8,103 research outputs found

    Liver function indicators and risk of hepatocellular carcinoma: a bidirectional mendelian randomization study

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    Observational studies have shown an association between liver dysfunction and hepatocellular carcinoma (HCC), but the causality relationship between them is unclear. We aimed to determine whether there is a bidirectional causal relationship between liver function indicators (alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; γ-glutamyltransferase, GGT) and HCC. Our two-sample Mendelian randomization (MR) study acquired single nucleotide polymorphisms (SNPs) associated with liver function indicators (ALT, n = 134,182; AST, n = 134,154; GGT, n = 118,309; ALP, n = 105,030) and with HCC (n = 197,611) from publicly available genome-wide association studies (GWAS) of East Asian ancestry in Japan (BioBank Japan, BBJ). Univariable MR analyses were performed to identify whether the genetic evidence of exposure was significantly associated with outcome. Multivariable MR analysis was conducted to estimate the independent effects of exposures on outcome. Univariable MR analysis indicated that the level of ALT, AST, and GGT was the risk factor for HCC incidence. Meanwhile, multivariable MR analysis revealed that AST was an independent risk factor for HCC. The hazard ratio (HR) of the probability of HCC was 3.045 [95% confidence interval (95%CI), 1.697–5.463, p = 0.003] for AST. The results of reverse MR analyses showed that gene-predictive HCC incidence could increase the levels of AST (HR = 1.031, 95%CI: 1.009–1.054, p = 2.52 × 10−4) and ALT (HR = 1.040, 95%CI: 1.019–1.063, p = 0.005). Meanwhile, HCC may be negatively correlated with ALP levels (HR = 0.971, 95%CI: 0.947–0.995, p = 0.018). This study provides evidence to support that genetically predicted higher levels of AST are related to increased risk of HCC, with no strong evidence of a causal effect of genetically predicted ALP, ALP, and GGT on HCC. In addition, genetic predisposition to HCC could influence blood concentration of ALT, AST, and ALP. Thus, this may create a vicious cycle

    HBV DNA and HBsAg Levels at 24 Weeks Off-Treatment Predict Clinical Relapse and HBsAg Loss in HBeAg-Negative Patients Who Discontinued Antiviral Therapy

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    Background &amp; Aims: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. Methods: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)–negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. Results: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P &lt;.001) and a lower chance of HBsAg loss (HR, 0.454; P &lt;.001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P &lt;.001) and a lower chance of HBsAg loss (HR, 0.263; P &lt;.001). A combination of both HBsAg &lt;100 IU/mL and HBV DNA &lt;100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg &gt;100 IU/mL and HBV DNA &gt;100 IU/mL (P &lt;.001). Conclusions: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg &lt;100 IU/mL with HBV DNA &lt;100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.</p

    Treatment of HCV with direct-acting antivirals on reducing mortality related to extrahepatic manifestations: a large population-based study in British Columbia, CanadaResearch in context

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    Summary: Background: HCV infection is associated with mortality due to extrahepatic manifestations (EHM). Sustained virologic response (SVR) following direct-acting antiviral (DAA) therapy has been linked to decreased all-cause and liver-related mortality. However, evidence regarding the impact of DAA on EHM-related deaths is lacking. This study aimed to assess the impact of DAA and SVR on EHM-related mortality. Methods: The British Columbia Hepatitis Testers Cohort comprises ∼1.7 million people tested for HCV between 1990 and 2015 and is linked with administrative health data. Among individuals diagnosed with HCV by 12/31/2020, those who received at least one DAA treatment were matched to those who never received treatment by the year of their first HCV RNA positive date. We compared three groups: treated &amp; SVR, treated &amp; no-SVR, and untreated; and generated EHM mortality rates and incidence curves. To account for differences in baseline characteristics, we used inverse probability of treatment weights (IPTW). IPTW-weighted multivariable cause-specific Cox regression models were adjusted for competing risk and confounders. Findings: Study population included 12,815 treated (12,287 SVR, 528 no-SVR) and 12,815 untreated individuals (median follow-up 3.4 years, IQR 2.9). The untreated group had the highest EHM mortality rate (30.9 per 1000 person-years [PY], 95% CI 29.2–32.8), followed by the treated &amp; no-SVR group (21.2 per 1000 PY, 95% CI 14.9–30.1), while the treated &amp; SVR group had the lowest EHM mortality rate (7.9 per 1000 PY, 95% CI 7.1–8.7). In the multivariable model, EHM mortality in the treated &amp; SVR group was significantly decreased (adjusted cause-specific hazard ratio [acsHR] 0.20, 95% CI 0.18–0.23). The treated &amp; SVR group had significant reductions in mortality related to each of the EHMs (78–84%). Interpretation: Treatment of HCV with DAA was associated with significant reductions in EHM-related mortality. These findings emphasize the critical importance of timely diagnosis and treatment of HCV to prevent deaths associated with EHM, and have important implications for clinical practice and public health. Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-348216, PJT-156066, and PHE-337680]. DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and Doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC)

    The co-existence of NAFLD and CHB is associated with suboptimal viral and biochemical response to CHB antiviral therapy: a systematic review and meta-analysis

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    Background and aimsChronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are leading causes of liver-related morbidity and mortality. The interaction between these two disease processes is poorly defined and the impact of NAFLD on HBV-related cirrhosis and HCC remains unclear. The aim of this study was to evaluate the impact of NAFLD on response to antiviral CHB therapy to inform the debate on changing CHB treatment thresholds for these comorbid patients.MethodsStudies with a minimum of 50 adult CHB patients on nucleoside analogue therapy with or without concurrent NAFLD were identified from PubMed/Medline and EMBASE to February 21, 2023. Data extraction from each study included HBeAg and treatment status, diagnostic method of NAFLD, frequency of monitoring intervals, patient age, gender, grade of hepatic steatosis, BMI and metabolic comorbidities. The outcomes of interest, complete virological response (CVR), biochemical response (BR) and HBeAg loss/seroconversion, were recorded at each available monitoring interval. Comparing CHB-NAFLD and CHB-only groups, pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using random- or fixed-effects models depending on heterogeneity.ResultsFrom a search of 470 citations, we identified 32 potentially relevant papers. Overall, 11 studies, comprising 2580 unique patients, met the inclusion criteria of the meta-analysis. CHB-NAFLD patients exhibited significantly lower rates of CVR compared to CHB-only patients. This was demonstrated by an OR of 0.59 (0.38-0.93, p=0.001, I2 = 72%) at 12 months, which tapered off to an OR of 0.67 (0.48-0.95, p=0.02) at 60 months. CHB-NAFLD patients also exhibited significantly lower rates of BR compared to CHB-only patients, as demonstrated by ORs of 0.39 (0.24-0.62, p&lt;0.0001, I2 = 53%) at 12 months and 0.33 (0.17-0.63, p=0.0008) at 24 months.ConclusionPatients with concurrent CHB and NAFLD experience delayed CVR to antiviral therapy and more persistent biochemical abnormalities in comparison to patients with CHB only. This supports the argument for earlier antiviral therapy in order to avert CHB complications in these multi-morbid patients, as the global disease burden of NAFLD continues to increase

    Effect of integrated hepatitis C virus treatment on psychological distress in people with substance use disorders

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    People with substance use disorders (SUD) have a high prevalence of chronic hepatitis C virus (HCV) infection and mental health disorders. We aimed to assess the impact of integrated HCV treatment on psychological distress measured by Hopkins-symptom-checklist-10 (SCL-10). This multi-center randomized controlled trial evaluated psychological distress as a secondary outcome of integrated HCV treatment (INTRO-HCV trial). From 2017 to 2019, 289 participants were randomly assigned to receive either integrated or standard HCV treatment with direct-acting antiviral therapy. Integrated HCV treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in internal medicine outpatient clinics at centralized hospitals. Participants in the integrated treatment arm had a sustained virologic response of 93% compared to 73% for those in standard treatment arm. Psychological distress was assessed using SCL-10 prior to initiation of HCV treatment and 12 weeks after treatment completion. The mean SCL-10 score prior to HCV treatment was 2.2 (standard deviation [SD]: 0.7) for patients receiving integrated HCV treatment and 2.2 (SD: 0.8) for those receiving standard HCV treatment. Twelve weeks after the end of treatment, the mean SCL-10 score change was − 0.1 (− 0.3;0.0) in the integrated compared to the standard arm. Psychological distress did not substantially change during the treatment period and was not significantly different between the treatment arms

    The effect of autologous macrophage therapy in cirrhosis in response to individual immune reparative pathways: developing a novel therapy

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    BACKGROUND: Liver cirrhosis is the end stage of any injury process to the liver. Once established it inevitably progresses to complications such as portal hypertension, cancer and death. There is not cure for liver cirrhosis besides liver transplant. We face an unmet demand for treatment of this condition. The role of macrophages in fibrosis development and resolution in the liver has been extensively investigated. Prof Forbes group invested in the development of autologous macrophage product to promote fibrosis resolution hence cirrhosis regression. This has demonstrated its efficacy and safety in animal models. From these encouraging pre-clinic data a phase 1 first in human clinical trial of autologous activated macrophage product for cirrhotic patients was developed. METHODS: Using an established 3+3 dose escalation model we enrolled a total of 9 subject in the phase 1 trial reaching a maximum achieved and safe dose of 1x10^9 macrophages. In addition to adverse events, dose toxicity and macrophage activation syndrome (MAS) parameter, we evaluated a varied range of circulating cytokines and chemokine pre and post treatment using a commercial kit. Moreover we developed a protocol for P13- magnetic resonance spectrometry (MRS) for the analysis of the metabolically active liver parenchyma. Data from the phase 1 trial were used to improve the autologous cellular produce and phase 2 randomised controlled trial. RESULTS: The autologous activated macrophage produce is demonstrated not to cause any toxicity in this first in human study of cirrhotic population of different aetiology. Cytokine and chemokine analysis supports these findings and specifically demonstrates low levels of IL-8, which represent cardinal feature of MAS. Other interesting cytokine signals may support extra cellular matrix remodelling effect of the autologous macrophage product infusion. In addition we demonstrated a reproducible protocol for MRS in liver disease. DISCUSSION: Autologous activated macrophage infusion did not result in any toxicity in cirrhotic subjects taking part in this study and shows preliminary signs of efficacy in fibrosis resolution both clinically and biochemically. This work places the basis of development of cellular products for treatment of cirrhosis and fibrosis and provides invaluable insight in immune response to cellular treatment

    An Update on National Consensus Practice Guidelines for the Treatment of Hepatitis C & Literature Review in Epidemiology of Hepatitis C in Pakistan - 2022

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    Hepatitis C is a global health problem affecting around 58 million people worldwide and killing almost 0.29 million in on one year [1]. The world has united to fight against this lethal disease in 2016 with a moto to eliminate hepatitis by 2030. To achieve this goal WHO’s World Health Assembly has set some targets and individual countries have developed their own strategies to achieve those targets [2]. &nbsp;Pakistan has the 2nd highest prevalence of hepatitis C in the world with 5.8% viremia positive patients [3]. Pakistan is amongst the few countries that have been assisted by the Center for Disease Control and Prevention(CDC) to prevent and control Hepatitis[4]. &nbsp;&nbsp; With the availability of Direct Acting Antivirals(DAAs), the whole paradigm of treatment of hepatitis C has changed not only globally but also in Pakistan. However, the patients in Pakistan are unable to gain access to the latest DAAs at the pace, as they are available globally. International guidelines are being updated on regular basis as per global evidence, recommending such combinations which are not readily available to many parts of the world. Hence there is a dire need to develop national guidelines, keeping in consideration the efficacy of the drugs as well as their availability, in the broader canvas of achieving the targets of eliminating Hepatitis set by WHO. &nbsp; In this context, our consensus guidelines are an effort to fill the gap created because of upgraded scientific evidence and possible combinations available in our part of the world. Furthermore, quite some good research and evidence has also been shared in the literature from Pakistan during last five years (2016-2021). Hence a literature review has also been carried out to update our own epidemiologic data, risk factors and treatment responses to Hepatitis C in Pakistan

    Clinical course and management of COVID-19 in the era of widespread population immunity

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    The clinical implications of COVID-19 have changed since SARS-CoV-2 first emerged in humans. The current high levels of population immunity, due to prior infection and/or vaccination, have been associated with a vastly decreased overall risk of severe disease. Some people, particularly those with immunocompromising conditions, remain at risk for severe outcomes. Through the course of the pandemic, variants with somewhat different symptom profiles from the original SARS-CoV-2 virus have emerged. The management of COVID-19 has also changed since 2020, with the increasing availability of evidence-based treatments in two main classes: antivirals and immunomodulators. Selecting the appropriate treatment(s) for patients with COVID-19 requires a deep understanding of the evidence and an awareness of the limitations of applying data that have been largely based on immune-naive populations to patients today who most likely have vaccine-derived and/or infection-derived immunity. In this Review, we provide a summary of the clinical manifestations and approaches to caring for adult patients with COVID-19 in the era of vaccine availability and the dominance of the Omicron subvariants, with a focus on the management of COVID-19 in different patient groups, including immunocompromised, pregnant, vaccinated and unvaccinated patients.Peer reviewe

    Trends in long‐term outcomes of patients with HCV‐associated hepatocellular carcinoma after hepatectomy: A comparison before and after introduction of direct‐acting antivirus therapy

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    Abstract Backgrounds The success of direct‐acting antiviral (DAA) therapy provides a cure for patients chronically infected with hepatitis C virus (HCV); however, outcomes after hepatectomy for HCV‐associated hepatocellular carcinoma (HCC) before and after DAA introduction remain poorly studied. Methods Patients who underwent R0/R1 hepatectomy for HCV‐associated HCC were retrospectively analyzed. Two time periods were defined: Pre‐DAA (2007–2011, December 2013 was defined as the end of follow‐up) and Post‐DAA groups (2014–2018, December 2020 was defined as the end of follow‐up). Propensity score matching (PSM) analyses were performed to highlight the effect of DAA therapy. Results A total of 155 patients with HCV‐associated HCC were included in this study (Pre‐DAA group, n = 103 and post‐DAA group, n = 52). In the Post‐DAA group, DAA therapy was performed in 26 patients (50.0%), and all of these patients achieved sustained virologic response (SVR) (preoperative SVR, n = 7; postoperative SVR, n = 19). There was no significant difference between the two groups regarding surgical settings and tumor pathology. There was no significant difference in the 5‐year overall survival (OS) rate (61.1% and 64.8%, pre‐ and post‐DAA group, respectively, p = 0.441); meanwhile, the 5‐year recurrence‐free survival (RFS) rate in the post‐DAA group was better than the pre‐DAA group (21.1% and 40.2%, p = 0.073) with a trend toward significance. After PSM except for the postoperative SVR status, there were no significant differences in OS (p = 0.586) and RFS (p = 0.888). Conclusions This study showed that survival outcomes were not changed in hepatectomized cases of HCV‐associated HCC before and after the introduction of DAA therapy
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