasing the risk of hepatitis C virus reinfection and associated complications. We aimed to determine hepatitis C virus recurrence in renal transplant recipients who had achieved endof-treatment response before transplant.
MATERIALS AND METHODS
Per our institutional dialysis protocol, patients who do not achieve rapid virological response are treated with 6 months of direct-acting antiviral agents. All patients who achieve end-of-treatment response are then referred for renal transplant. Our study included kidney transplant recipients who were treated with directacting antiviral agents and had a hepatitis C virus polymerase chain reaction test 3 months after renal transplant. We obtained demographic and clinical data of patients and used SPSS version 20.0 for statistical analyses.
RESULTS
Our study included 48 transplant recipients; most were males (81.1%) with mean age of 28.7 ± 9.4 years. All patients received sofosbuvir, daclatasvir, and ribavirin combination before transplant. Most patients (70%) received treatment for 3 months. The polymerase chain reaction test for hepatitis C virus was conducted after a mean of 8.3 ± 3.3 months posttransplant. Laboratory parameters showed total bilirubin of 3.6 ± 17.5 mg/day, alanine aminotransferase of 51.5 ± 80.2 IU/L, and gammaglutamyltransferase of 133.9 ± 220 IU/L. Two recipients (4.2%) had posttransplant recurrence of hepatitis C virus infection.
CONCLUSIONS
To our knowledge, this study is the first to document excellent response of direct-acting antivirals in renal transplant recipients who had been referred early for transplant. Thus, dialysis patients can undergo transplant after achieving end-oftreatment response.
Topics: Male; Humans; Young Adult; Adult; Female; Antiviral Agents; Hepacivirus; Kidney Transplantation; Hepatitis C, Chronic; Treatment Outcome; Renal Dialysis; Hepatitis C; Drug Therapy, Combination; Recurrence
PubMed: 38385392
DOI: 10.6002/ect.MESOT2023.P6 -
Frontiers in Pediatrics 2024Human adenovirus (HAdV) infections in children can lead to profound pulmonary injury and are frequently associated with severe complications, particularly in cases...
Combined intravenous ribavirin and recombinant human interferon α1b aerosol inhalation for adenovirus pneumonia with plastic bronchitis in children: a case report and review of literature.
BACKGROUND
Human adenovirus (HAdV) infections in children can lead to profound pulmonary injury and are frequently associated with severe complications, particularly in cases concomitant with plastic bronchitis. Managing this condition presents significant challenges and carries an exceptionally high fatality rate. Regrettably, there are currently no specific antiviral agents that have demonstrated efficacy in treating severe adenovirus pneumonia in children.
CASE PRESENTATION
We report a 10-month-old infant suffering from severe adenovirus pneumonia combined with plastic bronchitis (PB). He received intravenous ribavirin combined with recombinant human interferon α1b (INFα1b) aerosol inhalation and his condition eventually improved. No side effects occurred during the treatment, and the long-term prognosis was favorable.
CONCLUSION
In this case, the combination therapy of intravenous ribavirin and INFα1b seems to have contributed to the resolution of illness and may be considered for similar cases until stronger evidence is generated.
PubMed: 38379910
DOI: 10.3389/fped.2024.1295133 -
Virus Evolution 2024Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection,...
Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection, and even death. How the host immune environment of the hematopoietic stem cell transplant (HCT) adults can affect viral genetic variation during an acute infection is not understood well. In the present study, we performed whole genome sequencing of RSV/A or RSV/B from samples collected longitudinally from HCT adults with normal (<14 days) and delayed (≥14 days) RSV clearance who were enrolled in a ribavirin trial. We determined the inter-host and intra-host genetic variation of RSV and the effect of mutations on putative glycosylation sites. The inter-host variation of RSV is centered in the attachment (G) and fusion (F) glycoprotein genes followed by polymerase (L) and matrix (M) genes. Interestingly, the overall genetic variation was constant between normal and delayed clearance groups for both RSV/A and RSV/B. Intra-host variation primarily occurred in the G gene followed by non-structural protein (NS1) and L genes; however, gain or loss of stop codons and frameshift mutations appeared only in the G gene and only in the delayed viral clearance group. Potential gain or loss of O-linked glycosylation sites in the G gene occurred both in RSV/A and RSV/B isolates. For RSV F gene, loss of N-linked glycosylation site occurred in three RSV/B isolates within an antigenic epitope. Both oral and aerosolized ribavirin did not cause any mutations in the L gene. In summary, prolonged viral shedding and immune deficiency resulted in RSV variation, especially in structural mutations in the G gene, possibly associated with immune evasion. Therefore, sequencing and monitoring of RSV isolates from immunocompromised patients are crucial as they can create escape mutants that can impact the effectiveness of upcoming vaccines and treatments.
PubMed: 38361816
DOI: 10.1093/ve/vead086 -
JHEP Reports : Innovation in Hepatology Mar 2024Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection....
BACKGROUND & AIMS
Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts.
METHODS
Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland.
RESULTS
A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease (0.001), hepatocellular carcinoma (0.001), higher baseline ALT levels ( 0.02), HCV genotype 3 (0.001), and prior VEL/SOF treatment ( 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%).
CONCLUSIONS
Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective.
IMPACT AND IMPLICATIONS
Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF.
PubMed: 38357421
DOI: 10.1016/j.jhepr.2023.100994 -
BMC Gastroenterology Feb 2024Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the... (Comparative Study)
Comparative Study
BACKGROUND
Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV.
PATIENTS AND METHODS
178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study.
RESULTS
DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis ( P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups.
CONCLUSION
In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C.
Topics: Humans; Antiviral Agents; Benzimidazoles; Benzopyrans; Carbamates; China; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Isoindoles; Lactams, Macrocyclic; Liver Cirrhosis; Proline; Retrospective Studies; Ribavirin; Sofosbuvir; Sulfonamides; Treatment Outcome
PubMed: 38355447
DOI: 10.1186/s12876-024-03147-5 -
Cureus Jan 2024Background The COVID-19 pandemic has posed an unprecedented challenge to the global healthcare system, necessitating effective therapeutic strategies to mitigate its...
Background The COVID-19 pandemic has posed an unprecedented challenge to the global healthcare system, necessitating effective therapeutic strategies to mitigate its impact. This study investigates the significance of early antiviral therapy in the context of intensive care units (ICUs) and its potential to influence the progression and outcomes of severe COVID-19 cases. Methodology This retrospective cohort study leveraged a diverse patient population with confirmed severe COVID-19 admitted to ICUs. A total of 1,250 patients were included in the analysis, and their medical records were comprehensively reviewed. The study aimed to assess the impact of early antiviral therapy on patient outcomes, focusing on the administration of remdesivir within the first 48 hours of ICU admission. Results In a study of 1,250 COVID-19 patients, early antiviral therapy with remdesivir significantly reduced ICU admissions by 30% (N = 225) compared to standard care (N = 525). The early therapy group also exhibited a 20% lower mortality rate (N = 120) than the control group (N = 150). Demographic associations with antiviral usage were observed. Kaletra was favored by females, non-Saudi individuals, and healthcare workers, while favipiravir was associated with gender. Remdesivir and ribavirin use were linked to gender and Saudi nationality, while oseltamivir was related to gender, Saudi nationality, and body mass index. Microbiological cure rates were 15.4%, with 84.6% not achieving it. ICU outcomes included 37.7% deaths, 55.7% home discharges, and 6.6% transfers, while hospital outcomes featured 38.5% deaths, 54.4% home discharges, and 7.1% transfers. Conclusions This study presents a comprehensive analysis of COVID-19 patient demographics, antiviral medication associations, and clinical outcomes. The findings highlight the significance of tailoring treatment strategies based on patient characteristics and viral history. These insights contribute to a deeper understanding of COVID-19 management and can inform clinical decision-making and further research in this field.
PubMed: 38344559
DOI: 10.7759/cureus.52096