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1.
Arch Endocrinol Metab ; 68: e220480, 2024 May 06.
Article En | MEDLINE | ID: mdl-38709148

Objective: The aim of this study was to evaluate the glycated hemoglobin (HbA1c) levels before and after sustained virologic response (SVR) and investigate the baseline characteristics associated with improved glycemic control in patients with chronic hepatitis C (CHC) achieving SVR after directacting antivirals (DAA) therapy. Materials and methods: Consecutive adult patients with CHC who achieved SVR after DAA treatment between January 2016 and December 2017 at Hospital de Clínicas de Porto Alegre (RS, Brazil) were prospectively included. Levels of HbA1c were measured up to 24 weeks before DAA therapy and 12 weeks after SVR. Exclusion criteria were decompensated cirrhosis, HIV and/or hepatitis B virus, liver disease of other etiologies, and/or modification of prediabetes/ type 2 diabetes mellitus (PDM/T2DM) management. The primary outcome was a comparison of HbA1c levels before and after SVR. Secondary outcomes were the baseline variables associated with improved glycemic control. Results: The study included 207 patients with a mean age of 60.6±10.7 years, of whom 51.7% were women, 56% had cirrhosis, 37.7% had HCV genotype 3, and 54.5% had baseline T2DM or PDM. The median HbA1c level reduced significantly after SVR (5.5%, interquartile range [IQR] 4.9%-6.3%) compared with baseline (5.7%, IQR 5.3%-6.7%; p = 0.01). The baseline characteristics associated with improved HbA1c after SVR were cirrhosis, genotype 3, and age ≤ 60 years. Conclusion: Among patients with CHC, SVR after DAA was associated with HbA1c reduction, particularly in those with cirrhosis, genotype 3, and age ≤ 60 years.


Antiviral Agents , Blood Glucose , Glycated Hemoglobin , Hepatitis C, Chronic , Sustained Virologic Response , Humans , Female , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/blood , Male , Middle Aged , Glycated Hemoglobin/analysis , Blood Glucose/analysis , Blood Glucose/drug effects , Aged , Prospective Studies , Treatment Outcome , Hepacivirus/genetics , Hepacivirus/drug effects , Brazil , Adult , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood
2.
J Med Virol ; 96(5): e29675, 2024 May.
Article En | MEDLINE | ID: mdl-38746997

Early confirmation of sustained virologic response (SVR) or viral relapse after direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection is essential based on public health perspectives, particularly for patients with high risk of nonadherence to posttreatment follow-ups. A total of 1011 patients who achieved end-of-treatment virologic response, including 526 receiving fixed-dose pangenotypic DAAs, and 485 receiving other types of DAAs, who had available off-treatment weeks 4 and 12 serum HCV RNA data to confirm SVR at off-treatment week 12 (SVR12) or viral relapse were included. The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 to predict patients with SVR12 or viral relapse were reported. Furthermore, we analyzed the proportion of concordance between SVR12 and SVR24 in 943 patients with available SVR24 data. The PPV and NPV of SVR4 to predict SVR12 were 98.5% (95% confidence interval [CI]: 98.0-98.9) and 100% (95% CI: 66.4-100) in the entire population. The PPV of SVR4 to predict SVR12 in patients receiving fixed-dose pangenotypic DAAs was higher than those receiving other types of DAAs (99.8% [95% CI: 98.9-100] vs. 97.1% [95% CI: 96.2-97.8], p < 0.001). The NPVs of SVR4 to predict viral relapse were 100%, regardless of the type of DAAs. Moreover, the concordance between SVR12 and SVR24 was 100%. In conclusion, an off-treatment week 4 serum HCV RNA testing is sufficient to provide an excellent prediction power of SVR or viral relapse at off-treatment week 12 among patients with HCV who are treated with fixed-dose pangenotypic DAAs.


Antiviral Agents , Hepacivirus , Hepatitis C, Chronic , RNA, Viral , Sustained Virologic Response , Humans , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Male , Female , Middle Aged , Hepacivirus/genetics , Hepacivirus/drug effects , Aged , Adult , RNA, Viral/blood , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Recurrence , Follow-Up Studies , Treatment Outcome , Hepatitis C/drug therapy , Hepatitis C/virology
3.
PLoS One ; 19(5): e0303265, 2024.
Article En | MEDLINE | ID: mdl-38739590

More than 58 million individuals worldwide are inflicted with chronic HCV. The disease carries a high risk of end stage liver disease, i.e., cirrhosis and hepatocellular carcinoma. Although direct-acting antiviral agents (DAAs) have revolutionized therapy, the emergence of drug-resistant strains has become a growing concern. Conventional cellular models, Huh7 and its derivatives were very permissive to only HCVcc (JFH-1), but not HCV clinical isolates. The lack of suitable host cells had hindered comprehensive research on patient-derived HCV. Here, we established a novel hepatocyte model for HCV culture to host clinically pan-genotype HCV strains. The immortalized hepatocyte-like cell line (imHC) derived from human mesenchymal stem cell carries HCV receptors and essential host factors. The imHC outperformed Huh7 as a host for HCV (JFH-1) and sustained the entire HCV life cycle of pan-genotypic clinical isolates. We analyzed the alteration of host markers (i.e., hepatic markers, cellular innate immune response, and cell apoptosis) in response to HCV infection. The imHC model uncovered the underlying mechanisms governing the action of IFN-α and the activation of sofosbuvir. The insights from HCV-cell culture model hold promise for understanding disease pathogenesis and novel anti-HCV development.


Hepacivirus , Hepatocytes , Humans , Hepatocytes/virology , Hepatocytes/pathology , Hepacivirus/genetics , Hepacivirus/physiology , Antiviral Agents/pharmacology , Sofosbuvir/pharmacology , Cell Line , Virus Replication , Interferon-alpha/pharmacology , Hepatitis C/virology , Apoptosis , Mesenchymal Stem Cells/virology , Mesenchymal Stem Cells/metabolism
4.
PLoS One ; 19(5): e0303314, 2024.
Article En | MEDLINE | ID: mdl-38739668

BACKGROUND: Globally, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death due to a lack of early predictive and/or diagnostic tools. Thus, research for a new biomarker is important. LncRNAs play a functional role in target gene regulation and their deregulation is associated with several pathological conditions including HCC. OBJECTIVE: This study aimed to explore the diagnostic potential of two LncRNAs MALAT1 and CASC2 in HCC compared to the routinely used diagnostic biomarker. MATERIALS AND METHODS: The current study is a case-control study carried out at Fayoum University Hospital and conducted on 89 individuals. The study included three groups of 36 HCC patients on top of HCV(HCC/HCV), 33 HCV patients, and 20 healthy volunteers as a control group. All study subjects were subjected to radiological examinations. The determination of CBC was performed by the automated counter and liver function tests by the enzymatic method were performed. In addition, HCV RNA quantification and the expression level of two LncRNAs (MALAT1 and CASC2) were performed by qRT-PCR. RESULTS: The results revealed a statistically significant difference between study groups regarding liver function tests with a higher mean in HCC/HCV group. Also, serum MALAT1 significantly up-regulated in HCV (11.2±2.8) and HCC/HCV (4.56±1.4) compared to the control group. Besides, serum CASC2 levels in the HCV group were significantly upregulated (14.9±3.6), while, downregulated in the HCC group (0.16± 0.03). Furthermore, The ROC analysis for diagnostic efficacy parameters indicated that CASC2 has higher accuracy (94.6%) and sensitivity (97.2%) for HCC diagnosis than AFP with an accuracy of (90.9%), sensitivity (69.4%), and MALAT1 showed an accuracy of (56.9%), sensitivity (72.2%). CONCLUSION: Our study results indicated that CASC2 is a promising biomarker and is considered better and could help in HCC diagnosis on top of HCV than MALAT1 and the routine biomarker AFP.


Biomarkers, Tumor , Carcinoma, Hepatocellular , Liver Neoplasms , RNA, Long Noncoding , Tumor Suppressor Proteins , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/blood , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/virology , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Liver Neoplasms/virology , Male , Female , Middle Aged , Case-Control Studies , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Tumor Suppressor Proteins/genetics , Hepatitis C/complications , Hepatitis C/virology , Hepatitis C/diagnosis , Hepatitis C/genetics , Hepacivirus/genetics , Aged , Gene Expression Regulation, Neoplastic , Adult , ROC Curve , Clinical Relevance
5.
Sci Rep ; 14(1): 10864, 2024 05 13.
Article En | MEDLINE | ID: mdl-38740815

Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p < 0.001). Post-Tx LOXL2 levels, fibrosis-4 index, platelet counts, Wisteria floribunda agglutinin-positive human Mac-2 binding protein levels, and alpha-fetoprotein (AFP) levels were identified as independent predictive factors for post-SVR HCC development in the univariate analysis. The incidence of post-SVR HCC development was significantly higher in patients with post-Tx LOXL2 levels ≥ 2.08 ng/mL and AFP levels ≥ 5.0 ng/mL than in patients with elevated levels of either marker or with lower marker levels. Serum LOXL2 levels can serve as a predictive biomarker for HCC development after achieving SVR. The combination of serum LOXL2 and AFP levels provides robust risk stratification for HCC development after SVR, suggesting an enhanced surveillance strategy.


Amino Acid Oxidoreductases , Antiviral Agents , Carcinoma, Hepatocellular , Hepatitis C, Chronic , Liver Neoplasms , Sustained Virologic Response , Humans , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/virology , Liver Neoplasms/blood , Liver Neoplasms/virology , Male , Female , Middle Aged , Amino Acid Oxidoreductases/blood , Retrospective Studies , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/virology , Aged , Antiviral Agents/therapeutic use , Hepacivirus , Biomarkers, Tumor/blood , alpha-Fetoproteins/metabolism , alpha-Fetoproteins/analysis , Adult
6.
J Immunol Res ; 2024: 6343757, 2024.
Article En | MEDLINE | ID: mdl-38715844

This study aims to explore the influence of coinfection with HCV and HIV on hepatic fibrosis. A coculture system was set up to actively replicate both viruses, incorporating CD4 T lymphocytes (Jurkat), hepatic stellate cells (LX-2), and hepatocytes (Huh7.5). LX-2 cells' susceptibility to HIV infection was assessed through measurements of HIV receptor expression, exposure to cell-free virus, and cell-to-cell contact with HIV-infected Jurkat cells. The study evaluated profibrotic parameters, including programed cell death, ROS imbalance, cytokines (IL-6, TGF-ß, and TNF-α), and extracellular matrix components (collagen, α-SMA, and MMP-9). The impact of HCV infection on LX-2/HIV-Jurkat was examined using soluble factors released from HCV-infected hepatocytes. Despite LX-2 cells being nonsusceptible to direct HIV infection, bystander effects were observed, leading to increased oxidative stress and dysregulated profibrotic cytokine release. Coculture with HIV-infected Jurkat cells intensified hepatic fibrosis, redox imbalance, expression of profibrotic cytokines, and extracellular matrix production. Conversely, HCV-infected Huh7.5 cells exhibited elevated profibrotic gene transcriptions but without measurable effects on the LX-2/HIV-Jurkat coculture. This study highlights how HIV-infected lymphocytes worsen hepatic fibrosis during HCV/HIV coinfection. They increase oxidative stress, profibrotic cytokine levels, and extracellular matrix production in hepatic stellate cells through direct contact and soluble factors. These insights offer valuable potential therapies for coinfected individuals.


Bystander Effect , Coculture Techniques , Coinfection , Cytokines , HIV Infections , Hepacivirus , Hepatic Stellate Cells , Hepatitis C , Liver Cirrhosis , Humans , Hepatic Stellate Cells/metabolism , HIV Infections/complications , HIV Infections/metabolism , HIV Infections/virology , HIV Infections/immunology , Hepacivirus/physiology , Hepatitis C/metabolism , Hepatitis C/virology , Hepatitis C/complications , Hepatitis C/immunology , Jurkat Cells , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/virology , Liver Cirrhosis/etiology , Cytokines/metabolism , Hepatocytes/metabolism , Hepatocytes/virology , HIV/physiology , Oxidative Stress , Cell Communication , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Extracellular Matrix/metabolism
9.
Sci Rep ; 14(1): 10244, 2024 05 03.
Article En | MEDLINE | ID: mdl-38702350

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.


Antiviral Agents , Benzimidazoles , Benzopyrans , Cyclopropanes , Hepacivirus , Heterocyclic Compounds, 4 or More Rings , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Quinoxalines , Ribavirin , Sofosbuvir , Humans , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Female , Male , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Ribavirin/therapeutic use , Ribavirin/adverse effects , Middle Aged , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/adverse effects , Benzimidazoles/therapeutic use , Benzimidazoles/adverse effects , Hepacivirus/genetics , Hepacivirus/drug effects , Adult , Cyclopropanes/therapeutic use , Cyclopropanes/adverse effects , Feasibility Studies , Carbamates/therapeutic use , Drug Therapy, Combination , Africa, Western , Africa, Central , Fluorenes/therapeutic use , Fluorenes/adverse effects , Sustained Virologic Response , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Treatment Outcome , Proline/therapeutic use , Hepatitis C/drug therapy , Aminoisobutyric Acids , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Genotype
10.
Clin Transplant ; 38(5): e15325, 2024 May.
Article En | MEDLINE | ID: mdl-38716770

BACKGROUND/AIMS: Direct-acting antiviral (DAA) therapy has revolutionized solid organ transplantation by providing an opportunity to utilize organs from HCV-viremic donors. Though transplantation of HCV-viremic donor organs into aviremic recipients is safe in the short term, midterm data on survival and post-transplant complications is lacking. We provide a midterm assessment of complications of lung transplantation (LT) up to 2 years post-transplant, including patient and graft survival between HCV-viremic transplantation (D+) and HCV-aviremic transplantation (D-). METHODS: This is a retrospective cohort study including 500 patients from 2018 to 2022 who underwent LT at our quaternary care institution. Outcomes of patients receiving D+ grafts were compared to those receiving D- grafts. Recipients of HCV antibody+ but PCR- grafts were treated as D- recipients. RESULTS: We identified 470 D- and 30 D+ patients meeting inclusion criteria. Crude mortality did not differ between groups (p = .43). Patient survival at years 1 and 2 did not differ between D+ and D- patients (p = .89, p = .87, respectively), and graft survival at years 1 and 2 did not differ between the two groups (p = .90, p = .88, respectively). No extrahepatic manifestations or fibrosing cholestatic hepatitis (FCH) occurred among D+ recipients. D+ and D- patients had similar rates of post-transplant chronic lung allograft rejection (CLAD) (p = 6.7% vs. 12.8%, p = .3), acute cellular rejection (60.0% vs. 58.0%, p = .8) and antibody-mediated rejection (16.7% vs. 14.2%, p = .7). CONCLUSION: There is no difference in midterm patient or graft survival between D+ and D-LT. No extrahepatic manifestations of HCV occurred. No differences in any type of rejection including CLAD were observed, though follow-up for CLAD was limited. These results provide additional support for the use of HCV-viremic organs in selected recipients in LT.


Graft Rejection , Graft Survival , Hepacivirus , Hepatitis C , Lung Transplantation , Postoperative Complications , Viremia , Humans , Lung Transplantation/adverse effects , Female , Male , Retrospective Studies , Middle Aged , Follow-Up Studies , Prognosis , Hepatitis C/surgery , Hepatitis C/virology , Hepacivirus/isolation & purification , Viremia/virology , Viremia/etiology , Survival Rate , Graft Rejection/etiology , Risk Factors , Tissue Donors/supply & distribution , Adult , Antiviral Agents/therapeutic use , Transplant Recipients
11.
Viral Immunol ; 37(3): 126-138, 2024 04.
Article En | MEDLINE | ID: mdl-38593460

Hepatitis C virus (HCV), despite the availability of effective direct-acting antivirals (DAAs) that clear the virus from >95% of individuals treated, continues to cause significant health care burden due to disease progression that can lead to fibrosis, cirrhosis, and/or hepatocellular carcinoma. The fact that some people who are treated with DAAs still go on to develop worsening liver disease warrants further study into the immunopathogenesis of HCV. Many viral infections, including HCV, have been associated with activation of the inflammasome/pyroptosis pathway. This inflammatory cell death pathway ultimately results in cell lysis and release of inflammatory cytokines, IL-18 and IL-1ß. This review will report on studies that investigated HCV and inflammasome activation/pyroptosis. This includes clinical in vivo data showing elevated pyroptosis-associated cytokines in the blood of individuals living with HCV, studies of genetic associations of pyroptosis-related genes and development of liver disease, and in vitro studies aimed at understanding the mechanism of pyroptosis induced by HCV. Finally, we discuss major gaps in understanding and outstanding questions that remain in the field of HCV-induced pyroptosis.


Hepatitis C, Chronic , Hepatitis C , Liver Neoplasms , Humans , Hepacivirus , Inflammasomes/metabolism , Pyroptosis , Antiviral Agents/therapeutic use , Antiviral Agents/pharmacology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hepatitis C/drug therapy , Cytokines
12.
PLoS One ; 19(4): e0299891, 2024.
Article En | MEDLINE | ID: mdl-38630782

Viruses can infect the brain in individuals with and without HIV-infection: however, the brain virome is poorly characterized. Metabolic alterations have been identified which predispose people to substance use disorder (SUD), but whether these could be triggered by viral infection of the brain is unknown. We used a target-enrichment, deep sequencing platform and bioinformatic pipeline named "ViroFind", for the unbiased characterization of DNA and RNA viruses in brain samples obtained from the National Neuro-AIDS Tissue Consortium. We analyzed fresh frozen post-mortem prefrontal cortex from 72 individuals without known viral infection of the brain, including 16 HIV+/SUD+, 20 HIV+/SUD-, 16 HIV-/SUD+, and 20 HIV-/SUD-. The average age was 52.3 y and 62.5% were males. We identified sequences from 26 viruses belonging to 11 viral taxa. These included viruses with and without known pathogenic potential or tropism to the nervous system, with sequence coverage ranging from 0.03 to 99.73% of the viral genomes. In SUD+ people, HIV-infection was associated with a higher total number of viruses, and HIV+/SUD+ compared to HIV-/SUD+ individuals had an increased frequency of Adenovirus (68.8 vs 0%; p<0.001) and Epstein-Barr virus (EBV) (43.8 vs 6.3%; p=0.037) as well as an increase in Torque Teno virus (TTV) burden. Conversely, in HIV+ people, SUD was associated with an increase in frequency of Hepatitis C virus, (25 in HIV+/SUD+ vs 0% in HIV+/SUD-; p=0.031). Finally, HIV+/SUD- compared to HIV-/SUD- individuals had an increased frequency of EBV (50 vs 0%; p<0.001) and an increase in TTV viral burden, but a decreased Adenovirus viral burden. These data demonstrate an unexpectedly high variety in the human brain virome, identifying targets for future research into the impact of these taxa on the central nervous system. ViroFind could become a valuable tool for monitoring viral dynamics in various compartments, monitoring outbreaks, and informing vaccine development.


DNA Virus Infections , Epstein-Barr Virus Infections , HIV Infections , Substance-Related Disorders , Torque teno virus , Virus Diseases , Male , Humans , Middle Aged , Female , Virome , Epstein-Barr Virus Infections/complications , DNA, Viral/genetics , Herpesvirus 4, Human/genetics , HIV Infections/epidemiology , Virus Diseases/complications , Torque teno virus/genetics , Brain , Hepacivirus/genetics , Substance-Related Disorders/complications
13.
Sci Rep ; 14(1): 8473, 2024 04 11.
Article En | MEDLINE | ID: mdl-38605149

Nearly half of the deaths among hospitalized human immuno deficiency virus-infected patients in the highly active antiretroviral therapy era have been attributed to liver disease. This may range from an asymptomatic mild increase of liver enzymes to cirrhosis and liver failure. Different works of literature elucidated both retroviral infection and the adverse effects of highly active antiretroviral therapy as a cause of hepatotoxicity. Individual adaptations to medications and environmental exposures, shaped by cultural norms and genetic predispositions, could potentially modulate the risk and progression of liver disease in this population. Therefore, this study aims to assess the predictors of severe hepatotoxicity in retroviral-infected adults receiving highly active antiretroviral therapy regimens within the Ilubabor Zone, Southwest Ethiopia. A facility-based cross-sectional study was conducted among adult retroviral-infected patients in five selected anti-retro virus therapy clinics from May1 to July 30/2022. A systematic sampling technique was used to select 457 study participants and Binary logistic regression statistical data analysis was used, P value < 0.05 was considered statistically significant. The prevalence of severe hepatotoxicity was 21.44% in the study population. CD+4 count < 200 cells/mm3 (AOR = 2.19, 95% CI 1.04-5.22, P = 0.01), human immunodeficiency virus co-infection with tuberculosis (AOR = 2.82, 95% CI 1.01-8.29, P = 0.03) and human immuno deficiency virus co-infection with hepatitis-B/hepatitis C virus (AOR = 5.02, 95% CI 1.82-16.41) were predictors of severe hepatotoxicity. The magnitude of severe hepatotoxicity was high among adult retroviral-infected patients on highly active anti-retroviral drug regimens. Co-infection of human immuno deficiency virus with hepatitis B virus or hepatitis C virus, tuberculosis and CD4+T-cell count below 200 cells/mm3 were predictors of severe hepatotoxicity. Therefore, HIV patients on highly active antiretroviral therapy require close attention and regular monitoring of their liver function.


Chemical and Drug Induced Liver Injury , Coinfection , Digestive System Diseases , Drug-Related Side Effects and Adverse Reactions , HIV Infections , Hepatitis C , Liver Diseases , Tuberculosis , Adult , Humans , Antiretroviral Therapy, Highly Active/adverse effects , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Ethiopia/epidemiology , Cross-Sectional Studies , Hepatitis C/drug therapy , HIV , Liver Diseases/etiology , Tuberculosis/drug therapy , Hepacivirus , Drug-Related Side Effects and Adverse Reactions/etiology , Digestive System Diseases/drug therapy , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/drug therapy , CD4 Lymphocyte Count
14.
World J Gastroenterol ; 30(14): 1949-1957, 2024 Apr 14.
Article En | MEDLINE | ID: mdl-38681127

In Japan, liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus (HCV) and diagnosing HCV-related hepatocellular carcinoma (HCC). However, due to the development of effective antiviral treatments and advanced imaging, the necessity for biopsies has significantly decreased. This change has resulted in fewer chances for diagnosing liver disease, causing many general pathologists to feel less confident in making liver biopsy diagnoses. This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan. First, it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence. Second, it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions, because clinically diagnosable HCCs are not targets for biopsy. Third, the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs. In conclusion, pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.


Antiviral Agents , Carcinoma, Hepatocellular , Hepacivirus , Liver Neoplasms , Liver , Humans , Japan/epidemiology , Biopsy , Liver/pathology , Liver/virology , Liver/diagnostic imaging , Liver Neoplasms/pathology , Liver Neoplasms/virology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Antiviral Agents/therapeutic use , Hepacivirus/isolation & purification , Hepacivirus/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Hepatitis C/diagnosis , Hepatitis C/pathology , Hepatitis C/drug therapy , Hepatitis C, Chronic/pathology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/diagnosis , Fatty Liver/pathology , Fatty Liver/virology , Fatty Liver/diagnosis
15.
Int J Biol Macromol ; 267(Pt 2): 131629, 2024 May.
Article En | MEDLINE | ID: mdl-38631585

Current management of HCV infection is based on Direct-Acting Antiviral Drugs (DAAs). However, resistance-associated mutations, especially in the NS3 and NS5B regions are gradually decreasing the efficacy of DAAs. Among the most effective HCV NS3/4A protease drugs, Sofosbuvir also develops resistance due to mutations in the NS3 and NS5B regions. Four mutations at positions A156Y, L36P, Q41H, and Q80K are classified as high-level resistance mutations. The resistance mechanism of HCV NS3/4A protease toward Sofosbuvir caused by these mutations is still unclear, as there is less information available regarding the structural and functional effects of the mutations against Sofosbuvir. In this work, we combined molecular dynamics simulation, molecular mechanics/Generalized-Born surface area calculation, principal component analysis, and free energy landscape analysis to explore the resistance mechanism of HCV NS3/4A protease due to these mutations, as well as compare interaction changes in wild-type. Subsequently, we identified that the mutant form of HCV NS3/4A protease affects the activity of Sofosbuvir. In this study, the resistance mechanism of Sofosbuvir at the atomic level is proposed. The proposed drug-resistance mechanism will provide valuable guidance for the design of HCV drugs.


Antiviral Agents , Drug Resistance, Viral , Hepacivirus , Molecular Dynamics Simulation , Mutation , Sofosbuvir , Viral Nonstructural Proteins , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , DEAD-box RNA Helicases , Drug Resistance, Viral/genetics , Hepacivirus/drug effects , Hepacivirus/genetics , Hepacivirus/enzymology , Nucleoside-Triphosphatase , Serine Endopeptidases , Serine Proteases , Sofosbuvir/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteases
16.
Sci Rep ; 14(1): 9143, 2024 04 21.
Article En | MEDLINE | ID: mdl-38644402

Hepatitis C, a particularly dangerous form of viral hepatitis caused by hepatitis C virus (HCV) infection, is a major socio-economic and public health problem. Due to the rapid development of deep learning, it has become a common practice to apply deep learning to the healthcare industry to improve the effectiveness and accuracy of disease identification. In order to improve the effectiveness and accuracy of hepatitis C detection, this study proposes an improved denoising autoencoder (IDAE) and applies it to hepatitis C disease detection. Conventional denoising autoencoder introduces random noise at the input layer of the encoder. However, due to the presence of these features, encoders that directly add random noise may mask certain intrinsic properties of the data, making it challenging to learn deeper features. In this study, the problem of data information loss in traditional denoising autoencoding is addressed by incorporating the concept of residual neural networks into an enhanced denoising autoencoder. In our experimental study, we applied this enhanced denoising autoencoder to the open-source Hepatitis C dataset and the results showed significant results in feature extraction. While existing baseline machine learning methods have less than 90% accuracy and integrated algorithms and traditional autoencoders have only 95% correctness, the improved IDAE achieves 99% accuracy in the downstream hepatitis C classification task, which is a 9% improvement over a single algorithm, and a nearly 4% improvement over integrated algorithms and other autoencoders. The above results demonstrate that IDAE can effectively capture key disease features and improve the accuracy of disease prediction in hepatitis C data. This indicates that IDAE has the potential to be widely used in the detection and management of hepatitis C and similar diseases, especially in the development of early warning systems, progression prediction and personalised treatment strategies.


Deep Learning , Hepatitis C , Neural Networks, Computer , Humans , Hepatitis C/virology , Hepatitis C/diagnosis , Hepacivirus/isolation & purification , Hepacivirus/genetics , Algorithms
17.
J Nat Prod ; 87(4): 1059-1066, 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38561238

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).


Acremonium , Sesquiterpenes , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Animals , Molecular Structure , Acremonium/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Porifera/chemistry , Hepacivirus/drug effects , Humans , Pseudomonas aeruginosa/drug effects
18.
BMC Public Health ; 24(1): 1055, 2024 Apr 15.
Article En | MEDLINE | ID: mdl-38622549

BACKGROUND: The World Health Organization (WHO) has outlined a set of targets to achieve eliminating hepatitis C by 2030. In May 2022, Lithuanian health authorities initiated a hepatitis C virus (HCV) screening program to start working towards elimination. In the program, bonus was given to general practitioners (GPs) to promote and conduct anti-HCV tests for two situations: (1) one time testing for individuals born in 1945-1994 and (2) annual HCV testing for persons who inject drugs or are living with human immunodeficiency virus (HIV) regardless of age. This study aimed to model the current viral hepatitis C epidemiological status in Lithuania and to outline the requirements for WHO elimination targets using the first-year HCV screening results. METHODS: Individuals were invited to participate in the anti-HCV screening by GPs during routine visits. Patients who tested positive were then referred to a gastroenterologist or infectious disease doctor for further confirmatory testing. If a patient received a positive RNA test and a fibrosis staging result of ≥ F2, the doctor prescribed direct-acting antivirals. Information on the patients screened, diagnosed, and treated was obtained from the National Health Insurance Fund. The Markov disease progression model, developed by the CDA Foundation, was used to evaluate the screening program results and HCV elimination progress in Lithuania. RESULTS: Between May 2022 and April 2023, 790,070 individuals underwent anti-HCV testing, with 11,943 individuals (1.5%) receiving positive results. Anti-HCV seroprevalence was found to be higher among males than females, 1.9% and 1.2%, respectively. Within the risk population tested, 2087 (31.1%) seropositive individuals were identified. When comparing the screening program results to WHO elimination targets through modelling, 2180 patients still need to be treated annually until 2030, along with expanding fibrosis restrictions. If an elimination approach was implemented, 1000 new infections would be prevented, while saving 150 lives and averting 90 decompensated cirrhosis cases and 110 hepatocellular carcinoma cases. CONCLUSIONS: During the first year of the Lithuanian screening program, GPs were able to screen 44% of the target population. However, the country will not meet elimination targets as it currently stands without increasing treatment levels and lifting fibrosis restrictions.


Drug Users , Hepatitis C, Chronic , Hepatitis C , Substance Abuse, Intravenous , Male , Female , Humans , Aged , Lithuania/epidemiology , Antiviral Agents/therapeutic use , Seroepidemiologic Studies , Hepatitis C, Chronic/drug therapy , Hepatitis C/diagnosis , Hepatitis C/epidemiology , Hepatitis C/prevention & control , Hepacivirus , World Health Organization , Fibrosis
19.
PLoS One ; 19(4): e0301973, 2024.
Article En | MEDLINE | ID: mdl-38626232

BACKGROUND: Globally, hepatitis B virus (HBV) and hepatitis C virus (HCV) cause considerable morbidity and mortality from their acute and chronic infections. The transmission of the viruses within the prisons is high due to overcrowding, and other risk behaviors such as drug use, and unsafe sexual practices. This study aimed at determining the prevalence and associated factors of HBV and HCV infections among prisoners in Gondar city, Northwest Ethiopia. METHODS: A cross-sectional study was conducted in the Gondar City Prison Center from May 1, 2022, to July 30, 2022. A total of 299 prison inmates were selected by using a systematic random sampling technique. A semi-structured questionnaire was used to collect data on sociodemographic, clinical, behavioral and prison related factors. Five milliliters of blood sample were collected, and the serum was separated from the whole blood. The serum was tested for HBV surface antigen (HBsAg) and anti-HCV antibody by using an Enzyme-Linked Immunosorbent Assay (ELISA). Data was entered using EpiData version 4.6.0 and exported to SPSS version 20 for analysis. Logistic regression analysis was done to assess the association between the independent variables and HBV and HCV infections. P-values < 0.05 were considered statistically significant. RESULTS: The overall seroprevalence of HBV or HCV infections was 10.4%. The seroprevalence of HBV and HCV infections was 7.0% and 4.0%, respectively. It has been demonstrated that having several heterosexual partners, sharing sharp materials in prison, having longer imprisonment, and having a body tattoo are significantly associated with HBV infection. The presence of a body tattoo, a history of surgical procedures, and previous imprisonment are associated risk factors for HCV infection. CONCLUSION: The prevalence of HBV and HCV were high-intermediate and high, respectively. Therefore, preventative and control initiatives are needed in prisons to decrease the rate of infection and transmission.


Hepatitis B , Hepatitis C , Prisoners , Humans , Hepacivirus , Seroepidemiologic Studies , Cross-Sectional Studies , Ethiopia/epidemiology , Hepatitis C/epidemiology , Hepatitis C/complications , Hepatitis B/epidemiology , Hepatitis B/complications , Risk Factors , Hepatitis B virus , Prevalence
20.
J Infect Dev Ctries ; 18(3): 441-449, 2024 Mar 31.
Article En | MEDLINE | ID: mdl-38635621

INTRODUCTION: The aim of this national, multicenter, cross-sectional, retrospective chart review study was to determine the proportion of patients in Turkey who received hepatitis C virus (HCV) treatment after receiving positive anti-HCV results during HCV screening. METHODOLOGY: Data related to patients' demographics, laboratory results, time interval from obtaining a positive anti-HCV result to treatment initiation, specialty of the physician requesting anti-HCV screening, and type of hospital were analyzed. RESULTS: Among 1,000 patients who received a positive anti-HCV result, 50.3% were male and 78.5% were screened for HCV-RNA. Among HCV-RNA screened patients, 54.8% (n = 430) had a positive result. Among patients who tested positive for HCV-RNA, 72.8% received HCV treatment in line with their positive anti-HCV results. The median time from obtaining a positive anti-HCV result to initiation of HCV treatment was 91.0 days (interquartile range 42.0 to 178.5). Non-surgical branches requested HCV-RNA testing more frequently than surgical branches (p < 0.001). The rate of access to HCV treatment was higher among patients screened in university hospitals than among patients screened in training and research hospitals (p < 0.001). CONCLUSIONS: Our results indicate a higher rate of treatment initiation among patients with HCV infection than is described in the published literature. Furthermore, the time from screening to treatment initiation was considerably shorter compared with other international studies. However, since HCV-RNA testing was not requested in a significant portion of patients with a positive anti-HCV test result, there might be a large patient population with HCV who do not receive treatment.


Hepacivirus , Hepatitis C , Humans , Male , Female , Hepacivirus/genetics , Retrospective Studies , Tertiary Care Centers , Turkey/epidemiology , Cross-Sectional Studies , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C Antibodies , RNA, Viral
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