ARTICLE | doi:10.20944/preprints202302.0475.v2
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis C virus; Genetic; Chronic Hepatitis C; Liver; Elastography
Online: 22 May 2023 (13:56:53 CEST)
IHepatitis C virus (HCV) has a high genetic diversity, with seven genotypes with 86 subtypes. This genetic variability confers persistence in the infection and escape of the immune system with evolution to cirrhosis and cancer. Environmental factors can contribute to different disease progression, being essential to assess the viral genotype in the infection and discuss the environmental particularities of Eastern Amazon, and the frequencies of Liver fibrosis between different HCV genotypes in patients living in a region of the Brazilian Eastern Brazilian Amazon. Consists in an observational cross-sectional study. Sociodemographic and clinical data of 76 individuals diagnosed with Hepatitis C between 2019 and 2020 in public health services were selected. Data collected was tabulated in Microsoft Excel 2010TM spreadsheets and analysed in GraphPad Prism 5.0TM. Liver fibrosis was associated with genetic subtypes. Subtype 1b was predominant (42.1%), followed by 1a (13%) and 3a (1.3%). 69.7% of participants had chronic hepatitis, with mild fibrosis (F1/F2) being the most prevalent (38.1%). Severe fibrosis was detected in 75% of individuals infected with the subtype 1b, that is associated with more severe disease. We suggest further studies, to assess other communities in the region, as well as the monitoring of these patients with Liver Elastography to determine the disease evolution and its better management.
ARTICLE | doi:10.20944/preprints202211.0057.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis; HCV; epidemiology; genotype; subgenotype; recombinant; RF1_2k/1b; direct-acting antivirals
Online: 2 November 2022 (11:08:11 CET)
Hepatitis C virus (HCV) causes both acute and chronic disease of the liver that can lead to liver cirrhosis, cancer and liver failure. HCV is characterized by high genetic diversity and substantial variations in prevalence of specific HCV genotypes in different countries of the world. Many effective regimens of direct-acting antivirals (DAAs), including pan-genotypic, can successfully treat HCV infection. However, genotype-specific treatments for HCV are being actively employed in the national plans for elimination of HCV infection around the world. Evaluation of HCV genotype prevalence in a country is mandatory for successful implementation of the national plans for elimination of HCV infection and allocation of financial resources to DAAs most effecting for specific HCV genotypes prevalent in a country. Here, we analyzed HCV genotypes, subgenotypes and recombinants in 10,107 serum samples from patients with chronic HCV infection from all Federal districts of Russia collected in 2015-2017. This is the first, largest evaluation of HCV genotypes performed on samples from all territories of Russia, from its Central Federal district to the Far East. Moreover, we have updated retrospective epidemiological analysis of chronic and acute HCV infection in Russia in 2001-2021. We demonstrate that the incidence of acute HCV infection in Russia reduced from 16.7 cases per 100,000 population in 2001 to 0.6 cases per 100,000 population in 2021. The number of cases of chronic HCV infection decreased from 29.5 to 16.4 per 100,000 population during this period. HCV genotype analysis indicated that HCV genotype 1 dominates in Russia (53.6%). Genotypes 3 and 2 were detected in 35.4% and 7.8% of patients respectively. These proportions are virtually identical in all regions of Russia except for Far East, where HCV genotype 2 amounts only to 1%. HCV genotypes 1 and 2 are more widespread in women, while HCV genotype 3 in men. The highest frequency of identification of genotype 3 was found in the age group of 31-40 years old (44.9%, respectively), and genotype 1 was more prevalent in a group of over 70 years old (72.2%). The proportion of HCV genotype 2 is predominant among HCV-infected persons older than 40 years. Discriminating HCV genotype 2 and recombinant RF1_2k/1b, which are frequently misclassified, is important for successful antiviral treatment of such patients. For the first time, we demonstrate the countrywide prevalence of HCV RF1_2k/1b in different regions of Russia. HCV RF1_2k/1b amounts to 3.2% in the structure of HCV genotypes, reaching 30% among samples classified as genotype 2 by some commercial genotyping tests. The highest proportion of HCV RF1_2k/1b was detected in the north-west (60%), southern (41.6%) and central (31.6%) federal district. Its frequency in Far Eastern and North Caucasus Districts was ~ 14.3%. HCV RF1_2k/1b was not detected in the Volga, Ural and Siberian districts. To conclude, this is the first and most complete evaluation of HCV epidemiology and genotype/subgenotype distribution in Russia.
ARTICLE | doi:10.20944/preprints201904.0148.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: chronic hepatitis C; chronic hepatitis B; innate immune response; adaptive immune response; cytokine; chemokine
Online: 12 April 2019 (10:59:21 CEST)
Background: Cytokines and chemokines are critical regulators of innate and adaptive immunities during viral infection. We examined innate and adaptive immune responses to hepatitis C virus (HCV) and hepatitis B virus (HBV) at baseline and against controls. Methods: Twenty-seven cytokines were evaluated before treatment in 27 patients with chronic hepatitis C(CHC) [genotype1 (n=20), genotype2 (n=7), HCVRNA 5.72IU/ml] and 12 chronic hepatitis B(CHB) [e-antigen (Ag) (+) (n=5), e-Ag (-) (n=7), HBVDNA 6.191.31Logcopies/ml] and against controls(n=5). Results: Th1 and Th2 cytokines were significantly higher (p<0.05) in CHB than in CHC. The levels of IL-IL10 in CHC and CHB, and IL15 in CHC(genotype2) and CHB were significantly lower (p<0.05) than in controls. The levels of CXCL8 in CHC and CHB, IL12 in CHC and CHB [e-Ag (-)] and CXCL10 in CHC and CHB were significantly higher (p<0.05) than in controls. IFN-γwas higher in CHB than in controls. Conclusion: Cytokines levels differed between CHB and CHC before treatment. Innate immune responses were impaired in CHB with HBeAg(-) and CHC, but not in CHB with HBeAg(+) with high viral loads. Adaptive immune responses were impaired in CHB and CHC and appear to reflect the distinct state of virus-host immune interactions between CHB and CHC.
ARTICLE | doi:10.20944/preprints202307.0311.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Baltic states; chronic hepatitis C; epidemiology; hepatitis C virus; genotype; Ukraine
Online: 5 July 2023 (12:30:04 CEST)
Background and objectives: Since 2013, highly effective direct-acting (DAA) chronic hepatitis C (CHC) antiviral therapy became available, which has cure rates of over 95%. For choice of optimal CHC treatment, assessment of hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage are necessary. Information about distribution of these parameters among CHC patients in Baltic states and especially in Ukraine is scarce. This study was performed to obtain epidemiological data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (Baltic states) and lower-middle income (Ukraine) countries. Materials and Methods: This was an epidemiological, retrospective, cross-sectional study that included 1451 CHC patients. Demographic and disease information from medical charts was collected for each patient during a single visit. Results: Most frequent suspected mode of viral transmission was blood transfusions (17.8%), followed by injection drug use (15.7%); however, in 50.9% of patients exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%) transmission by the injection drug use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1 - 66.4%; GT3 - 28.1; and GT2 - 4.1%. The prevalence of GT1 was the highest in Latvia (84%), and the lowest in Ukraine (63%, p<0.001). Liver fibrosis stages were distributed as follows: F0 - 12.2%, F1 - 26.3%, F2 - 23.5%, F3 – 17.1% and F4 - 20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p <0.001). Conclusions: This study contributes to the knowledge of epidemiological characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.
REVIEW | doi:10.20944/preprints202309.2138.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Hepatitis C virus; chronic HCV; antivirals; Sustained virological response; IFN therapy; Vaccines
Online: 30 September 2023 (05:39:36 CEST)
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection by 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 have generated the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFN-, then IFN-α plus ribavirin (IFN-RBV); then, pegylated-IFN--RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing the patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced SVR (> 90%); the compounds were able to inhibit HCV replication without significant side effects, even in pediatric populations. The management of coinfected patients HBV-HCV and HCV-HIV has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. 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 focuses 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 to different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
ARTICLE | doi:10.20944/preprints202209.0079.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: Hepatitis C virus; core protein; TNFα
Online: 6 September 2022 (03:38:14 CEST)
Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in proliferation, inflammation and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal) we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing HCV 4a core protein were more susceptible to the LPS/Dgal model while mice expressing HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis, while linking HCV core protein genetic variability to differential pathology in vivo.
REVIEW | doi:10.20944/preprints201810.0033.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: apoptosis; viral persistence, hepatitis C virus; immunity; chronic infection
Online: 2 October 2018 (16:34:19 CEST)
Hepatitis C virus (HCV) represents a challenging global health threat in ~200 million infected individuals. Clinical data suggests that only ~10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts a myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence that includes, but not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here, we discussed a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
REVIEW | doi:10.20944/preprints202306.0456.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: hepatitis e virus; hepatitis e infection; immunocompromised host; organ transplantation; extrahepatic manifestation; chronic hepatitis E; hepatology
Online: 6 June 2023 (11:53:35 CEST)
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are 4 main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans by undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.
ARTICLE | doi:10.20944/preprints202207.0239.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Frequency of hepatitis; Lifestyle determinants of hepatitis; Risk factors of hepatitis; Socio-demographic determinants of hepatitis
Online: 15 July 2022 (16:00:00 CEST)
Hepatitis is the eighth highest cause of mortality globally and second-highest in Pakistan. The purpose of this study was to determine frequency of Hepatitis B and C and related lifestyle and socio-demographic risk factors among adults. The data were collected though questionnaire from Hepatitis B and C patients from Mayo and Jinnah hospital Lahore. The data was analyzed using SPSS version 18. There were 5095 patients with Hepatitis B and C out of which 146 patients (67 males and 79 females) filled questionnaire. The frequency of hepatitis C was higher than hepatitis B. The significant risk factors associated with hepatitis B and C were education, marital status, family history, household income, and type of food consumed. Therefore, socio-demographic and lifestyle risk factors related interventions are needed to reduce frequency of Hepatitis B and C.
ARTICLE | doi:10.20944/preprints202001.0295.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B virus; hepatocyte nuclear factor 4 alpha; long-term infection; ERK signaling pathway
Online: 25 January 2020 (15:25:57 CET)
Hepatitis B virus (HBV) infection is a major factor in development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play key role in development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting ERK signaling pathway. Our data showed that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provided several proofs for the effect of HBV infection in manipulating HNF4α regulatory pathway in HCC development.
REVIEW | doi:10.20944/preprints202207.0341.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B Virus; Chronic Hepatitis infection; Oncogenesis
Online: 22 July 2022 (13:18:26 CEST)
Chronic Hepatitis B (CHB) Virus infection is major etiological factor for liver cirrhosis and/ or liver cancer. The viral protein, major contributor in predisposition of chronicity and Hepatocellular Carcinoma (HCC) is Hepatitis B x (HBx) protein. Its dynamic subcellular distribution to an extent determines its multifactorial role. It is a regulatory protein which modulates viral as well as host machinery in favours to HBV persistence. An insight on HBx stabilising factors is critical for therapeutic purpose. The precise role of HBx in the pathogenesis of Chronicity of HBV is not known. Summary: This review comprehensively summarizing different mechanisms and their regulation by HBx protein with respect to chronicity and HCC emphasising viral persistence. Key Messages 1. HBx is a key protein for viral persistence. 2. Dynamic subcellular distribution of HBx determines its function. 3. HBx modulates cellular machinery to favours HBV survival. 4. HBx affects various intermediary mechanisms contributing to disease progression. 5. HBx may be a potent target to prevent the disease progression towards HCC.
REVIEW | doi:10.20944/preprints201809.0092.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Hepatitis B; Bangladesh; prevalence; vertical transmission; occult infection; genotypes.
Online: 5 September 2018 (09:24:31 CEST)
Despite a considerable body of published research on Hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about Hepatitis B epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus on a number of epidemiological questions, as well as a commentary on the trends of Hepatitis B research as it has taken place in Bangladesh. The key themes to emerge from this review are: first, beyond noting a declining trend, it is difficult to provide conclusive estimates about Hepatitis B prevalence in the general population of Bangladesh. The majority of the studies, even the ones conducted on apparently healthy populations, fail to be adequately representative for the reasons explored in the article. Secondly, Hepatitis B in Bangladesh is sharply stratified across sociodemographic lines, which speaks to the role of awareness and risk exposure in Hepatitis B prevalence. Third, more research on occult infection rates is required to estimate the extent of risk posed by the current blood donation screening program, which relies exclusively on Hepatitis B surface antigen as a biomarker. The same considerations apply for the comparative importance of vertical vs. horizontal transmission, and prevalence among particular risk groups like healthcare workers with high occupational exposure. Finally, while recent studies do allow us, albeit with some ambiguity, to draw conclusions about distribution of Hepatitis B genotypes in Bangladesh, there needs to be an added emphasis on molecular epidemiology. It is hoped that the present review, the first of its kind in Bangladesh, will serve as an up-to-date summary of the course Hepatitis B epidemiology research in Bangladesh has taken thus far, as well as crucial gaps to address going forward.
ARTICLE | doi:10.20944/preprints202308.1060.v1
Subject: Public Health And Healthcare, Public, Environmental And Occupational Health Keywords: Pakistan; Hepatitis B; Hepatitis C; Elimination; Prevalence; Screening; Refugees
Online: 15 August 2023 (09:31:50 CEST)
Hepatitis B and C are major health issues in developing countries such as Pakistan and Afghan-istan. The aim of this study was to determine the prevalence and effectiveness of a screening program for hepatitis B and C in a region with no existing programs, and to estimate their prev-alence in the general population in Khyber Pakhtunkhwa Province, Pakistan, as well as in Afghan refugees or migrants. A retrospective cohort study was done in the general population of Peshawar and its adjacent districts, as well as migrants from neighboring provinces of Afghani-stan, who presented to our tertiary-care health facility. A Microsoft Excel registry was created for data collection, which were analyzed using IBM SPSS via descriptive analysis, normal distribution curve histograms, and chi-squared tests. A total of 9563 individuals were screened for hepatitis (5894 males and 3669 females), including Afghan migrants in Peshawar and surrounding districts. 876 individuals tested positive for hepatitis, with 538 positive for hepatitis B (383 males and 155 females) and 330 positive for hepatitis C (198 males and 134 females). Eight individuals had a hepatitis B and C co-infection. Among the study population, the prevalence rates were 2.2% for hepatitis B and 2.3% for hepatitis C, of which the Afghan migrants accounted for 2.7% and 0.5%, respectively. According to the gender-based distribution, hepatitis B was more prevalent in males, whereas there was no significant gender-based difference for hepatitis C. Our results highlight the need for a comprehensive approach to control hepatitis B and C in Pakistan and Afghanistan. Increased awareness, improved healthcare, and preventive measures such as screening and elimination programs to prevent severe liver diseases and eradicate hepatitis are necessary.
ARTICLE | doi:10.20944/preprints202004.0324.v1
Subject: Medicine And Pharmacology, Dentistry And Oral Surgery Keywords: hepatitis B; hepatitis C; occupational health; dental education; needlestick injury
Online: 19 April 2020 (04:37:08 CEST)
Introduction: Dental health care workers, particularly dental medicine students (DMS), are at an increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The aim of our study was to assess the level of knowledge on HBV and HCV, estimate needlestick injury (NSI) prevalence and reporting practice in DMS at the University of Zagreb and analyze how enrolment in obligatory and supplemental courses affects knowledge and needlestick injury reporting practice. Materials and methods: The knowledge was assessed by our questionnaires based on Centers for Disease Control general handouts. Additional information was collected to examine the prevalence and reporting practice of NSI. Data was analyzed by descriptive statistical analysis, independent-samples t-tests, proportion analyses and combined factor analyses of categorical and quantitative variables in SPSS and R. Results: In total, 206 students participated. The overall level of HBV and HCV-related knowledge was poor with average scores being 61.90% and 51.35% respectively. Moreover, students enrolled in the first year demonstrated significantly lower levels of knowledge in comparison with their older peers. Of all participants 18.2% sustained a needlestick injury, and majority of them (78.95%) never reported the injury. Conclusion: In conclusion, DMS have low levels of knowledge on important occupational pathogens and poor NSI reporting practice. Moreover, formal education in the current form failed to significantly improve competence of students and theoretical knowledge translates poorly into more conscientious injury reporting practice. We should look for a better way to increase student awareness and level of knowledge on this topic.
REVIEW | doi:10.20944/preprints202211.0335.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Spontaneous bacterial peritonitis; Hepatitis B virus; Hepatitis C virus; liver cirrhosis; prevalence; cancer
Online: 17 November 2022 (10:30:13 CET)
Background and Aim: Spontaneous bacterial peritonitis is a common infection in liver cirrhosis. This systematic review and meta-analysis provides detailed information on the prevalence of SBP among HBV and HCV-related liver cirrhosis globally. Methods: A systematic search for articles describing the prevalence of SBP in HBV, and HCV related cirrhosis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Our search returned ten (10) eligible articles involving 1,713 viral cirrhosis cases representing eight (8) countries. A meta-analysis was performed on our eligible studies using the random effect model. A protocol was registered with PROSPERO (CRD42022321790). Results: The pooled prevalence of SBP in HBV associated cirrhosis had the highest estimate [8.0% (95% CI, 2.7 – 21.0%; I2= 96.13%; p < 0.001)], followed by SBP in HCV associated liver cirrhosis [4.0% (95% CI, 1.3% – 11.5%; I2 = 88.99%; p < 0.001)]. China (61.8%, CI: 57.1 – 66.3%), the USA (50.0%, CI: 34.6 – 65.4%), and Holland (31.1%, CI: 21.6 – 42.5%) had the highest estimate for SBP in HBV associated liver cirrhosis, SBP in HCV associated liver cirrhosis and SBP in HBV+HCV associated liver cirrhosis respectively. There was a significant difference in the prevalence of SBP in viral hepatitis-associated liver cirrhosis with the year of sampling and method of SBP detection at P<0.001. There was an increase in SBP incidence at the beginning of 2016 across the liver cirrhosis in this study. Conclusion: The findings of this review revealed an increase in the incidence of SBP in viral hepatitis over the last decade, the latter could be due to the global increase in Bacterial resistance. This indicates a possible future rise in the global prevalence of SBP among HBV, and HCV-related liver cirrhosis.
ARTICLE | doi:10.20944/preprints202102.0488.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Hepatitis C virus; Chronic viral hepatitis C; Liver fibrosis; Liver cirrhosis; Diagnosis of liver fibrosis; Machine learning
Online: 22 February 2021 (15:31:11 CET)
Aim. The purpose of the work was the development of a machine learning model for diagnosing the stage of liver fibrosis in patients with chronic viral hepatitis C according to the data of routine clinical examination. Materials and methods. A total of 1240 patients with chronic viral hepatitis C was examined. A set of data obtained from 689 patients balancing by the stage of liver fibrosis was used for developing and testing machine learning models. 9 routine clinical parameters were selected as the most important predictors for determining the likelihood of liver fibrosis the 3–4 stages presence: age, height, weight and body mass index of the patient, the number of platelets in the clinical blood test, levels of alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, and total bilirubin in a biochemical blood test. Results. The accuracy of the developed method for determining the 3–4 stages of liver fibrosis in patients with chronic viral hepatitis C in comparison with the «gold standard» of diagnosis (liver biopsy) was 80.56% (95% CI: 69.53–88.94%), sensitivity — 66.67%, specificity — 94.44%. Conclusion. The developed method is an alternative to more expensive and geographically inaccessible studies. The method does not require the purchase of additional equipment or software, as well as additional laboratory tests, when used in real clinical practice. The introduction of the method into clinical practice can help to solve the problem of low material and territorial availability of diagnostic tests and allow determining the stage of liver fibrosis in patients with chronic viral hepatitis C.
ARTICLE | doi:10.20944/preprints202007.0045.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: Chronic hepatitis C; Direct-acting antiviral agents; Hepatitis C virus; Consultation-liaison psychiatry; Depression; Anxiety
Online: 5 July 2020 (05:15:08 CEST)
In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients’ mental status, before and 12 weeks after DAA therapy, by assessment scales and psychometric instruments. We subdivided patients into two groups, CHC patients with (Group A) or without (Group B) a current and/or past psychiatric history. After DAA treatment, Group A patients showed low anxiety and improved depression, no variation in self-report distress, but worse general health perceptions. No significant difference emerged from coping strategies. Depression and anxiety improved in Group B, and no change emerged from total self-reported distress, except for somatization. Moreover, Group B increased problem-focused strategies for suppression of competing activities, and decreased strategies of instrumental social support. Contrarily, Group B reduced significantly emotion-focused strategies, such as acceptance and mental disengagement, and improved vitality, physical and social role functioning. DAA therapy is safe and free of hepatological and psychiatric side effects in CHC patients, regardless of current and/or past psychiatric history. In particular, patients without a psychiatric history also remarkably improved their quality of life.
ARTICLE | doi:10.20944/preprints202310.0952.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Hepatitis C; machine learning; severity prediction; data preprocessing; hyperparameter tuning; classification models
Online: 16 October 2023 (09:33:57 CEST)
Hepatitis C presents a significant global health challenge, necessitating early diagnosis and precise severity classification for timely medical intervention. This study explores the application of machine learning techniques to predict the severity of hepatitis C, leveraging an extensive dataset. Our approach encompasses rigorous data preprocessing, advanced model development, and fine-tuned hyperparameter optimization to ensure accurate and reliable predictions. We evaluated four classification models: Logistic Regression, Random Forest, Gradient Boosting, and Support Vector Machine (SVM), comparing their accuracy in classifying patients. The results showed that the Random Forest and Gradient Boosting models outperformed the others with an accuracy of approximately 93.50%, demonstrating their potential in assisting Hepatitis C diagnosis. Further model enhancements through hyperparameter tuning and feature engineering can improve the precision of Hepatitis C diagnosis, contributing to better patient care.
ARTICLE | doi:10.20944/preprints201703.0025.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: hepatitis E virus; proteomic comparative analysis; pregnancy serum
Online: 6 March 2017 (04:59:30 CET)
Hepatitis E virus (HEV) is a common cause of acute hepatitis worldwide, accounting for approximately 25% of deaths among pregnant women. We previously reported that pregnancy serum facilitates HEV replication in vitro. However, the differences in host cells with HEV infection induced by pregnancy serum and fetal bovine serum (FBS) are unclear. In this study, differentially expressed proteins were identified in HEV-infected hepatoma cells (HepG2) supplemented with different sera by using isobaric tags for relative and absolute quantitation. Proteomic analysis indicated that HEV infection significantly induced 1014 differentially expressed proteins in HEV-infected HepG2 cells when supplemented with FBS compared with pregnancy serum. Further validation by Western blot confirmed that filamin A, heat-shock proteins 70 and 90, Cytochrome c, and Thioredoxin were associated with HEV infection. This comparative analysis provides an important basis to further investigate HEV pathogenesis in pregnant women and HEV replication.
BRIEF REPORT | doi:10.20944/preprints202306.1419.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B surface antigen (HBsAg); Hepatitis B core antibodies (anti-HBc); HBV; HIV; Botswana; Africa
Online: 20 June 2023 (09:42:20 CEST)
: (1) Background: Hepatitis B core antibodies (anti-HBc) are a marker of hepatitis B virus (HBV) exposure; hence a normal HBV serology profile is characterized by HBV surface antigen (HBsAg) and anti-HBc positivity. However atypical HBV serologies occur and we aimed to determine the prevalence of an atypical profile (HBsAg+/anti-HBc-) in a cohort of people with HIV-1 (PWH) in Botswana. (2) Methods: Plasma samples from an HIV-1 cohort in Botswana (2013-2018) were used. Samples were screened for HBsAg and anti-HBc. Next generation sequencing was done using the GridION platform. Wilcoxon rank-sum test and Chi-squared tests were used for comparison of continuous and categorical variables respectively. (3) Results: HBsAg+/anti-HBc- prevalence was 13.7% (95% CI 10.1 – 18.4) (36/263). HBsAg+/anti-HBc- participants were significantly younger (p<0.001), female (p=0.02), ART naïve (p=0.04) and had detectable HIV viral load (p=0.02). There were no mutational differences in sequences isolated from participants with HBsAg+/anti-HBc- versus those with HBsAg+/anti-HBc+ serology. (4) Conclusions: We report a high HBsAg+/anti-HBc– atypical serology profile prevalence among PWH in Botswana. We caution against HBV testing algorithms that consider only anti-HBc+ samples for HBsAg testing as they are likely to underestimate HBV prevalence. Studies to elucidate the mechanisms and implications of this profile are warranted.
ARTICLE | doi:10.20944/preprints202307.1265.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis virus; HBV; HCV; surveillance; Gabon; Africa
Online: 19 July 2023 (08:09:22 CEST)
Viral hepatitis remains one of the largest public health concerns worldwide. Especially in Central Africa, information on hepatitis virus infections has been limited, although the prevalence in this region has been reported to be higher than the global average. To reveal the current status of hepatitis B and C viruses (HBV and HCV) infections and the genetic diversity of the viruses, we conducted longitudinal surveillance in Gabon. We detected 22 HBV and 9 HCV infections in 2,047 patients with febrile illness. Genetic analyses of HBV identified subgenotype A1 for the first time in Gabon and an insertion generating a frameshift to create an X-preC/C fusion protein. We also revealed that most of the detected HCVs belonged to the “Gabon-specific” HCV subtype 4e (HCV-4e), and the entire nucleotide sequence of the HCV-4e polyprotein was determined to establish the first reference sequence. HCV-4e strains possessed resistance-associated substitutions similar to those of other HCV-4 strains, indicating that the use of direct-acting antiviral therapy may be complex. These results provide a better understanding of the current situation of hepatitis B and C virus infections in Central Africa, and will help public health organizations develop effective countermeasures to eliminate chronic viral hepatitis in this region.
REVIEW | doi:10.20944/preprints201810.0158.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis C virus, Genotyping, Mixed infection, Fluorescence melting curve analysis, Viral Load, Quantification
Online: 8 October 2018 (16:08:48 CEST)
Hepatitis-C is one of the most common viral diseases caused by hepatitis C virus (HCV). It is responsible for millions of deaths each year in the developing world. The common dissemination paths of HCV include the use of contaminated water and transfusion of infected blood. Control of this virus has become a challenge for scientists and health professionals due to its versatility and adaptability in different host environments. Along with other problems, lack of efficient diagnosis, quantification and genotyping of viral strains are the major hindrances in a management of this notorious epidemic. The knowledge of HCV genotype and an amount of virus in patient’s blood are pre-requisites to determine the duration and method of treatment. In this review, we discuss the implications of HCV molecular diagnostic methods and their clinical applications. We conclude that while, several commercial and home-brewed methods are available for this purpose, and there is a visible vacuum for cost effective, robust, sensitive assays that can detect multiple viral genotypes in a single reaction. We are of the view that the level of sensitivity offered by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) technique is unequivocal as compared to other techniques. Therefore, researchers may explore further possibilities using this technique in the management of HCV.
ARTICLE | doi:10.20944/preprints202001.0001.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B virus; prevalence of HBsAg; rural and urban zone; Togo
Online: 1 January 2020 (14:31:28 CET)
Infection with the hepatitis B virus (HBV) is a public health problem in many parts of the world, due to its frequency, complications and socio-economic consequences. This study aimed to assess the seroprevalence of hepatitis B virus infection in rural areas and in urban areas. This cross-sectional study assessed the prevalence of HBV infection from 2015-2018 at CHR-Sokodé and USP of Ogaro. Biological data of 3000 participants (500 per year in each zone) enrolled and results of HBsAg were assessed during the study period. Female are represented 60% with average age comprised between [20, 29] years old. The high rate of participants enrolled (45.10%) are come for the monitoring of pregnancy. The prevalence of VHB during the study are 20.33% (610/3000), high prevalence (6.27%) and the means of VHB prevalence are shown in the age range between [30; 39] with 12.17% (365/3000) of female and 8.17% (235/3000) of male are positive after diagnostic detection of HBsAg (antigen of Hepatitis B virus). The prevalence of HBV in rural zone (Ogaro) are 5.23% and 15.07% in urban zone (Sokodé) and the high prevalence (17.50%) are shown in urban zone. The high prevalence of young suggests that some effort will be due to sensibilized young for HBV sexual transmission and the way of prevention. In addition, some research would be done in research of alternative therapy against this infection.
ARTICLE | doi:10.20944/preprints202211.0286.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis E virus; Paslahepevirus balayani; seroprevalence; molecular epidemiology; zoonosis; disease outbreaks
Online: 15 November 2022 (10:28:45 CET)
The factors influencing hepatitis E virus (HEV) circulation remain largely unexplored. We investigated HEV seroprevalence in humans and the prevalence of infection in farm pigs and rabbits in different regions of the Russian Federation, as well as the genetic diversity and population dynamics of HEV. Anti-HEV IgG antibody detection rates in the general population increase significantly with age, from 1.5% in children and adolescents under 20 years old to 4.8% in adults aged between 20 and 59 years old, to 16.7% in people aged 60 years and older. HEV seroprevalence varies between regions, with the highest rate observed in Belgorod Region (16.4% compared with the national average of 4.6%), which also has the country’s highest pig population. When compared with the archival data, both increases and declines in HEV seroprevalence have been observed within the last 10 years, depending on the study region. Virus shedding has been detected in 19 out of the 21 pig farms surveyed. On one farm, circulation of the same viral strain for five years was documented. All human and animal strains belonged to the HEV-3 genotype, with its clade 2 sequences being predominant in pigs. Sequences from patients, pigs, and sewage from pig farms clustered together, suggesting a zoonotic infection in humans and possible environmental contamination. The HEV-3 population size predicted using SkyGrid reconstruction demonstrated exponential growth in the 1970s–1990s, with a subsequent decline followed by a short rise around the year 2010, the pattern being similar to the dynamics of the pig population in the country. The HEV-3 reproduction number (Re) predicted using Birth-Death Skyline analysis has fluctuated around 1 over the past 20 years in Russia, but is 10 times higher in Belgorod Region. In conclusion, HEV-3 circulation varies both geographically and temporally, even within a single country. The possible factors contributing to this variability are largely related to the circulation of the virus among farm pigs.
REVIEW | doi:10.20944/preprints202201.0226.v4
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Hepatitis C virus (HCV); liver; blood; electrochemiluminescence (ECL); ELISA method (Enzyme-Linked Immunosorbent Assay)
Online: 19 October 2023 (10:53:58 CEST)
The study aimed to manage and to analyse the results of the laboratory tests, routinallypractice for hepatitis C diagnosis, using blood tests. Statistical analysis of this study results, was performed using the laboratory informatic system. The results of the study are substantial and intricate reffering to comparision between two methods concretlly ELISA method (Enzyme-Linked Immunosorbent Assay) and chemiluminescence methods and their results. Good to know our opinion that RT-PCR technique, it is considered proper for the diagnosis of HCV ( Hepatitis C virus).
ARTICLE | doi:10.20944/preprints202206.0096.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis E; Associated risk factors; Pregnant women; Environment; Prevention; Senegal
Online: 7 June 2022 (08:06:52 CEST)
In West Africa, research on the hepatitis E virus (HEV) is barely covered despite the recorded outbreaks. The still low level of access to safe water and adequate sanitation is one of the main factors of HEV spread in developing countries. HEV infection induces acute or sub-clinical liver diseases with a mortality rate ranging from 0.5 to 4%. The mortality rate is more alarming (15 to 25%) among pregnant women, especially in the last trimester of pregnancy. Here, we conducted a multicentric socio-demographic and seroepidemiological survey of HEV in Senegal among pregnant women. A total of 1,227 consenting participants attending antenatal clinics responded to our questionnaire. Plasma samples were collected and tested for anti-HEV IgM and IgG by using the WANTAI HEV-IgM and IgG ELISA assay. HEV global seroprevalence was 7.9% with 0.5% and 7.4% for HEV IgM and HEV IgG, respectively. One participant's sample was IgM/IgG positive, while four were declared indeterminate to anti-HEV IgM as per the manufacturer's instructions. From one locality to another, the seroprevalence of HEV antibodies varied from 0 to 1% for HEV IgM and from 1.5 to 10.5% for HEV IgG. The data also showed that seroprevalence varied significantly by marital status (p<0.0001), by the regularity of income (p=0.0043) and by access to sanitation services (p=0.0006). These data could serve as a basis to setup national prevention strategies focused on socio-cultural, environmental and behavioral aspects for a better management of HEV infection in Senegal.
ARTICLE | doi:10.20944/preprints202310.1139.v1
Subject: Public Health And Healthcare, Health Policy And Services Keywords: Hepatitis C; Elimination; Global Burden of Disease; Mortality
Online: 18 October 2023 (17:35:15 CEST)
This study assesses the feasibility of hepatitis B and C elimination, using an analysis of trends of epidemiology data (1990-2019) from the global burden of disease. Joinpoint regression analysis was used to identify significant changing points in trends of Age-standardizes Prevalence Rate (ASPR) and Age-standardizes Mortality Rate (ASMR) and to estimate the annual percentage changes (APC) and the average annual percentage changes (AAPC) for the period. Sociodemographic Index (SDI) was used to analyze trends between countries. The total percentage change of the ASPR (2019/1990) was -31.4% and -12.8% for HBV and HCV worldwide respectively, the rate ratio (HBV/HCV) was 2.5. Mortality has decreased for HBV but not for HCV. The total percentage change for the ASMR (2019/1990) was -26.7% and 10.0%, for HBV and HCV respectively. While ASMR of HBV decreased, HCV increased during this period. The percentage change in ASMR of HBV was highest in countries with high-middle SDI and lowest in countries with high SDI. For HCV, the percentage change in ASMR was highest in countries with High SDI (increase) and only in countries with low SDI decreased. The global HBV and HCV rates have fallen with different AAPC associated with the SDI. Despite the advances, there is still a long way forward to achieve the 2030 elimination goals. An important challenge is related to finding a way to speed up the yearly rate at which the decline is happening.
REVIEW | doi:10.20944/preprints202106.0176.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: chronic hepatitis B; covalently closed circular DNA; viral integration; transcription factor; nuclear receptor; transcriptional inhibitor; RNA interference
Online: 7 June 2021 (12:43:06 CEST)
Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of an effective HBV vaccine. During chronic infection, HBV forms two distinct templates responsible for viral gene transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host-genome integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription, and their impact on the stability of viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA, small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA and small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrant templates. These antivirals mediate their effects by reducing viral transcripts abundance, eventually leading to loss of surface antigen expression, and can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.
ARTICLE | doi:10.20944/preprints201810.0314.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis B virus (HBV); cccDNA; basal core promoter; X promoter; single nucleotide polymorphisms; logo analyses; genotype alignments
Online: 15 October 2018 (13:03:06 CEST)
Over 250 million people are infected chronically with hepatitis B virus (HBV), the leading cause of liver cancer worldwide. HBV persists due in part to its compact, stable minichromosome, the covalently-closed, circular DNA (cccDNA), which resides in the hepatocytes’ nuclei. Current therapies target downstream replication products, however, a true virological cure will require targeting the cccDNA. Finding targets on such a small, compact genome is challenging. For HBV, to remain replication-competent, it needs to maintain nucleotide fidelity in key regions, such as the promoter regions, to ensure that it can continue to utilize the necessary host proteins. HBVdb (HBV database) is a repository of HBV sequences spanning all genotypes (A-H) amplified from clinical samples, and hence implying an extensive collection of replication-competent viruses. Here, we analyzed the HBV sequences from HBVdb using bioinformatics tools to comprehensively assess the HBV core and X promoter regions amongst the nearly 70,000 HBV sequences for highly-conserved nucleotides and variant frequencies. Notably, there is a high degree of nucleotide conservation within specific segments of these promoter regions highlighting their importance in potential host protein-viral interactions and thus the virus’ viability. Such findings may have key implications for designing antivirals to target these areas.
ARTICLE | doi:10.20944/preprints202310.0425.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis B; antiviral; drug discovery; HBc protein; pharmacophore-based screening; drug repurposing
Online: 8 October 2023 (05:11:37 CEST)
Background: Chronic Hepatitis B Virus (HBV) infection is a global health concern, associated with severe liver diseases, necessitating ongoing research on novel drug candidates. This study aims to identify potential drug candidates targeting HBV core protein (HBcAg) and disrupting capsid assembly, a critical step in the virus's life cycle. Methods: HBcAg in complex with HBV inhibitors were obtained from the Protein Data Bank (PDB). CavityPlus server was used for analysis of druggable cavity. Structure-based pharmacophores were extracted from identified cavities, and potential allosteric ligand binding sites were assessed using CavPharmer, CorrSite, and CovCys. LigandScout was employed for ligand-based pharmacophore screening against an FDA-approved library. The ZINC database was screened with features extracted from CavPharmer. Molecular docking studies were conducted using Autodock Vina. Lead compounds were selected based on docking scores, binding modes, and interactions within the druggable cavity. Results: Strong druggable pockets were found for Ciclopirox, while Compound 24, NVR10-001E2, and others showed medium to weak pockets. Ligand-based pharmacophores varied in size and complexity. Screening revealed potential hits matching these pharmacophores, including Ciclopirox olamine, Voriconazole, Enasidenib, and Statins. A large compound database search yielded additional hits like ZINC86859997 and ZINC63280172. Docking analyses confirmed these hits' potential, highlighting their interactions with critical HBc protein residues, offering promising leads for hepatitis B drug development. Conclusions: Voriconazole, Enasidenib, and Lovastatin have shown promises. These hits displayed favorable interactions with crucial HBc protein residues, indicating their potential as lead compounds The mechanism of action of statins with anti-HBV activities also highlighted. This comprehensive approach offers valuable insights into targeting HBc protein for antiviral drug discovery.
ARTICLE | doi:10.20944/preprints201609.0074.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: hepatocellular carcinoma; hepatitis B virus X protein; Notch1 pathway; ERK; AKT
Online: 21 September 2016 (09:49:13 CEST)
Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.
ARTICLE | doi:10.20944/preprints202210.0031.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis B virus; genotypes; subgenotypes; HBsAg subtypes; molecular epidemiology; Siberia; Siberian natives; aboriginal population
Online: 5 October 2022 (10:44:12 CEST)
A total of 381 hepatitis B virus (HBV) DNA sequences collected from 9 groups of Siberian native populations were phylogenetically analyzed along with 179 HBV strains sampled in different urban populations of former western USSR republics and 50 strain from Central Asian republics and Mongolia. Different HBV subgenotypes predominated in various native Siberian populations. Subgenotype D1 was dominant in Altaian Kazakhs (100%), Tuvans (100%), and Teleuts (100%) of southern Siberia as well as in Dolgans and Nganasans (69%), who inhabit the polar Taimyr Peninsula. D2 was the most prevalent subgenotype in the combined group of Nenets, Komi, and Khants of the northern Yamalo-Nenets Autonomous Region (71%), and in Yakuts (36%) from northeastern Siberia. D3 was the main subgenotype in South Altaians (76%) and Buryats (40%) of southeastern Siberia, and in Chukchi (51%) of the Russian Far East. Subgenotype C2 was found in Taimyr (19%) and Chukchi (27%), while subgenotype A2 was common in Yakuts (33%). In contrast, D2 was dominant (56%) in urban populations of the former western USSR, and D1 (62%) in Central Asian republics and Mongolia. Statistical analysis demonstrated that the studied groups are epidemiologically isolated from each other and might have contracted HBV from different sources during the settlement of Siberia.
ARTICLE | doi:10.20944/preprints202305.2189.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: chronic hepatitis C; nonalcoholic steatohepatitis; IL-23/IL-17 axis; immunohepatotoxicity
Online: 31 May 2023 (07:46:51 CEST)
Considering the relevance of the pathogenesis research of different liver diseases, in our study we investigated the possible activity of IL-23/IL-17 axis on the im-munohepatotoxicity of two etiologically different CLD. A total of patients with CHC infection, 19 with NASH and 20 healthy controls (CG) were recruited. After histological verification from liver tissue obtain by liver biopsy, patients with CHC were divided into two groups: CHC-NSF (F0/F1/F2)-non-significant fibrosis, 20 patients, and CHC-SF (F3/F4)-significant fibrosis/cirrhosis, 16 patients. All anthropometric, biochemical, immunological cytokines (IL-6, IL-10, IL-17 and IL-23) tests were performed accordance to standard procedure. The plasma levels of IL-6, Il-17A and IL-23 were significantly higher in CHC-SF and NASH in compared with CG. Also, plasma levels of IL-23/IL-17A were significantly higher in NASH in compared to CHC-SF. In CHC-SF we had significantly lowest IL-10 level in compared with all three groups. Liver tissue levels of IL-17A and IL-23 in CHC-NSF were significantly lower in compared with NASH. IN CHC-SF and NASH, IL17-A and IL-23 in liver tissue were significantly higher in compare to plasma levels. In conclusan, proinflammatory response of IL-23/17A axis is dominant in plasma and liver tissue in CHC with higher levels of liver fibrosis and in NASH patients.
ARTICLE | doi:10.20944/preprints201810.0254.v1
Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: Solanum fruit juice; biochemical markers; chronic hepatitis C; oxidative stress; antioxidants
Online: 12 October 2018 (04:55:44 CEST)
Variations in liver metabolism as a result of hepatitis C virus have been established by numerous clinical trials. The use of antioxidants supplements has been reported to minimize the implication of this disease. In this regard, we examined the suitability of Solanum fruit juice, a natural source of vitamin C and citrus flavoniod as a precursor for the treatment of patients with chronic hepatitis C. Forty adult patients who were diagnosed with chronic hepatitis C and were under antiviral therapy were divided into two equal groups. Group 1 patients received their antiviral therapy with normal food and water and served as the control group while patients in group 2 were supplemented with Solanum fruit juice for eight consecutive weeks. Measurements for Anthropometric data, C reactive protein (CRP), atherogenic indices, biochemical parameters and activities of liver marker enzymes were recorded before and after eight weeks. No alterations were found in waist circumference, body mass and body fat following regular use of Solanum fruit juice. The serum levels of oxidative stress markers, LDL-cholesterol, total cholesterol, CRP and atherogenic indices decreased in the Solanum fruit juice group when compared to the control group. Moreover, the activities of the liver marker enzyme AST decreased in those who had high levels before the intervention. These results underscore the benefits of Solanum fruit juice in the diet of patients with HCV as a result of decreased cholesterol in blood serum, decreased inflammation, and increase in antioxidant capacity as well as maintaining body mass index. This clinical trial is registered at Pan African Clinical Trial Registry (www.pactr.org) with unique identification number PACTR201802003092138.
ARTICLE | doi:10.20944/preprints202311.0152.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: Antigua and Barbuda; hepatitis B; vaccination coverage; birth dose; elimination
Online: 2 November 2023 (09:57:25 CET)
The Hepatitis B virus, chronically infects over 240 million persons worldwide. The Hepatitis B vaccine is 90% effective in preventing perinatal transmission if the first dose is given within the first 24 hours of life followed by a minimum of 2 subsequent doses. In October 2021, Antigua and Barbuda, through it’s only public hospital - the Sir Lester Bird Medical Centre, instituted a hospital based Hepatitis B vaccine birth dose policy. Timely birth dose coverage was 72% and total birth dose coverage 81%. 10.5% of parents refused the hepatitis b – birth dose, of which 76% either felt uncomfortable or preferred to wait. 100% of babies born before arrival received timely vaccine administration, likewise 100% of Hepatitis B exposed babies were vaccinated, with 83% of them receiving the Hepatitis B Immunoglobulin. A maternal Hepatitis B surface antigen result was available for 90.4% of mothers. Barriers to timely birth dose administration included vaccination hesitancy, gaps in healthcare worker knowledge, and the consistent supply of Hepatitis B vaccine. Instituting a quality improvement team, health information system, robust educational efforts, and addressing barriers will make achieving the WHO programmatic targets of eliminating mother to child transmission of hepatitis B by 2030 possible.
ARTICLE | doi:10.20944/preprints202308.2008.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: ELISA, Hepatitis E virus, Portugal, red deer, risk factors, wild boar
Online: 30 August 2023 (13:56:37 CEST)
Hepatitis E virus (HEV) is a zoonotic foodborne virus with an annual infection prevalence of 20 million human cases, which seriously affects public health and economic development in both developed and developing countries. To better understand the epidemiology of HEV in the Centre of Portugal, a cross-sectional study was conducted from 2016 to 2023 with sera samples from wild ungulates. The seroprevalence and risk factors for HEV seropositivity were evaluated in the present study. Specifically, antibodies against HEV were determined by a commercial enzyme-linked immune-sorbent assay (ELISA). Our results show that in the 650 sera collected from 298 wild red deer and 352 wild boars from Portugal, 9.1% red deer (95% confidence interval [CI]: 6.312.9%) and 1.7% wild boar (95% CI: 0.63.3%) were positive for antibodies to HEV. Regarding age, the seropositivity in juvenile wild ungulates was 1.3% (95% CI: 0.273.72%) and 7.2% in adults (95% CI: 4.910.11%). Logistic regression models investigated risk factors for seropositivity. The odds of being seropositive was 3.6 higher in adults than in juveniles (95% CI: 1.7218.11%) and the risk was 4.2 higher in red deer than in wild boar (95% CI: 1.64–10.69%). Both wild ungulate species were exposed to HEV. The higher seroprevalence in red deer suggests that this species may have a major contribution to the ecology of HEV in the Centre of Portugal. Further research is important to understand how wildlife affects the epidemiology of HEV infection in Portugal.
BRIEF REPORT | doi:10.20944/preprints202207.0220.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B virus; HepG2-NTCP cells; Immunofluorescence; Sodium taurocholate cotransporting polypeptide (NTCP) Receptor; Subcloning; Limiting dilution; Myrcludex B
Online: 14 July 2022 (12:06:08 CEST)
HepG2 cells reconstituted with Hepatitis B virus (HBV) entry receptor sodium taurocholate co-transporting polypeptide (NTCP) are widely used as a convenient in vitro cell culture infection model for HBV replication studies. As such, it is pertinent that HBV infectivity is maintained at steady-state levels for accurate interpretation of in vitro data. However, variations in HBV infection efficiency due to imbalanced NTCP expression levels in the HepG2 cell line may affect experimental results. In this study, we performed single cell cloning of HepG2-NTCP-A3 parental cells via limiting dilution and obtained multiple subclones with increased permissiveness to HBV. Specifically, one subclone (HepG2-NTCP-A3/C2) yielded more than 4-fold higher HBV infection compared to the HepG2-NTCP-A3 parental clone. In addition, though HBV infectivity was universally reduced in the absence of polyethylene glycol (PEG), subclone C2 maintained relatively greater permissiveness under PEG-free conditions, suggesting the functional heterogeneity within parental HepG2-NTCP-A3 may be exploitable in developing a PEG-free HBV infection model. The increased viral production correlated with increased intracellular viral antigen expression as evidenced through HBcAg immunofluorescence staining. Further, these subclones were found to express different levels of NTCP, albeit with no remarkable morphology or cell growth differences. In conclusion, we isolated subclones of HepG2-NTCP-A3 which support efficient HBV production and thus provide an improved in vitro HBV infection model.
ARTICLE | doi:10.20944/preprints202308.1423.v1
Subject: Public Health And Healthcare, Other Keywords: Hepatitis E Virus; seroprevalence; risk factors; mining gold villages; Southeastern Senegal
Online: 21 August 2023 (10:43:05 CEST)
Rapid proliferation of traditional gold mining sites in Kédougou a Southeast region in Senegal, led to mass population migration from the neighboring West African countries and rapid expansion of small mining villages with poor hygiene and sanitation conditions. An outbreak of hepatitis E was reported in 2014 with several cases of febrile jaundice among traditional mine workers. In this study, we analyzed both HEV IgM and IgG seroprevalence and the associated risk factors of infection by testing any suspected case and contacts collected from February 2012 to November 2014. RNA-negative sera from suspected cases and contacts were tested for anti-HEV IgM and anti-HEV IgG. A total of 799 sera were collected from 290 suspected cases, 470 contacts and 39 individuals with missing information. The median age of the cohort study was 19 years (1-88 years) with a male/female sex-ratio of 1.9. We found an overall prevalence of 43.68% (332/760) of anti-HEV IgM and 38.15% (290/760) of anti-HEV IgG sera. Our data provide new insights into the HEV epidemiology and point to the crucial need to estimate the disease’s burden in Kédougou and assess the viral mechanisms driving the disease’s severity in pregnant women.
ARTICLE | doi:10.20944/preprints202012.0557.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Hepatitis E virus (HEV); interferon (IFN); the capsid protein; DDX3; RNA helicase
Online: 22 December 2020 (12:19:32 CET)
DDX3 is an ATP-dependent RNA helicase involved in multiple cellular activities, including RNA metabolism and innate immunity. DDX3 is known to assist the replication of some viruses while restricting some others through direct interaction with the viral proteins. However, the role of DDX3 in the replication of the hepatitis E virus (HEV) is unknown. In this study, DDX3 is shown to interact with the HEV capsid protein and provide an indispensable role in HEV replication. The DDX3 C-terminal domain was demonstrated to interact with the capsid protein, which was previously demonstrated to inhibit the production of type I interferons. Knockdown of DDX3 compromised the capsid protein-mediated blockage of interferon induction. Notably, DDX3 silencing led to a significant reduction in HEV replication. Also, the ATPase activity of DDX3 is required for the HEV replication as an ATPase-null mutant DDX3 failed to rescue the viral replication in the DDX3-silenced cells. These results demonstrate a pro-viral role of DDX3 in HEV replication, providing further insights into the virus-cell interactions.
ARTICLE | doi:10.20944/preprints202211.0233.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Hepatitis B virus; knowledge; stigma; health-seeking behaviors; Sierra Leone
Online: 14 November 2022 (03:51:01 CET)
Hepatitis B virus (HBV) is a major global health challenge. Emerging evidence suggests that poor knowledge and stigma are impacting HBV control efforts in sub-Saharan Africa (SSA), however their role is not well understood. We conducted a cross-sectional study of adults aged ≥ 18 years in a community and pharmacy setting in Freetown, Sierra Leone. A structured questionnaire was used to assess knowledge, stigmatizing attitudes, and health-seeking behaviors regarding HBV. Logistic regression was used to identify predictors of HBV knowledge and related stigma. A total of 306 adult participants were enrolled (50.7% male, 7.5% HBV positive and 11.7% vaccinated). Overall, 52.2% had comprehensive HBV knowledge and 49.3% expressed a stigmatizing attitude towards people with HBV. Notwithstanding, 72.2% stated they would receive the HBV vaccine if offered, 80.4% would take anti-HBV medication and 78.8% would be willing to attend clinic regularly. Comprehensive HBV knowledge was associated with HBV positive status (aOR 4.41; p = 0.029) and being vaccinated against HBV (aOR 3.30; p = 0.034). HBV-related stigma was associated with secondary or higher level of education (aOR 2.36; p < 0.001), good HBV knowledge (aOR 2.05; p = 0.006) and pharmacy setting (aOR 1.74, p = 0.037). These findings suggest that education and stigma reduction may benefit HBV elimination efforts in SSA.
ARTICLE | doi:10.20944/preprints202207.0018.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatocellular carcinoma (HCC); hepatitis B virus (HBV); mutations; HBV/HIV co-infection; Botswana; Africa
Online: 1 July 2022 (16:31:00 CEST)
Mutations within the hepatitis B virus (HBV) genome have been associated with rapid progres-sion to hepatocellular carcinoma (HCC); however, there is limited information regarding the prevalence and impact of these mutations in most of sub-Saharan Africa, including Botswana. We aimed to determine the prevalence of HBV mutations known to be associated with progression to HCC using a retrospective, cross-sectional analysis of 48 previously generated HBV sequences from adults with concomitant HBV/HIV initiating HIV antiretroviral therapy in Botswana. The sequences were aligned with reference sequences, and HCC-associated mutations were manually identified using BioEdit. Sixteen (33.3 %) of 48 participant samples had 20 HCC-associated mu-tations. Seven HCC mutations were present in the core region, 4 in the preCore region, 7 in the X region, and one mutation in the surface region, as well as deletions within the preSurface 1 region. Seven of the 16 participants (43.8%) had multiple HCC-associated mutations. There were also previously uncharacterized mutations at positions with known HCC-associated mutations. HCC-associated mutations were common in this cohort; hence, some participants may require close clinical monitoring as they might be more prone to rapid disease progression. Other functionally uncharacterized polymorphisms were also detected and require characterization in future studies.
ARTICLE | doi:10.20944/preprints202112.0122.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: hepatitis B virus; besifovir dipivoxil maleate (BSV); nucleos(t)ide analog; drug resistance; reverse transcription
Online: 8 December 2021 (12:06:52 CET)
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
ARTICLE | doi:10.20944/preprints201809.0428.v1
Subject: Biology And Life Sciences, Virology Keywords: inter- and intra-host nucleotide variations; Hepatitis A virus; next-generation sequencing; pyrosequencing
Online: 21 September 2018 (04:59:34 CEST)
The accurate virus detection, strain discrimination, and source attribution of contaminated food items remains a persistent challenge because of the high mutation rates anticipated to occur in foodborne RNA viruses, such as Hepatitis A virus (HAV). This has led to predictions of the existence of more than one sequence variant between the hosts (inter-host) or within an individual host (intra-host). However, there have been no reports of intra-host variants from an infected single individual, and little is known about the accuracy of the single nucleotide variations (SNVs) calling with various methods. In this study, the presence and identity of viral SNVs, either between HAV clinical specimens or among a series of samples derived from HAV clone1-infected FRhK4 cells, were determined following analyses of nucleotide sequences generated using next-generation sequencing (NGS) and pyrosequencing methods. The results demonstrate the co-existence of inter- and intra-host variants both in the clinical specimens and the cultured samples. The discovery and confirmation of multi-viral RNAs in an infected individual is dependent on the strain discrimination at the SNV level, and critical for successful outbreak traceback and source attribution investigations. The detection of SNVs in a time series of HAV infected FRhK4 cells improved our understanding on the mutation dynamics determined probably by different selective pressures. Additionally, it demonstrated that NGS could potentially provide a valuable investigative approach toward SNV detection and identification for other RNA viruses.
ARTICLE | doi:10.20944/preprints202307.0307.v1
Subject: Public Health And Healthcare, Public, Environmental And Occupational Health Keywords: endemicity pattern; hepatitis A; hepatitis B; hepatitis C; hepatitis D; hepatitis E; seroprevalence; general population; Kyrgyzstan; post-Soviet country; WHO European Region
Online: 5 July 2023 (12:40:33 CEST)
Historically, viral hepatitis is a considerable public health problem in Central Asian countries, which may have worsened after dissolution of the Soviet Union. However, up-to-date seroepidemiological studies are lacking. The aim of the present study was, therefore, to provide current estimates of seroprevalence of viral hepatitis in Kyrgyzstan, one of the economically least developed countries in the region. We conducted a population-based cross-sectional study in 2018 in the capital of Kyrgyzstan, Bishkek (n=1075). Participants, children and adults, were recruited from an outpatient clinic. Data were collected during face-to-face interviews. A blood sample (6 ml) was collected from each participant and tested with ELISA for the presence of serological markers for five viral hepatitides (A, B, C, D and E). Poststratification weighting was performed to obtain nationally representative findings. The overwhelming majority of the study participants were positive for anti-HAV (estimated seroprevalence, 75.3%; 95% confidence interval: 72.5–77.9%). The weighted seroprevalence estimates of HBsAg, anti-HCV and anti-HDV were 2.2% (1.5–3.3%), 3.8% (2.8–5.1%), and 0.40% (0.15–1.01%), respectively. Anti-HEV seropositivity was 3.3% (2.4–4.5%). Of the 33 HBsAg positive participants, five (15%) were anti-HDV positive. Our study confirms that Kyrgyzstan remains a high endemic country for hepatitis virus A and C infections. However, seroprevalences of HBV and HDV were lower than previously reported, and based on these data, the country could potentially be reclassified from high to (lower) intermediate endemicity. The observed anti-HEV seroprevalence resembles the low endemicity pattern characteristic of high-income countries.
REVIEW | doi:10.20944/preprints202311.1971.v1
Subject: Biology And Life Sciences, Other Keywords: Autoimmune hepatitis; International Autoimmune Hepatitis Group; simplified diagnostic criteria; histology; plasma cell clusters; lobular hepatitis, portal hepatitis
Online: 30 November 2023 (10:14:46 CET)
Autoimmune hepatitis (AIH) is a chronic, relapsing and remitting, immune mediated liver disease which progresses to cirrhosis if left untreated. A significant number of patients may present with acute hepatitis or acute liver failure, which are often misdiagnosed as toxic liver injury. AIH shows a preponderance for young women but may be seen in children and elderly. Diagnosis requires integration of clinical, biochemical and serologic parameters along with supportive liver histology and exclusion of other causes of liver disease. Liver biopsy is a pre-requisite for diagnosis of AIH, to assess severity and stage of disease, exclude other entities and recognize any concurrent morbidities. No single biomarker or histologic feature is pathognomonic for AIH. The diagnostic and histologic criteria have undergone several modifications since the Original Scoring system proposed by the International Autoimmune Hepatitis Group (IAIHG) in 1993. Recently, IAIHG has proposed consensus recommendations for histologic criteria, relevant for both acute and chronic AIH. This review article will describe the evolving diagnostic criteria for AIH with their limitations and utility, with an emphasis on the role of liver histology in diagnosis and management of AIH.
REVIEW | doi:10.20944/preprints202105.0301.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Hepatitis E virus; Genotype; Epidemic hepatitis; Sporadic hepatitis; Pregnancy; Foetus; Neonate; Vaccine
Online: 13 May 2021 (13:52:29 CEST)
The adverse relationship between viral hepatitis and pregnancy in developing countries was seen as a reflection of retrospective biased hospital-based data collection by the West. However, the discovery of HEV from an epidemic of non-A, non-B hepatitis in Kashmir and documenting increased incidence and severity of hepatitis E in pregnancy from a house-to-house survey unmasked the unholy alliance. Among the family of HEV’s, genotype (gt)-1, with a unique ORF4-encoded protein enhancing viral polymerase activity and viral replication, is the sole HEV that shows this adverse relationship. The epidemics caused by HEV-gt1 and not by HEV-gt2 show adverse relationship with pregnancy. The pathogenesis of the unholy alliance is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the mother including: infection, replication and damage to the maternal-foetal interface by HEV-gt1; vertical transmission of HEV to foetus causing severe foetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the mother promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of ALF. Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.
ARTICLE | doi:10.20944/preprints201810.0201.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: hepatitis c viruses; hepatitis e virus; dentists
Online: 10 October 2018 (05:21:20 CEST)
Health care workers (HCWs), specifically dentists, are at the front line for acquiring blood-borne virus infections. The highest proportion of occupational transmission is through percutaneous injuries via hollow-bore needles. Several studies around the world have reported that hepatitis viruses and human immunodeficiency virus are the main pathogens for most cases of occupationally acquired blood-borne infection. We aim to investigate the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), and human immunodeficiency virus (HIV) among Mexican dentists. Methods. We included 159 dentists who attended the annual meeting at the Medica Sur Clinic & Foundation held in Mexico City in May 2016. A survey was applied in order to obtain data of occupational exposure to blood-borne viruses (BBV). Serum samples were screened serologically using enzyme-linked immunosorbent assays. Results. Two dentists (1.2%) were positive for antibodies against HCV antigen, one (0.6%) was positive for antibodies against HBV antigen and three (1.8%) were positive for the detection of IgG antibodies against HEV. Two cases (1.2%) were positive for antibodies against HIV. Conclusions. The infection by HEV was the most prevalent among dentists. However, the prevalence of BBV in dentists was similar to that in the general population.
ARTICLE | doi:10.20944/preprints201809.0525.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis E virus; innate immunity; interferon response; JAK/STAT pathway; zoonosis; emerging pathogen
Online: 27 September 2018 (03:34:49 CEST)
Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the non-structural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and in particular the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. By contrast, MetPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent as MetPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.
REVIEW | doi:10.20944/preprints202308.2114.v1
Subject: Biology And Life Sciences, Virology Keywords: HBV; woodchuck hepatitis virus; early virus-host DNA integration; virus-induced oxidative DNA damage; dsDNA repair; NHEJ; retrotransposons; ocogenesis; hepatocellular carcinoma
Online: 31 August 2023 (09:34:45 CEST)
Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions suggesting a mechanism for spontaneous HBV DNA disperse throughout hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions indicating their creation by non-homologous-end-joining (NHEJ). Their formation coincided with robust oxidative damage of hepatocyte DNA. This was associated with activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair as reflected by augmented transcription of PARP1 and XRCC1, the PARP1 binding partner, OGG1, a responder to oxidative DNA damage, and by increased activity of NAD+, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains HTJ format of the initial merges. The findings showed that HBV and WHV are immediate inducers of oxidative DNA damage, hijack dsDNA repair to integrate into hepatocyte genome and by this may initiate pro-oncogenic process. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.
CASE REPORT | doi:10.20944/preprints202309.1048.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: drug induced autoimmune hepatitis; AIH; DILI; acute hepatitis
Online: 15 September 2023 (10:56:37 CEST)
Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.
ARTICLE | doi:10.20944/preprints202310.0104.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis A; Hepatitis E; Norovirus; Real-time RT-qPCR
Online: 3 October 2023 (04:25:03 CEST)
Enteric viruses are the major cause of gastroenteritis and enteric hepatitis worldwide, but in some areas like Saudi Arabia little data is known about their presence in water sources. The available information from clinical samples is not enough to figure their actual prevalence. The aim of this study was to gather information for the first time in Saudi Arabia on the presence of Norovirus (NoV) genogroup GI and GII, hepatitis A virus (HAV) and hepatitis E virus (HEV) in water. For this purpose, thirteen monthly samples were collected in lake Wadi Hanifa and surrounding wells from December 2014 to November 2015. Viruses were detected and quantified by Real-time RT-qPCR. Despite HEV findings were anecdotic, our results highlight interesting behaviors of the other viruses. There was a higher prevalence of noroviruses in Wadi Hanifa samples than in well water samples (46.43% vs12.5% of NoV GI; 66.67% vs8.33% of NoV GII). On the contrary, similar levels of HAV positivity were observed (40.48% in surface water vs 43.06% in well water). Also, a strong influence of flooding events on HAV and NoV GI occurrence was observed in both surface and well water samples, being NoV GII apparently not affected.
ARTICLE | doi:10.20944/preprints202208.0292.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Chronic Hepatitis B Virus Infection; Liver; Pregnant Women; Cord blood; PBMCs (Peripheral Blood Mononuclear Cells); subclinical index
Online: 16 August 2022 (14:17:53 CEST)
BACKGROUND&AIMS: Hepatitis B virus (HBV) infection remains a major public health problem. The interaction between HBV and the host inflammatory response is an important factor contributing to liver damage and disease development. We compared the correlation between the subclinical index and PBMCs concentration in two groups of pregnant women (HBsAg positive), which are different in HBV DNA concentration in Vietnam. METHODS: The Hierarchical cluster analysis (HCA) was run with 20 different clustering methods on data collected from 80 Vietnamese pregnant women and their babies (60/80 cord blood). RESULTS: In the high viral load group (HBV DNA ≥ 5x10^7 copies/ml), a strong correlation between CBMCs with serum maternal Haemoglobin concentration and maternal platelet and maternal ALT. Their R values are: -0.88, 0.82, and 0.84 with p=8.97E-03, 2.41E-02 and 1.75E-01, respectively. CONCLUSIONS: We found a significant correlation shift of subclinical index between the two groups, which may be important in diagnosing pregnant women with chronic hepatitis B virus infection.
REVIEW | doi:10.20944/preprints201710.0065.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: hepatitis B virus; chronic hepatitis B; cccDNA; CRISPR/Cas9; gene therapy
Online: 10 October 2017 (17:59:11 CEST)
BACKGROUND: Chronic hepatitis B infected with Hepatitis B virus remains a major health concern worldwide. Despite standard interferon-α and nucleotide analogues have been shown to reduce the deterioration of liver disease among chronic hepatitis B patients, covalently closed circular DNA was still difficult to eradicate. METHODS: A literature search of Pubmed and Web of science was performed with the following key words: ‘CRISPR’, ‘CRISPR/Cas9’, ‘hepatitis B’, ‘HBV’, ‘chronic hepatitis B’ and ‘HBV cccDNA’. The information about CRISPR/Cas9 for the treatment of HBV cccDNA or hepatitis B was reviewed. RESULTS: CRISPR/Cas9 could treat hepatitis B through suppressing or clearing HBV cccDNA with different gRNAs. CONCLUSION: With the emergence of CRISPR/Cas9 (the RNA-guided clustered regulatory interspaced short palindromic repeats, CRISPR) editing technology, clearance of hepatitis B virus and better prevention of liver carcinoma seemed to be possible.
ARTICLE | doi:10.20944/preprints202301.0353.v1
Subject: Biology And Life Sciences, Virology Keywords: Coverage of hepatitis B vaccination; Hepatitis B virus; Healthcare workers; primary health facilities
Online: 19 January 2023 (09:19:23 CET)
Background: Occupational accidents contribute 46-65% of hepatitis B virus (HBV) infections among healthcare workers (HCWs). Vaccine against HBV infection offers protection of more than 90%. Despite availability of the vaccines in Tanzania, it’s uptake among HCWs in primary health facilities remains understudied. This study explored HBV vaccine uptake and associated factors among HCWs in rural and urban settings of north western Tanzania. Methodology: A cross-sectional analytical study was conducted between June and July in 2022 among HCW in Misungwi and Ilemela districts. Data were collected using a self-administered questionnaire and analyzed using IBM SPSS® version 25. Results: A total of 402 HCWs were recruited, their mean age was 34.9±7.77 years. Approximately half (54.7% (220/402) of HCWs had received at least one shot of HBV vaccine with only (18% (76/402) being fully vaccinated. Ilemela showed significantly higher uptake (χ2=23.64, df=1, p=0.00) of HBV vaccine as compared to their counterparts in Misungwi. Being male (aOR=2.38, 95% CI 1.28-4.45, p=0.006), working in urban (aOR=5.75, 95% CI 2.91-11.35, p=0.00) and employment duration of more than two years (aOR=3.58, 95%CI 1.19-10.74, p=0.023) were significantly associated with higher odds of HBV vaccination. Moreover, high perceived susceptibility to HBV infection (aOR=2.20, 95% CI1.02-4.75, p=0.044) and history of needle prick injuries (aOR=6.87, 95%CI 3.55-13.26, p=0.00) were also significantly associated with higher odds of HBV vaccination. Conclusion: There was low uptake of HBV vaccine among HCW in primary health facilities with a noteworthy difference between rural and urban settings.. Therefore, advocacy campaigns as well as resource mobilization towards promotion of HBV vaccination in primary health facilities are pivotal.
ARTICLE | doi:10.20944/preprints202305.1517.v2
Subject: Biology And Life Sciences, Virology Keywords: Antiviral; Thiourea derivatives; Hepatitis B Virus; Chronic hepatitis B infection; Mitochondria dysfunction; Exhausted hepatocytes
Online: 29 May 2023 (14:29:16 CEST)
Chronic hepatitis B (CHB) infection and the Hepatitis B virus X protein (HBx) are major risk factors associated with hepatocellular carcinoma (HCC). In CHB infection, HBx induces mitochondrial dysfunction, exhaustion and impaired function in hepatocytes. Restoring hepatocyte health along with reduction in virus replication could be an ideal treatment for CHB. Thiourea derivatives are well known for their antiviral property though their effect on mitochondrial and/ or hepatocyte health remains obscure. This study focus on the repurposing of thiourea derivatives (DSA-00, DSA-02, and DSA-09) on hepatocyte replenishment. HepG2.2.15 cells were treated with thiourea derivatives, alongside Entecavir (ETV). The proteomics analysis showed both DSA-00 and ETV were enriched with proteins associated with antiviral responses. In addition, DSA-00 additionally showed increase in proteins linked to mitochondrial response. Whereas DSA-02 exhibited association with innate immune system and citric acid cycle and DSA-09 displayed pathways similar to DSA-00 and ETV. Treated groups exhibited enhanced bio-energetic and antiviral response as compared to the untreated group. FACS analysis revealed the restoration of exhausted hepatocytes by thiourea derivatives through targeting mitochondria. Our findings suggest that thiourea derivatives hold potential as a novel therapeutic agent that seems to restore mitochondrial health along with anti-viral response in CHB.
REVIEW | doi:10.20944/preprints202311.0804.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: metabolic dysfunction-associated fatty liver disease (MAFLD); chronic viral hepatitis; Hepatitis B virus (HBV); Hepatitis C virus; Hepatic Fibrosis; Cirrhosis; and Hepatocellular carcinoma
Online: 14 November 2023 (05:28:01 CET)
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one third of global population and became the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) also remain significant challenges to liver health even in the 21st century. The coexistence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. Thorough understanding of the pathobiological interlink and interactions between MAFLD and these two chronic viral hepatitis infections are crucial for appropriate management of patients. We update these interlinks in this comprehensive clinical review.
ARTICLE | doi:10.20944/preprints202310.0496.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: viral hepatitis; infectious diseases; notification system
Online: 10 October 2023 (02:53:29 CEST)
The World Health Organization has highlighted the substantial impact of viral hepatitis on individuals, healthcare systems, and economies worldwide. This study's objective is to monitor disease notifications to assess their trend. Data were analyzed from infectious disease notifications detected in the Marche Region (Italy) and entered on the Nuovo Sistema Informativo Sanitario portal between 01/01/2012 and 31/12/2021. In this period there were 399 confirmed reports, of which 47,9% were for hepatitis A, 26,8% for B, 7% for C, 18,3% for E; 67.4% were male and the average age was 43.5 years old. The year with the highest peak was 2017, with 18% of reports, while the year with the lowest number was 2020 followed by 2021, with 3.8% and 4.5% respectively. Effective surveillance systems are key to combating the spread of hepatitis and reducing its impact, although they have been affected by the Sars-CoV-2 pandemic, with many cases remaining undetected.
ARTICLE | doi:10.20944/preprints202306.0252.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: BCG; hepatitis B; vaccination; allergy; atopic eczema
Online: 5 June 2023 (07:57:17 CEST)
Previous studies have shown that immunization within the first hours/days after birth promotes the shift from the intrauterine Th2 immune response toward the Th1 immunity resulting in lower risk of developing allergic diseases. We are currently conducting a prospective cohort study among 307 participants divided into groups based on their TB and hepatitis B vaccination status (vaccinated at birth, within the first 12 months of life or unvaccinated) and also based on whether the participants had factors contributing to the development of allergic diseases. In each group we assessed the fact of primary diagnosis of atopic dermatitis at 12 and 18 months of age. It was demonstrated that atopic dermatitis (AD) was diagnosed from birth to 12 months of age much less frequently in those infants who had received the tuberculosis (TB) vaccine from day 3 to day 7 and hepatitis B vaccine within the first 24 hours of birth, including newborns with a high risk of developing allergic diseases. The probability of onset of AD at 12 and 18 months was also lower in timely vaccinated children, even though a burdened allergic anamnesis starts playing a more central role in development of AD at this age. Our findings testify to the fact that timely BCG-M and hepatitis B vaccination can produce a protective effect against the onset of AD, yet this effect diminishes with aging.
COMMUNICATION | doi:10.20944/preprints202305.1381.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: chronic viral hepatitis; socio-economic status; children
Online: 19 May 2023 (05:07:14 CEST)
In the present research, chronic viral hepatitis in children is approached from a multidisciplinary point of view, considering social status, economic and medical aspects. We conducted a 4-year observational prospective study. A questionnaire regarding the socio-economic status of pediatric patients diagnosed with chronic viral hepatitis B or C was applied. In total, 159 patients were included, 52 % from urban areas, 2.5 % coming from centres for abandoned children. Among 119 school-aged children, 66% were attending classes. All patients are registered with a general practitioner. Regarding the monthly income per family, 49% had less than 1000 RON (5 RON = 1$), of which 17% had no income, 28% had an income ranging between 1000 and 2000 RON and in only 23% of cases the income exceeded 2000 RON (5% had more than 4000 RON). There were between 3 and 12 members per family. Concerning parents` educational level, the average years of study for mothers was 7.8, while for fathers, it was 8.2. For 17 % of children, at least one of the parents was illiterate, and for 5.6 %, both parents were illiterate. For a third of patients, both parents were unemployed. Regarding social living conditions, 38.4% did not have water facilities or sewerage, and 32 % used personal objects (scissors, nail clippers) in common. The socio-economic level can have a significant impact on disease epidemiology (infectiousness) and access to treatment, and it is tightly related to educational level and access to information, which are critical factors in disease prevention through general and specific measures and in disease management (treating infected patients and limiting the transmission).
ARTICLE | doi:10.20944/preprints202301.0003.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: Hepatitis B Virus; Knowledge; Attitude; Practice; Jordan
Online: 3 January 2023 (04:33:04 CET)
The World Health Organization estimated that around 66 thousand HBV are caused by needlestick injuries annually. Healthcare students should be aware of HBV transmission route and preventive measures. This study assessed the knowledge, attitudes, and practices toward HBV among Jordanian healthcare students and its associated factor. A cross-national study conducted from March to August. The participants were asked to complete the questionnaire. It had four sections: participants' sociodemographic, knowledge, attitudes, and practices about HBV. 2322 participants were enrolled, 67.9% were females, 26.4% were medical student, 35.9% were in the 3rd year. 40% of the participants held a high level of knowledge and attitude. 63.9% of participants had good practices toward HBV. Medical students in the last year of study, encountered HBV patients , had better knowledge. Male students from medicine college, encountered HBV patients and had extra HBV courses showed better attitude. High practice level was associated with being dentistry student, at 5th year, encountered HBV patient and extras HBV courses. This study demonstrated insufficient knowledge and attitudes toward HBV, the practices level toward HBV among healthcare students was promising. Subsequently, public health efforts should modify the knowledge and attitude gaps to reinforce awareness and minimizing risks of the infection.
ARTICLE | doi:10.20944/preprints202307.1845.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: hepatitis D; prevalence; anti-HDV antibody; HDV RNA
Online: 27 July 2023 (10:26:46 CEST)
Background: It is assumed that the prevalence of hepatitis D in HBsAg-positive individuals reaches 4.5-13% in the world, and on average about 3% in Europe. Data from several European countries, including Slovakia, are missing or are from an older period. Methods: We analyzed all available data on hepatitis D from Slovakia, including reports from the Slovak Public Health Authority and the results of one prospective study, and three smaller surveys. The determination of anti-HDV IgG and IgM antibodies and/or HDV RNA was used to detect hepatitis D. Results: In the years 2005-2022, no confirmed case of acute or chronic HDV infection was reported in Slovakia. The presented survey includes a total of 343 patients, of which 126 were asymptomatic HBsAg carriers, 33 acute hepatitis B, and 184 chronic hepatitis B cases. In a recent prospective study of 206 HBsAg-positive patients who were completely serologically and virologically examined for hepatitis B and D, only 1 anti-HDV IgG positive and no anti-HDV IgM or HDV RNA positive cases were detected. In other smaller surveys, 2 anti-HDV IgG positive patients were found without the possibility of HDV RNA confirmation. In total, only 3 of 329 HBsAg-positive patients (0.91%) tested positive for anti-HDV IgG antibodies and none of 220 tested positive for HDV RNA. Conclusion: The available data show that Slovakia is one of the countries with a very low prevalence of HDV infection reaching less than 1% in HBsAg-positive patients. Routine testing for hepatitis D is lacking in Slovakia, and therefore it is necessary to implement testing of all HBsAg-positive individuals according to international recommendations.
ARTICLE | doi:10.20944/preprints202305.1690.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis B; anti HBcore; risk factors; blood donors
Online: 24 May 2023 (04:37:56 CEST)
Background and Aim. Recently made analysis for anti-HBcor prevalence within Kazakhstan blood donors population concluded 17.2% rate. Considering these data are among the highest of infectivity results worldwide, an objective of this study was to define an association of positive Hepatitis B serology markers with risk and behavior factors. Methods. The blood donors’ samples were tested for anti-HBcore total (IgG/IgM) and anti-HBs, by CLIA on the Architect i2000SR platform (Abbott). Surrogate alanine transferase (ALT) markers for all blood donors were tested by kinetic method on the Biosystems A25 analyzer. A questionnaire was developed for socio-demographic characteristics, donors’ nutrition habits, cholesterol levels and history of smoking, alcohol consumption. Informed consent was obtained from all study participants. Statistics was calculated using the R software program (version 4.1.1, USA, 2021). Results. A group of 5709 blood donors participated in the study. Participants with positive anti-HBcore scores were on average older (41.8 vs 34.4 years, p<0.001), Kazakh (88.7% vs 83.0%, p<0.001), married (74.0% vs 55.6%, p<0.001), had a secondary education (70.1% vs. 59.4%, p=0.03), smoked (27.9% vs. 24.3%, p=0.05), had a longer smoking history (13.6±9.5 years vs. 9.8±8.5 years, p<0.001), and various hypercholestesterolaemia (6.2% vs 3.9%, p=0.02). Predominantly their main meal was dinner (17.0% vs 14.2%, p=0.03). Analysis for associations of socio-demographics characteristics, risk factors, nutrition with anti-HBs, showed that those who have secondary education level (70.1%) were more likely to be anti-HBs-positive (p=0.03). No other significant correlations for anti-HBs were observed. Conclusions. The risk factors and behavior analysis highlighted the blood donors’ overall health status. Positive Hepatitis B markers associated with statistically significant characteristics from socio-demography, nutrition habits or risk factors could support further pathogenesis studies looking for HBV treatment guides fulfilling the existing gaps.
REVIEW | doi:10.20944/preprints202305.0149.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: Acute liver failure; viral hepatitis; sub-Saharan Africa
Online: 3 May 2023 (12:40:38 CEST)
Though there has been a decline in the number of new cases of viral hepatitis-induced acute liver failure in Europe and the United States of America, viral hepatitis still remains the leading cause of acute liver failure in Asia-Pacific and South America. However, the epidemiology of viral-hepatitis-induced acute liver failure in sub-Saharan Africa-the world epicenter of viral hepatitis-is unclear. The aim of this review was to collate data on the incidence, prevalence, specific etiologic agents, features/diagnosis, treatment and prognosis of viral-induced acute liver failure in sub-Saharan Africa. One hundred and forty-seven cases of viral-induced acute liver failure were recorded in 11 studies conducted in six countries between 1981-2020. Etiological agents were: Hepatitis viruses A, B, C, and E, as well as Adenovirus, Enterovirus, Parvovirus, Herpes Simplex Virus (HSV) and EBV. HAV was the most frequent in paediatric subjects: (11/16) 69% and (19/30) 63%. HBV was the only etiological agent in the study that only included adults. HEV (genotype 2 in one study) contracted amidst hepatitis E outbreaks was the most commonly reported cause of ALF in pregnant women. Treatment was mainly supportive, and liver transplantation reported only in South Africa. Where reported, case fatality rates were high. In conclusion, viral-hepatitis induced acute liver failure is largely understudied in sub-Saharan Africa. The few available data are consistent with literature from the other parts of the world regarding aetiologic agents. Liver transplantation is not available in most sub-Saharan African countries, and short-term case fatality rates of individuals with acute liver failure could outstrip current rates from the other world regions.
CASE REPORT | doi:10.20944/preprints202302.0506.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: atypical; coinfection; Hepatitis B; human immunodeficiency virus; monkeypox
Online: 28 February 2023 (04:51:43 CET)
Mpox (monkeypox) is a zoonotic disease that has been endemic in African countries for decades, with a recent outbreak in several countries around the world. A 39-year-old male with HIV-HBV coinfection and poor adherence to antiretroviral treatment, who was severely immunocompromised and had a concurrent diagnosis of Mpox infection, presented to our hospital with disseminated dermatosis (over 350 lesions), perianal ulcers, odynophagia, oral intolerance, diarrhea, and soft-tissue bacterial superinfection of the lower extremities. Laboratory results were consistent with HBV infection, with an absolute CD4 cell count of 40 cells/uL and a positive PCR result for Mpox. An abdominopelvic CT scan showed evidence of severe proctitis and perineal soft-tissue infection. After 65 days of Mpox PCR, new lesions in the vesicular stage continued to appear, eventually developing hemodynamic instability and sepsis, resulting in a fatal outcome. Our case highlights the importance of intentionally looking for risk factors such as HIV/HBV coinfection and evaluating immune status (CD4 cell count) in patients with severe Mpox infection because it could be related to higher mortality.
ARTICLE | doi:10.20944/preprints201810.0448.v1
Subject: Biology And Life Sciences, Virology Keywords: liver stiffness; MERTK; chronic hepatitis C; cirrhosis; SNPs
Online: 19 October 2018 (10:56:19 CEST)
Background: The myeloid-epithelial-reproductive tyrosine kinase (MERTK) is involved in hepatic steatosis, inflammation and liver fibrosis. Here we evaluated the association between the MERTK rs4374383 single nucleotide polymorphism (SNP) and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. Methods: We performed a retrospective study (repeated measures design) in 208 patients who had liver stiffness measurement (LSM), which was assessed by transient elastography No patient had cirrhosis at baseline (LSM≥12.5 kPa). Results: At baseline, 53.8% were male, the median age was 47.1 years, 13.5% reported a high intake of alcohol, 10.1% were prior injection drug users, 85.3% were infected by HCV genotype 1, and 22.6% had previously failed antiviral therapy (pegylated-interferon-alpha/ribavirin). During a median follow-up of 46.6 months, 26 patients developed cirrhosis. The rs4374383 G carriers had a higher risk of increasing LSM (adjusted arithmetic mean ratio (aAMR)=1.14; p=0.006) and a higher likelihood of having an increase in LSM greater than 5 kPa (ΔLSM≥5 kPa) [adjusted odds ratio (aOR)=2.37; p=0.029], and greater than 7 kPa (ΔLSM≥7 kPa) [aOR=3.24; p=0.032], after controlling for confounding. The SNP’s association with cirrhosis progression was close to statistical significance (aOR=2.18; p=0.070). Conclusions: MERTK rs4374383 A carriers had a lower risk of liver fibrosis progression than G carriers, supporting the hypothesis that this SNP seems to have a critical role in the pathogenesis of liver disease in HCV-infected patients.
ARTICLE | doi:10.20944/preprints202307.2140.v1
Subject: Biology And Life Sciences, Virology Keywords: hepatitis B; HBeAg; rapid diagnostic test; ELFA; Burkina Faso
Online: 2 August 2023 (08:51:48 CEST)
Hepatitis B e antigen (HBeAg) is a marker of wild-type hepatitis B virus replication. In resource-limited countries where access to enzyme-linked immunosorbent assay (ELISA) remains a challenge, rapid diagnostic tests (RDT) constitute a good alternative. The HBeAg status is employed to evaluate eligibility for antiviral therapy and to prevent the transmission of hepatitis B from mother to child (PMTCT). The objective of this study was to assess the diagnostic performance of the SD-Bioline®HBeAg RDT commonly used for detecting HBeAg in laboratories in Burkina Faso. The sample panel used was collected from HBsAg positive patients received in the laboratory for the detection of HBeAg with the rapid test. The samples were retested for HBeAg using the VIDAS HBe/Anti-HBe enzyme-linked fluorescent assay (ELFA) (Gold standard). Then, the viral load (VL) of HBV DNA was determined using the GENERIC HBV CHARGE VIRLAE kit (GHBV-CV). The diagnostic performances of the SD-Bioline®HBeAg and its agreement with the gold standard were calculated with their 95% confidence intervals. 340 sera obtained from HBsAg positive patients were included in this evaluation Compared to the VIDAS HBe/Anti-HBe ELFA test, the sensitivity (Se) and specificity (Sp) of the SD-Bioline®HBeAg test were 33.3% and 97.9% respectively. The concordance between the two tests was 0.42. Depending on the viral load, the Se and Sp varied from 8.8% and 98.3% for a VL < 2,000 IU/mL to 35.5% and 98.4% for a VL > 2,000,000 IU/mL. The results showed a low Sensibility of the SD-Bioline®HBeAg RDT test, indicating that its use is inappropriate for the clinical management of HBV-infected patients. They also highlight the urgent need to develop HBeAg rapid tests with better sensitivities.
REVIEW | doi:10.20944/preprints202205.0024.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Outbreak; novel; unknown hepatitis; unknown aetiology; public health promotion
Online: 5 May 2022 (08:02:13 CEST)
Several clusters and individual cases of acute —often severe— hepatitis have been reported in Europe —mainly in the United Kingdom (U.K.)—, the United States (U.S.) and recently in Asia since October 2021. Laboratory investigation of the common viral hepatitis agents (HAV, HBV, HCV, HDV and HEV) yielded negative results prompting the use of the term “acute non hepA–E hepatitis” to describe this condition. The cases were characterized by the manifestations of acute hepatitis (abdominal pain, vomiting, diarrhea, jaundice and very high levels of liver enzymes) affecting children with a median age of 3–4 years. The exact underlying etiology has not been revealed yet; however, a leading hypothesis is that an infectious agent is the culprit underlying cause or at least a risk factor for acute non hepA–E hepatitis occurrence. So far, laboratory testing has shown the presence of adenovirus serotype 41 (Ad–41) which is classified in group F of adenoviruses in about three-fourths of the reported cases. However, the definitive link between adenoviruses and acute non hepA–E hepatitis has not been fully elucidated, which necessitates further investigation of this possible correlation. As of the end of April 2022, more than 200 cases were reported worldwide, the majority of which were in Europe: the U.K. (n=114), Italy (n=17), Spain (n=13), Israel (n=12), the U.S. (n=9), Denmark (n=6), Netherlands and Ireland (n=4), Japan (n=3), Austria, Belgium, France, and Norway (n=2), Germany, Poland, and Romania (n=1). Possible cases are being evaluated in Illinois, Minnesota, North Carolina, Wisconsin states of the U.S., Canada, Singapore and Slovenia. Vigilant surveillance and epidemiologic investigation to identify further cases are warranted at the global level to delineate the features of this emergent public health issue. The possible role of environmental and toxic agents including foodborne toxins should not be overlooked as well. Specific guidelines for identification of further cases is necessary particularly in low-income settings where testing for adenoviruses is not considered routinely. Genetic analysis of Ad–41 isolates is recommended to assess the potential changes in virus genome with subsequent possible altered virus behavior. Immunopathogenesis is another possibility that should be examined as well considering the absence of virus detection in liver biopsies of the affected children in the U.S.
ARTICLE | doi:10.20944/preprints202102.0352.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: hepatocellular carcinoma; hepatitis B; growth factors; biomarkers; antibody array
Online: 17 February 2021 (09:36:17 CET)
Background: Hepatocellular carcinoma (HCC) is one of most common cancers with a high mortality rate. HBV/HCV infection is an important risk factor to trigger HCC. Therefore, developing serum biomarkers for early diagnosis is crucial to prolong survival in HCC patients. Methods: An antibody array technology was utilized to detect serum from 20 HBV-related HCC patients, 20 chronic hepatitis B patients and 20 normal population, whose results were further validated by ELISA. Results: Both antibody array and ELISA showed that ten growth factors (SCF R, GDF-15, HGF, FGF-4, IGFBP-1, PIGF, GH, GDNF, BDNF and IGF-1) were significantly differential in HCC patients when compared to the non-HCC population. Among these growth factors, the levels of SCF R, GDF-15, HGF, GH and IGF-1 showed significant correlation with hepatitis B and its severity, indicating that these growth factors may promote HCC progression by an HBV-specific mechanism. A therapy targeting these growth factors in hepatitis B patients may help to prevent the development of HCC. FGF4 and GH were found, for the first time, to be upregulated in HCC, suggesting that these two growth factors may serve as novel serum biomarkers for the early diagnosis of HCC. Conclusion: The combined detection of all the differential growth factors may improve the diagnostic accuracy of HCC.
ARTICLE | doi:10.20944/preprints202304.0236.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: Fowl adenovirus; phylogenetic; hydropericardium hepatitis syndrome; gross lesions; Chickens; Azerbaijan
Online: 12 April 2023 (04:00:51 CEST)
Hydropericardium hepatitis syndrome (HHS) caused by fowl adenovirus-4 have been frequently reported in commercial chickens from several countries causing significant economical losses. In Azerbaijan, fowl adenovirus infections in broiler and layer breeders flocks cause severe disease and mortality. Here we investigated the pathological lesions and the dissemination of fowl adenovirus-4 into the visceral organs of infected birds. Tissue samples containing liver, heart and spleen from 20 necropsied chickens were collected on the FTA cards and presence of fowl adenovirus was analysed by PCR and sequencing. Postmortem findings of both broiler and layer breeder chickens were similar, and the most affected organs were the liver with hepatitis and the heart with hydropericardium lesions. Other postmortem signs include swollen kidneys with haemorrhages and small white foci on the surface of the spleens. In some birds intestinal congestion and ecchymotic hemorrhages were also apparent. The PCR analysis revealed that all collected organs from 20 birds showed presence of fowl adenovirus-4 genome. The sequence analysis showed that fowl adenovirus-4 prevalent in Azerbaijan carry more closer phylogenetic relationship with the viruses prevalent in the Middle East, Far East and Indian subcontinent. However, a distinct diversity was seen from the strains prevalent in Europe, North and South America. This study will provide evidence the impact of fowl adenovirus-4 on the poultry production and improved preventive disease control strategies are required to reduce the HHS disease in chickens in Azerbaijan.
REVIEW | doi:10.20944/preprints202205.0370.v1
Subject: Biology And Life Sciences, Virology Keywords: Acute non hepA–E hepatitis; clinical manifestations; epidemiological characteristics; prevention
Online: 27 May 2022 (08:41:42 CEST)
The emergence of acute, severe non hepA–E hepatitis of unknown etiology (ASHUE) has attracted global concern owing to the very young age of the patients and its unknown etiology. Although this condition has been linked to several possible causes, including viral infection, drugs, and/or toxin exposure, the exact cause remains unknown; this makes treatment recommendations very difficult. In this review, we summarize recent updates on the clinical manifestations, complemented with laboratory results, case numbers with the global distribution and other epidemiological characteristics, and the possible etiologies. We also provide the proposed actions that could be undertaken to control and prevent further spread of this hepatitis. Since many etiological and pathological aspects of the acute non hepA–E hepatitis remain unclear, further research is needed to minimize the severe impact of this disease.
ARTICLE | doi:10.20944/preprints202012.0732.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: trace element; liver transplantation; selenoprotein P; glutathione peroxidase; hepatitis C virus
Online: 29 December 2020 (15:18:30 CET)
The trace element selenium (Se) is taken up from the diet and becomes metabolized mainly by hepatocytes. Selenoprotein P (SELENOP) constitutes the liver-derived Se transporter. Biosynthesis of extracellular glutathione peroxidase (GPx3) in kidney depends on SELENOP-mediated Se supply. We hypothesized that Se status may serve as a useful prognostic marker for outcome in patients undergoing liver transplantation. Serum samples from patients were routinely collected before and after transplantation. Concentration of serum SELENOP and total Se as well as GPx3 activity were determined by standardized tests and related to survival, aetiology and pre-operative Child-Pugh and Model for End-Stage Liver Disease Scores. A total of 314 serum samples from 78 transplanted patients were available for analysis. The Se and SELENOP concentrations were on average below the reference ranges of healthy subjects. Patients with ethanol toxicity-dependent aetiology showed particularly low SELENOP and Se concentrations and GPx3 activity. Longitudinal analysis indicated declining Se concentrations in non-survivors. We conclude that severe liver disease necessitating organ replacement is characterized by a pronounced Se deficit before, during and after transplantation. A recovering Se status after surgery is associated with positive prognosis, and an adjuvant Se supplementation may thus support convalescence.
REVIEW | doi:10.20944/preprints202009.0706.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Chronic hepatitis B; NAFLD; NASH; biomarkers; magnetic resonance technology; NAFLD therapy
Online: 29 September 2020 (10:40:21 CEST)
Hepatitis B virus (HBV) infection remains a global public problem despite the availability of effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD, thus, reaches endemic in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining the disease severity, but it is an invasive procedure with potential complications. There is a growing body of literatures on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated especially for patients with CHB. Currently, there is no approved therapy for NAFLD though many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.
REVIEW | doi:10.20944/preprints202308.1670.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: Africa; birth-dose; hepatitis B; health systems; maternal and child health; vaccine
Online: 23 August 2023 (11:52:04 CEST)
The persistent burden of chronic hepatitis B among ≤5-year-old children in Africa suggests missed opportunities for controlling mother-to-child transmission (MTCT) of the hepatitis B virus (HBV). This scoping review maps the evidence base on the risk of HBV MTCT, the status of HBV MTCT mitigation strategies including hepatitis B birth-dose vaccination, and the role of systems complexity on the suboptimal adoption and performance of hepatitis B birth-dose vaccination programs in Africa. Overall, 88 peer-reviewed and grey literature sources published between 2000–2022 were included in this review. The evidence base consistently argues for a growing risk of HBV MTCT amidst the HIV co-epidemic in the region. Without universal HBV screening programs integrated within broader antenatal care services, current selective hepatitis B birth-dose vaccination is unlikely to effectively interrupt HBV MTCT. We underscore critical health systems-related barriers to universal adoption and optimal performance of hepatitis B birth-dose vaccination programs in the region. To better conceptualize the role of complexity and system-wide effects on the observed performance of the program, we propose an adapted systems-based logic model. Ultimately, exploring contextualized complex systems approaches to scaling-up universal hepatitis B birth-dose vaccination programs should form an integral part of the regional research agenda.
ARTICLE | doi:10.20944/preprints202310.1076.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Hepatocellular carcinoma (HCC); Human immunodeficiency virus (HIV); hepatitis; inflammatory cytokines; mitochondria DNA deletion
Online: 17 October 2023 (11:46:43 CEST)
Hepatocellular carcinoma (HCC) is a non-AIDS-defining cancer closely tied to the chronic HIV infection and associated with the release of inflammatory cytokines, immune system dysfunction, and genetic alterations within mitochondria. However, our understanding of how these factors contribute to HCC risk in PLWH is limited. The objective of the study was to ascertain the differential secretion of cytokines and mitochondria DNA (mtDNA) deletion in PLWH, and individuals diagnosed with HCC without HIV. A cross-sectional study was conducted with PLWH and HCC participants from the Korle-Bu Teaching Hospital. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood. The plasma samples were used to measure cytokines using ELISA and Luminex techniques. We determined mtDNA deletions from PBMCs. We found that the secretion of the cytokines TGF-β, FGF-2, IL-8, TNF-α, VEGF, and RANTES implicated in the pre-cancer, initiation, and early stages of HCC were similar in PLWH compared to HCC participants without HIV. PBMCs of PLWH exhibited high mtDNA deletion (60%) comparable to HCC participants without HIV (64%). These findings underscore the underlying risks associated with HCC development in PLWH. There is a need for HCC surveillance among PLWH and these cytokines could be used as biomarkers.
ARTICLE | doi:10.20944/preprints202309.2059.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Total serum bile acids; antipyrine clearance; liver-spleen scan; chronic hepatitis; liver cirrhosis; AUROCs
Online: 30 September 2023 (10:08:10 CEST)
Background Total serum bile acids (TSBA), liver-spleen scan and dynamic liver functional tests, in our case the antipyrine clearance (Ap Cl), have been long adopted. The aim of our study was that of assessing whether some diagnostic tests, scarcely performed due to the novel techniques implementation, were reliable diagnostic tools. Methods Data extracted from records of two well-matched for age and gender populations was retrospectively analysed. Specifically, 17 patients with biopsy-proven chronic hepatitis were confronted with 17 subjects suffering from liver cirrhosis. Clinical, laboratory and instrumental findings, such as the Child-Pugh classification, the number connection test for evaluating hepatic encephalopathy, prothrombin time, serum albumin levels, TSBA concentration, Ap Cl determination, abdominal ultrasound and liver-spleen scan imaging as well as endoscopy features were evaluated. Results Cirrhotics showed a median concentration of TSBA increased respect to that of patients with chronic hepatitis, independently from gender, 20.1 versus 12.24 micromol/L, P= 0.0054. The median AP Cl value of the patients with liver cirrhosis was reduced confronted with that of patients with chronic hepatitis, specifically, 13.92 opposed to 18.3 mcg Ap/dL, P= 0.045. Furthermore, the median liver-spleen scan score was higher in cirrhotics than in chronic hepatitis patients, i.e., 3.47 versus 1.47, P= 0.000. The AUROCs of TSBA levels and of the liver-spleen scan scores for differentiating patients with liver cirrhosis from those with chronic hepatitis were 0.82 and 0.96, respectively. When was applied a new predictive model, combining the previous ones, the AUROC to discriminate patients belonging to the two populations was 0.98. The best cut-off of the new index was 26, with a sensitivity and specificity of 100.00% and 82.35%, respectively, correctly classifying 91.18% of the patients. Discussion Both TSBA and liver-spleen scan were high discriminant as well as their combination, while Ap Cl showed some limitations as reliable diagnostic tool. TSBA and liver-spleen scan have been too soon and unnecessarily overlooked.
REVIEW | doi:10.20944/preprints202308.1082.v1
Subject: Biology And Life Sciences, Virology Keywords: Hepatitis B virus; HBV genotype H; immune response; metabolic interaction; clinical outcome; viral adaptation
Online: 15 August 2023 (08:50:43 CEST)
Hepatitis B Virus (HBV) is a challenge for global health services, affecting millions and leading hundreds to end-stage liver disease each year. This comprehensive review explores the interactions between HBV and the host, examining their impact on clinical outcomes. HBV infection encompasses a spectrum of severity, ranging from acute hepatitis B to chronic hepatitis B, which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B infection (OBI), characterized by low HBV DNA levels in hepatitis B surface antigen-negative individuals, can reactivate and cause acute hepatitis B. The identification of diverse HBV genotypes reveals distinct geographical distributions and associations with clinical outcomes. Moreover, single nucleotide polymorphisms (SNPs) within the host genome have been linked to several clinical outcomes, including cirrhosis, HCC, OBI, hepatitis B reactivation, and spontaneous clearance. The immune response plays a key role in controlling HBV infection by eliminating infected cells and neutralizing HBV in the bloodstream. Furthermore, HBV can modulate host metabolic pathways involved in glucose and lipid metabolism and bile acid absorption, further influencing disease progression. HBV clinical outcomes correlate with three levels of viral adaptation. In conclusion, the clinical outcomes of HBV infection could result from complex immune and metabolic interactions between the host and HBV. These outcomes can vary among populations and are influenced by HBV genotypes, host genetics, environmental factors, and lifestyle. Understanding the degrees of HBV adaptation is essential for developing region-specific control and prevention measures.
ARTICLE | doi:10.20944/preprints202303.0085.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Chronic hepatitis B infection; Therapeutic vaccines; Regulatory T cells; Functional cure; GMI-HBVac; Mafosfamide
Online: 6 March 2023 (03:37:38 CET)
Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B virus (CHB) infection is characterized by elevated levels of immunosuppressive regulatory T cells (Tregs), which can inhibit the function of effector T cells and lead to an insufficient immune clearance response against HBV in the host. Theoretically, suppression of Treg functionality and percentage could increase anti-HBV reactivity in CHB-infected patients, although this has not yet been explored. We attempted to enhance our previously established anti-CHB protocol utilizing the GM-CSF+IFN-α+rHBVvac regimen (GMI-HBVac) by incorporating Mafosfamide (MAF), which has been utilized in anticancer therapy in the past. Intravenous administration of MAF to rAAV8-1.3HBV-infected mice resulted in a dose-dependent reduction of Tregs in the blood, rebounding to pretreatment levels 10 days later. To determine the efficacy of anti-CHB, 2ug/ml MAF was combined with the GMI-HBVac in an HBV-infected animal model as an anti-Treg treatment. When rAAV8-1.3HBV-infected mice were immunized with MAF+GMI-HBVac, peripheral blood Tregs decreased significantly, leading to dendritic cell activation, HBV-specific T cell proliferation, and upregulation of IFN-gamma producing CD8+T cells. In addition, MAF+GMI-HBVac vaccination stimulates T cell infiltration in HBV-infected liver. These conditions may contribute to an enhanced immune response and the clearance of HBV-associated antigens, including serum HBsAg, serum HBcAg, and HBcAg+ hepatocytes. Overall, this is the first indication that MAF was utilized as an adjuvant to deplete Tregs and paired with GMI-HBVac as a unique therapeutic vaccine regimen against established CHB mice to produce a functional cure, as seen by the remarkable clearance of HBsAg.
ARTICLE | doi:10.20944/preprints202107.0585.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Functional receptor; Hepatitis B virus; Polymorphism; Sodium taurocholate co-transporting polypeptide; hepatic fibrosis; Egypt
Online: 26 July 2021 (14:42:42 CEST)
Background: Single nucleotide polymorphisms (SNPs) in the SLC10A1 gene, coding for a functional receptor of hepatitis B virus (HBV), sodium taurocholate co-transporting polypeptide (NTCP), may influence the susceptibility, the outcome, and disease course of HBV infection in some populations. Aim: to determine the prevalence of SNPs of NTCP gene, rs2296651 and rs943277, and their relationship with chronic HBV infection in a group of Egyptian patients. Methods: 137 patients with HBV and 65 healthy controls were enrolled, and the patients were divided into two groups; group I chronic HBV infection (68 patients with normal ALT and minimal or no liver necroinflammation or fibrosis) and group II chronic hepatitis B (69 patients with elevated ALT and moderate or severe liver necroinflammation). They were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound, and liver stiffness measurement using both Echosens® Fibroscan and acoustic radiation force impulse (ARFI). Real time PCR TaqMan 5’ allelic discrimination assay was applied to detect the SNPs in NTCP gene, rs2296651 and rs943277. Results: On studying the rs2296651 variant, all controls and patients had genotype GG without any significant association with HBV infection or disease progression. However, the rs943277 variant in all controls and 98% of patients had genotype GA, except for two chronic HBV infection patients who had genotype AA, but no significant difference between patients and controls was found. The non-invasive methods for liver fibrosis assessment ARFI, AST/platelet's ratio (APRI), and fibrosis-4 score (FIB-4) could predict the stages of fibrosis in agreement with Fibroscan with AUCOR 0.8, 0.79, and 0.76, respectively. Conclusion: These findings may suggest that there is no relation between these SNPs of the NTCP gene and susceptibility or chronicity of HBV infection in the Egyptian population. We also suggest that the use of the non-invasive methods for liver fibrosis assessment, ARFI, FIB-4, and APRI may decrease the need for liver biopsies in prediction of significant hepatic fibrosis in chronic HBV patients.
REVIEW | doi:10.20944/preprints201907.0282.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: HBV reactivation; lymphoma; hematology; immunosuppressive therapy; prophylaxis; hepatitis B virus; occult/active/inactive carrier
Online: 25 July 2019 (07:46:43 CEST)
It is well known that the event of hepatitis B virus reactivation can occur among patients undergoing treatment for hematological malignancies. In this paper we will present the available data regarding the risk of hepatitis B virus reactivation in this special population of immunosuppressed patients and explore the relevance of an accurate prevention and management of this condition. A computerized literature search was performed using appropriate terms arrangement, including English-written literature only or additional relevant articles. The evaluation of hepatitis B reactivation risk is a multidimensional process, which includes conducting an accurate clinical and physical history, considering the virological categories, the knowledge of the medication chosen to treat these hematological malignancies and the induced grade of immunosuppression. Adopting adequate preventive strategies and surveillance according to the current international recommendations is crucial to prevent HBVr and its dire clinical consequences (hepatitis, liver failure, interruption of lifesaving anti-neoplastic treatments). Universal HBV screening of patients scheduled to undergo treatment for hematological malignancies should be the chosen policy, and clinicians should be aware of the inherent risk of viral reactivation among the different virological categories and the classes of immunosuppressive drugs.
ARTICLE | doi:10.20944/preprints202310.1682.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Atezolizumab; bevacizumab; non-alcoholic fatty liver disease; non-alcoholic steato hepatitis; albumin-bilirubin (ALBI) score
Online: 26 October 2023 (09:01:45 CEST)
(1) Background: Although multiple studies have reported on the therapeutic effects of Atezo+Bev for the treatment of NASH-related liver cancer, few studies have focused on its effect on liver reserve. Here, we aimed to compare the changes in hepatic reserve during the Atezo+Bev treatment of NAFLD/NASH-related HCC and of non-NAFLD/non-NASH-related HCC. (2) Methods: We retrospectively compared the changes in ALBI score in 109 patients with NAFLD/NASH or non-NAFLD/non-NASH during 12 weeks of treatment with Atezo+Bev for advanced HCC between September 2019 and January 2022. PSM was performed, and the OS, PFS, and PPS of the two groups were compared. (3)Results: The ALBI after 12 weeks of Atezo+Bev treatment was significantly worse in the NAFLD/NASH group than in the non-NAFLD/non-NASH group. Analysis of the 24 propensity score-matched pairs of cases with NAFLD/NASH or non-NAFLD non-NASH yielded similar results. The prognoses of the two groups were similar with respect to OS and PFS, but the NAFLD/NASH group had a significantly shorter PPS. The 24 matched pairs had similar OS and PFS, but the PPS of the NAFLD/NASH group was shorter. (4)Conclusion: Atezo+Bev treatment may worsen hepatic reserve, and there-fore life expectancy, in patients with NAFLD/NASH-related liver cancer.
ARTICLE | doi:10.20944/preprints202209.0175.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: sexually transmitted infection (STI); HIV; viral hepatitis; transgender persons; in-depth interviews (IDIs); formative research
Online: 12 October 2022 (14:57:14 CEST)
Background: Sexualized substance use (SSU) is the practice of psychotropic substance usage, before or during sexual intercourse in order to increase sexual pleasure and arousal. It has a strong association with sexually transmitted infections (STIs). The present study aimed to assess the knowledge gaps regarding SSUs among the community health mobilizers by interviewing them regarding their knowledge, attitudes, and practices through qualitative approach. Methodology: In-depth interviews (IDIs) were conducted with a total of nineteen community health mobilizers engaged in counselling of sexualized substance users. A semi-structured open-ended questionnaire with socio-demographic information and probes related to SSU was administered. Informed consent was taken from each participant prior to data collection. Results: Gender-wise distribution indicated that 47% of the community mobilizers are men, followed by transgender persons (32%), and women (21%). Responses of participants highlighted that alcohol consumption was the most observed form of SSU. The findings indicated that drug administration through injection was most common, followed by sniffing and swallowing. Sources of drug pro-curement enlisted by participants included peddlers, peer groups, sexual parties, medical and liquor stores. Only 63% of participants had fair knowledge about STIs such as HIV, viral hepatitis, syphilis, and gonorrhoea. All were familiar with the administration of naloxone injections and the locations of nearby hospitals where patients could be transported in the event of an overdose. Conclusions: The in-depth interviews among the study participants reflected substantial know-ledge gaps related to various areas associated with SSU, which highlights the need for periodic workshops and training for upgradation of existing knowledge and practices among community health mobilizers. This will help to broaden their knowledge of different types of SSUs, the latest substances of abuse, the diseases caused by high-risk sexual practices, and additional health and psychological issues associated with SSUs, which would ultimately help in better counseling and management of sexualized substance users. It may also play a crucial role in the strengthening of capacity-building systems and engagements at the community level. This study may be used as formative research by researchers and policy makers to develop study protocols for multi-centric community-based studies among community health mobilizers and sexualized substance users across the country for further validation and exploration.
ARTICLE | doi:10.20944/preprints202104.0692.v1
Subject: Biology And Life Sciences, Virology Keywords: RACK1; HIV-1; IRES; Hepatitis C; HCV; AZT; HTA; Host-targeted antiviral; HEK293T; SD29-14
Online: 26 April 2021 (20:35:00 CEST)
Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.
ARTICLE | doi:10.20944/preprints202311.1267.v1
Subject: Biology And Life Sciences, Virology Keywords: new hepadnaviruses; hepatitis B virus; animal model; HBV cure; viral infection; metagenomics; next-generation sequencing (NGS)
Online: 21 November 2023 (09:59:58 CET)
Background: With continuous advances in next-generation sequencing (NGS), novel hepadnaviruses have been discovered in many species over the last 10 years. Methods: In this study, the cloud search and analysis of NGS data published in Nature by Edgar et al. was used as a basis to re-mine and reanalyze public NGS data for new hepadnaviruses. Results: Ultimately, at least 41 new species of hepadnaviruses were identified, including hepadnaviruses from the model animals hamster and mouse, frog hepadnavirus with pan-species infectivity, and diverse African cichlid hepadnaviruses that circulate within populations. Conclusions: The discovery of the new species of hepadnaviruses not only provides new clues for the study of the origin and evolution of hepadnaviruses, but also can be used to construct new hepadnavirus animal infection models, which will be helpful for the research of eradicative drugs for hepatitis B virus (HBV).
ARTICLE | doi:10.20944/preprints202308.2088.v2
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: acute cellular rejection; anti-HCV antibody; biliary complications; direct-acting antivirals; hepatitis C virus; liver transplantation
Online: 3 November 2023 (14:38:36 CET)
Background and Aims: The impact of antibody response after direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. Methods: In this observational cohort study, we aimed to explore the association of changes in anti-HCV antibody titers after pre-LT DAA therapy with allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). Results: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (DAA-naïve group). Higher incidence of post-LT BCs was observed in the DAA group (P = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (P = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (P < 0.005). Conclusion: In conclusion, we speculated that anti-HCV antibody titer upregulation, which might have been induced by restoration of HCV-specific immune responses with pre-LT DAA therapy, were associated with post-LT allograft injury.
ARTICLE | doi:10.20944/preprints202206.0240.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: artifacts; confounders; infant mortality rate; linear regression analysis; vaccination rates; vaccines; vaccine doses; hepatitis B vaccine
Online: 16 June 2022 (11:00:46 CEST)
Background—In 2011, Miller and Goldman published a study in Human and Experimental Toxicology that found a counterintuitive, positive correlation, r = 0.70 (r2 = 0.49, p < .0001), demonstrating that as nations require more vaccine doses for their infants, infant mortality rates (IMRs) tend to increase (worsen). The dataset (n = 30) included the United States, a nation that required the most vaccines for their infants, and all nations with better IMRs than the United States. Dr. E. Bailey, a professor at BYU, and her students, recently read the Miller-Goldman study and found it "troublesome that this manuscript is in the top 5% of all research outputs" and falsely claimed that its findings were due to "inappropriate data exclusion," i.e., failure to analyze the "full dataset" of all 185 nations. The "Bailey reanalysis," titled Infant vaccination does not predict increased infant mortality rate: correcting past misinformation, was posted to the medRxiv preprint server on September 10, 2021 (version 1) and October 5, 2021 (version 3) and Europe PMC preprint server on September 10, 2021. Objective—This present study examines the various claims postulated by the Bailey reanalysis and assesses the robustness of their methodology, analyses, and reported results and conclusions. Methods—Data discussed in this paper are based on the previously mentioned study by Miller and Goldman and the Bailey reanalysis. Results—Linear regression analysis of IMR and the number of vaccine doses for each country yield a statistically significant positive correlation of r = 0.70 (p < .0001) for the top nations (n = 30) chosen by Miller-Goldman and r = 0.16 (p < .04) for the "entire dataset" chosen by Bailey et al (n = 185). Bailey also conducted linear regression analyses (for the year 2019) of IMRs as a function of vaccination rates for each of eight different vaccines and reported statistically significant inverse correlations for 7 of 8 vaccines over the entire range of vaccination rates. However, Miller and Goldman reanalyzed the Bailey analyses for nations with vaccination rates below 60% and found no statistically significant correlation for six vaccines (DPT, Hib, hepatitis B, polio, rotavirus, and measles) and statistically significant positive correlations for tuberculosis (r = 0.8, p < .005) and pneumococcal (r = 0.6 p < .023) vaccines. Conclusions—Bailey’s reanalysis corroborates a statistically significant positive correlation originally reported by Miller and Goldman. However, Bailey’s reported correlation (r = +0.16, p < .04) is small, likely due to poor methodology (failing to account for covariates, i.e., disparities among numerous socioeconomic factors that add uncertainty to their conclusion). The r-value reported by the Bailey reanalysis demonstrates an effect size that is about one-fourth (0.16/0.70) that reported by Miller-Goldman—underscoring how critically important it is for Bailey's reanalysis to eliminate confounding variables. Moreover, Bailey’s linear regression analyses of IMR as a function of vaccination rates for each of eight different vaccines demonstrate that some countries with low vaccination rates have low IMRs, while other countries with high vaccination rates have high IMRs. Rather than supporting a strong inverse correlation, the Bailey reanalysis demonstrates high vaccination rates are neither necessary nor sufficient to cause low IMR.
ARTICLE | doi:10.20944/preprints202001.0279.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: NS3 inhibitors; allosteric inhibitors; NS4A; peptidomimetics; imidazole; hepatitis C virus; molecular dynamics; Flaviviridae; DSLS; binding assay
Online: 24 January 2020 (11:11:46 CET)
The non-structural protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been in consideration in literature, and therefore, we decided to explore this strategy to develop a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25` to Arg-28` at the core of NS4A21`-33` needed to activate the NS3 protease. Some of the synthesized MOC compounds were able to compete with and displace NS4A21`-33` for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21`-33` with a competition IC50 of 1.9 ± 0.12 µM in a fluorescence anisotropy assay, stabilized the denaturation of NS3 by increasing the aggregation temperature by ΔTagg 0.6 ± 0.140 ℃. MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations rationalized the structure-activity relationship (SAR) differences between the active MOC-24 and the inactive MOC-26. Our data shows that MOC compounds are possibly the first examples of NS4A peptidomimetics that demonstrated promising activities against NS3 proteins.
REVIEW | doi:10.20944/preprints202209.0482.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Telomerase reverse transcriptase; TERT; TERT promoter; TERTp; human papillomavirus; HPV; Epstein Barr virus (EBV); Kaposi sarcoma-associated herpesvirus; HHV-8; hepatitis B virus; HBV; hepatitis C virus; HCV; human T-cell leukemia virus-1; HTLV-1
Online: 30 September 2022 (10:11:58 CEST)
Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is commonly enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate recent findings on virus-telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer causing viruses.
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: coronavirus; COVID-19; Hepatitis C Virus (HCV); Human Immunodeficiency Virus (HIV); Influenza viruses ribonucleic acid (RNA); SARS-CoV-2
Online: 19 February 2021 (14:34:38 CET)
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiological agent of the current pandemic worldwide. The pathological condition induced by this pathogen is known as COVID-19 disease. SARS-CoV-2 associated pandemic has been defined as a “public health emergency of international concern” by the International Health Regulation Emergency Committee of the World Health Organization. To date, considerable efforts are in progress to develop more advanced strategies against SARS-CoV-2. Despite the numerous scientific studies published, our knowledge regarding this pathogen is still incomplete, as this virus has been identified only recently. Therefore, scientific investigation of the SARS-CoV-2 has been possible only for a short period of time and effective management of the serious forms of this disease is still lacking. Considerable efforts are in progress worldwide with the purpose to develop more advanced strategies against this pathogen. In this review, we have analyzed the structural and the biological SARS-CoV-2 characteristics and those of other well-known RNA viruses, with the aim to identify possible similarities and analogies between all these pathogens, may be a very useful approach. These infectious agents have been widely studied since several years ago and, a large series of scientific reports are available in the literature regarding this topic. Therefore, focusing on the Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and Influenza viruses (IVs), we have collected their historical data, clinical manifestations, pathogenetic mechanisms and related infections. Taking advantage of the results of our research, we have assembled this narrative review, with the aim to get useful insights and lessons from HIV, HCV and IVs characteristics and, consequently, to transfer the obtained knowledge to the study of SARS-CoV-2 biology. There are well known differences between all these pathogens. In particular, they present a distinct mode of transmission, as SARS-CoV-2 and Influenza viruses are airborne pathogens, whereas HIV and HCV are bloodborne infectious agents. However, these viruses exhibit some potential common clinical manifestations and pathogenetic mechanisms and their understanding may contribute to establishing preventive measures and new therapies against SARS-CoV-2. Accordingly, we have analysed and discussed the following points: 1) the biology, the pathogenesis and the clinical manifestations of SARS-CoV-2, HIV, HCV and IVs in mankind; 2) the onset and spreading of pandemics caused by respiratory viruses according to a perspective historical point of view; 3) the possible development of a persistent SARS-CoV-2 reservoir worldwide; 4) the possibility of SARS-CoV-2 reinfection/reactivation; 5) the possible involvement and impact of climatic factors in increasing the risk of SARS-CoV-2 spreading.
ARTICLE | doi:10.20944/preprints202104.0512.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: hepatitis B virus (HBV); Myr47 lipopeptide; cellular uptake; liposomes; sodium taurocholate cotransporting polypeptide (NTCP); HBV surface antigen (HBsAg); apolipoprotein E (ApoE)
Online: 19 April 2021 (17:08:53 CEST)
Myr47 lipopeptide consisting of hepatitis B virus (HBV) pre-S1 domain (myristoylated 2-48 peptide) is a commercialized effective anti-HBV drug, preventing the interaction of HBV with sodium taurocholate cotransporting polypeptide (NTCP) on human hepatocytes, of which the activity requires both N-myristoylation residue and specific amino acid sequence. Meanwhile, we recently reported that Myr47 reduces the cellular uptake of HBV surface antigen (HBsAg, subviral particle of HBV) in the absence of NTCP expression (Somiya; et al. Virology 2016, 497, 23–32). In this study, we analyzed how Myr47 reduces the cellular uptake of lipid nanoparticles (including liposomes (LPs) and HBsAg) without NTCP expression. By using Myr47 mutants lacking the HBV infection inhibitory activity, they could reduce the cellular uptake of LPs in an N-myristoylation-dependent manner whereas in an amino acid sequence-independent manner. Moreover, Myr47 and its mutants could reduce the interaction of LPs with apolipoprotein E3 (ApoE3) in an N-myristoylation-dependent manner regardless of their amino acid sequences. From these results, N-myristoyl residue of lipopeptides generally could interfere the LPs/HBsAg-ApoE3 complex formation, thereby reducing the cellular uptake of LPs/HBsAg. When lipid nanoparticles are used as a DDS (drug delivery system) nanocarrier, the surface modification with lipopeptides may be a new method to inhibit unwanted cellular uptake of DDS nanocarriers by non-target cells.
REVIEW | doi:10.20944/preprints202004.0464.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: COVID-19; SARS-CoV-19; Hepatitis B and C; Cirrhosis; Chronic Kidney Disease; Alcohol-related Liver Disease; Non-alcoholic Steatohepatitis; Necrosis
Online: 25 April 2020 (16:46:06 CEST)
Background: The mortality and severity in COVID-19 is increased in patients with comorbidities. The aim of this study was to evaluate the unknown risk of severity and mortality in COVID-19 patients with underlying kidney and liver diseases. Method: We retrieved data on the clinical features and primary composite end point of COVID-19 patients released from inception till 16th of April 2020 from Medline and Embase. The data on two comorbidities, liver diseases and chronic kidney disease, present in COVID-19 were pooled and statistically analysed to explain the associated severity and mortality rate. Results: 142 abstracts were screened, and 41 full articles were then read. In total, 22 studies including 5595 COVID-19 patients were included in this study with case fatality rate of 16%. The prevalence of liver diseases and CKD were 3% (95%CI; 2%-3%) and 1% (95%CI; 1%-2%) respectively. In patients with COVID-19 and underlying liver diseases, 57.33% (43/75) cases were severe with 17.65% mortality. While in CKD patients with COVID-19, 83.93% (47/56) severity and 53.33% (8/15) mortality were reported. Conclusion: This study found an increased risk of severity and mortality in COVID-19 patients with liver diseases and CKD. This will allow for better clinical management and inform more stringent preventative measures for this group of patients.
ARTICLE | doi:10.20944/preprints201910.0342.v1
Subject: Computer Science And Mathematics, Probability And Statistics Keywords: Tubercolusis (TB); Poisson Autoregressive (PAR); Poisson Exponentially Weighted Moving Average Model (PEWMA); Hepatitis; Human Immunodeficiency Virus (HIV); Acquired Immune Deficiency Syndrome (AIDs)
Online: 29 October 2019 (15:51:16 CET)
The research work examined the trend of HIV/AIDS, Tuberculosis, and Hepatitis diseases in Plateau state. Annual data from 2003 to 2018 was collected from the department of biostatistics at Plateau State Specialist Hospital (PSSH), Jos. The methods of analysis used are the Poisson Autoregressive Model (PAR(1)) and the Poisson Exponentially Weighted Moving Average Model (PEWMA). The results revealed a significant annual decrease of 23.9% and 4% in Tuberculosis and HIV/AIDS respectively. Furthermore, the results showed a significant annual increase of 46% in Hepatitis. The PEWMA model used revealed that TB increased by 0.02% when there is an increase in HIV but not significant, while Hepatitis significantly aggravates TB by at least 0.24%. Also, there is a significant rise in HIV by 0.85% when TB increases but Hepatitis has no such effect on HIV. Lastly, PEWMA model indicated a rise of 0.5% in Hepatitis cases when there is an increase in TB, but a surge in HIV has no such effect on Hepatitis cases in Jos. The study recommended that fight against TB should be intensified since TB cases significantly affect both HIV and Hepatitis in Jos, Nigeria.
REVIEW | doi:10.20944/preprints202009.0361.v2
Subject: Biology And Life Sciences, Virology Keywords: SARS-CoV-2; COVID-19; foodborne viruses; enteric viruses; fecal-oral transmission; fresh produce, berries, fruits, hepatitis A virus, Norovirus, ready-to-eat foods.
Online: 18 September 2020 (10:35:33 CEST)
Background:Although highly strict social distancing and viral spread protection guidelines are in force, the reported numbers of COVID-19 cases across the world are still increasing. This indicates that we are still unable to completely understand the transmission routes of SARS-CoV-2. One of the possible routes that can play a significant role is the fecal-oral transmission since SARS-CoV-2 can replicate in the intestines as demonstrated by isolation of infectious virus from fecal samples of COVID-19 cases. Scope and approach:In this review, we compare the characteristics of SARS-CoV-2 with the distinctive characteristics of enteric foodborne viruses. We also discuss and respond to the arguments given in some reports that downplay the importance of foodborne transmission route of SARS-CoV-2. Key findings and conclusions:Enteric viruses such as human noroviruses (HuNoVs) and hepatitis A virus (HAV) are known to transmit through foods such as fresh produce and berries, leading to frequent multistate foodborne disease outbreaks all over the world. SARS-CoV-2 was found to share four distinctive characteristics of foodborne viruses that allow them to transmit through foods. This similarity in characteristics, recent report of detecting SARS-CoV-2 particles from frozen food packages in China, and recent suspected foodborne COVID-19 case in New Zealand, indicate that foodborne transmission of SARS-CoV-2 is more evident than previously thought possible. To support or deny this route of transmission, urgent research needs to be undertaken to answer two primary questions and many secondary ones as described in this review.
ARTICLE | doi:10.20944/preprints202208.0324.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: T cytotoxic cells; Leukocyte-associated Immunoglobulin-like Receptor-1; LAIR-1; Hepatitis C virus genotype 4; HCV G4; hepatocellular carcinoma; cirrhosis; immune inhibitory checkpoints; inflammation; prognosis; insulin resistance
Online: 17 August 2022 (11:38:10 CEST)
Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis
ARTICLE | doi:10.20944/preprints202104.0020.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: hepatitis C virus; hepatocellular carcinoma; immunotherapy; multi-component DNA vaccine; nucleocapsid (core) protein; telomerase reverse transcriptase; eukaryotic expression; CD4+ and CD8+ T cell response; immune suppression; assays of reporter expression; induction of type I interferons
Online: 1 April 2021 (13:18:59 CEST)
Chronic HCV infection and associated liver cancer impose a heavy burden on the healthcare system. Direct acting antivirals eliminate HCV, unless it is drug resistant, and partially reverse liver disease, but they cannot cure HCV-related cancer. Possible remedy could be a multi-component immunotherapeutic vaccine targeting both HCV-infected and malignant cells, also those not infected with HCV. To meet this need we developed a two-component DNA vaccine based on the highly conserved core protein of HCV to target HCV-infected cells, and a renowned tumor associated antigen telomerase reverse transcriptase (TERT) based on the rat TERT, to target malignant cells. Their synthetic genes were expression-optimized, and HCV core was truncated after aa 152 (Core152opt) to delete the domain interfering with immunogenicity. Core152opt and TERT DNA were highly immunogenic in BALB/c mice, inducing IFN-γ/IL-2/TNF-α response of CD4+ and CD8+ T cells. Also, DNA-immunization with TERT enhanced cellular immune response against luciferase encoded by a co-delivered plasmid (Luc DNA). However, DNA-immunization with Core152opt and TERT mix resulted in abrogation of immune response against both components. A loss of bioluminescent signal after co-delivery of TERT and Luc DNA into mice indicated that TERT affects the in vivo expression of luciferase directed by the immediate early cytomegalovirus and interferon-β promoters. Panel of mutant TERT variants was created and tested for their expression effects. TERT with deleted N-terminal nucleoli localization signal and mutations abrogating telomerase activity still suppressed the IFN-β driven Luc expression, while the inactivated reverse transcriptase domain of TERT and its analogue, enzymatically active HIV-1 reverse transcriptase, exerted only weak suppressive effects, implying that suppression relied on the presence of the full-length/nearly full-length TERT, but not its enzymatic activity. The effect(s) could be due to interference of the ectopically expressed xenogeneic rat TERT with biogenesis of mRNA, ribosomes and protein translation in murine cells, affecting the expression of immunogens. HCV core can aggravate this effect, leading to early apoptosis of co-expressing cells, preventing the induction of immune response.