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The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B virus (HBV) surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with current therapeutics. We applied a multiplex droplet digital PCR assay to demonstrate that iDNA is responsible for maintaining HBsAg quantities in some individuals. Using paired bulk liver tissue from 16 HIV/HBV-coinfected persons on nucleos(t)ide analog (NUC) therapy, we demonstrate that people with larger HBsAg declines between biopsies derive HBsAg from cccDNA, whereas people with stable HBsAg levels derive predominantly from iDNA. We applied our assay to individual hepatocytes in paired tissues from 3 people and demonstrated that the individual with significant HBsAg decline had a commensurate loss of infected cells with transcriptionally active cccDNA, while individuals without HBsAg decline had stable or increasing numbers of cells producing HBsAg from iDNA. We demonstrate that while NUC therapy may be effective at controlling cccDNA replication and transcription, innovative treatments are required to address iDNA transcription that sustains HBsAg production.

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. ClinicalTrials.gov NCT01069133.

ObjectiveTo describe the various mechanisms of liver disease in patients with HIV infection, and to link these mechanisms to disease states which may utilise them.BackgroundNon-AIDS causes of morbidity and mortality are becoming increasingly common in patients chronically infected with HIV. In particular, liver-related diseases have risen to become one of the leading causes of non-AIDS-related death. A thorough understanding of the mechanisms driving the development of liver disease in these patients is essential when evaluating and caring for these patients.MethodsThe literature regarding mechanisms of liver disease by which different disease entities may cause hepatic injury and fibrosis was reviewed and synthesised.ResultsA number of discrete mechanisms of injury were identified, to include: oxidative stress, mitochondrial injury, lipotoxicity, immune-mediated injury, cytotoxicity, toxic metabolite accumulation, gut microbial translocation, systemic inflammation, senescence and nodular regenerative hyperplasia. Disease states may use any number of these mechanisms to exert their effect on the liver.ConclusionsThe mechanisms by which liver injury may occur in patients with HIV infection are numerous. Most disease states use multiple mechanisms to cause hepatic injury and fibrosis.

ObjectivesCirrhosis is associated with gut microbial dysbiosis, high readmissions and proton pump inhibitor (PPI) overuse, which could be inter-linked. Our aim was to determine the effect of PPI use, initiation and withdrawl on gut microbiota and readmissions in cirrhosis.MethodsFour cohorts were enrolled. Readmissions study: Cirrhotic inpatients were followed throughout the hospitalization and 30/90-days post-discharge. PPI initiation, withdrawal/continuation patterns were analyzed between those with/without readmissions. Cross-sectional microbiota study: Cirrhotic outpatients and controls underwent stool microbiota analysis. Beneficial autochthonous and oral-origin taxa analysis vis-à-vis PPI use was performed. Longitudinal studies: Two cohorts of decompensated cirrhotic outpatients were enrolled. Patients on chronic unindicated PPI use were withdrawn for 14 days. Patients not on PPI were started on omeprazole for 14 days. Microbial analysis for oral-origin taxa was performed pre/post-intervention.ResultsReadmissions study: 343 inpatients (151 on admission PPI) were enrolled. 21 were withdrawn and 45 were initiated on PPI resulting in a PPI use increase of 21%. PPIs were associated with higher 30 (p = 0.002) and 90-day readmissions (p = 0.008) independent of comorbidities, medications, MELD and age. Cross-sectional microbiota: 137 cirrhotics (59 on PPI) and 45 controls (17 on PPI) were included. PPI users regardless of cirrhosis had higher oral-origin microbiota while cirrhotics on PPI had lower autochthonous taxa compared to the rest. Longitudinal studies: Fifteen decompensated cirrhotics tolerated omeprazole initiation with an increase in oral-origin microbial taxa compared to baseline. PPIs were withdrawn from an additional 15 outpatients, which resulted in a significant reduction of oral-origin taxa compared to baseline.ConclusionsPPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

Background and aims: In alcoholic hepatitis (AH), increases in the total bilirubin (TB) and the prothrombin time (PT), which are included in the Maddrey’s discriminant function (MDF) and the model for end-stage liver disease (MELD), are associated with poor outcomes. However, the impact of which control PT in the MDF to use compared to the MELD on the outcomes in AH is unknown. Our aim is to determine whether the choice of the control PT used in the MDF calculations has any impact on steroid use and survival when compared to the MELD in those with AH. Methods: Through retrospective chart review, we analyzed 882 subjects who were admitted from 2012 to 2020 with acute AH. Their MDF was calculated [(TB + 4.6 × (PT–control)] using the following three different control PTs: 12, 13.5, and 14.8 s, and was compared to the MELD. The primary outcomes were steroid use and 30-day survival. Results: When it was stratified by the control PT, the percentage of MDF ≥ 32 (the threshold for steroids) decreased with increasing control PT (70%, 61%, and 52%, respectively), along with decreased steroid use (91%, 84%, and 75%, respectively). Those who received steroids were not shown to have improved 30-day survival compared to those who did not receive steroids (p = 0.41). The ability of the MDF for each control PT threshold to predict 30-day survival was similar (AUROC 0.735), and was lower compared to the MELD (0.767). Conclusion: While the choice of PT control in the MDF impacted the use of steroids in AH, the use of steroids and the choice of PT control used did not impact the overall survival. Regardless of which control PT was used in the MDF, the MELD was better at predicting 30-day survival. Important information: Background: Treatment with steroids is indicated in alcoholic hepatitis (AH) with Maddrey discriminant function (MDF) ≥ 32 and the model for end-stage liver disease (MELD) ≥ 20. The impact that the control prothrombin time (PT) value that is used in MDF has on steroid use and survival in AH is poorly understood. Findings: The choice of control PT that is used when calculating the MDF impacts the use of steroids but does not impact mortality. The MELD was better than the MDF at any control PT used in predicting survival in acute AH. Implications for patient care: Providers should be aware that higher control PT’s have an effect on treatment decisions but should not generally impact survival in this population. The MELD appears to better predict 30-day survival in this population.

The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogs (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased cccDNA transcription. To test this, we applied a multiplex droplet digital PCR that identifies the dominant source of HBsAg mRNAs to 3,436 single cells from paired liver biopsies obtained from 10 people with CHB and HIV receiving NUCs. With increased NUC duration, cells producing HBsAg mRNAs shifted their transcription from chiefly cccDNA to chiefly iDNA. This shift was due to both a reduction in the number of cccDNA-containing cells and diminished cccDNA-derived transcription per cell; furthermore, it correlated with reduced detection of proteins deriving from cccDNA but not iDNA. Despite this shift in the primary source of HBsAg, rare cells remained with detectable cccDNA-derived transcription, suggesting a source for maintaining the replication cycle. Functional cure must address both iDNA and residual cccDNA transcription. Further research is required to understand the significance of HBsAg when chiefly derived from iDNA.

Symptom burden, medical comorbidities, and functional well-being of patients with chronic hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical settings are not known. We characterized these patient-reported outcomes (PROs) among HCV-infected patients and explored associations with sociodemographic, liver disease, and psychiatric/substance abuse variables. PROP UP is a large US multicenter observational study that enrolled 1,600 patients with chronic HCV in 2016-2017. Data collected prior to initiating DAA therapy assessed the following PROs: number of medical comorbidities; neuropsychiatric, somatic, gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use features. Predictive models were explored using a random selection of 700 participants; models were then validated with data from the remaining 900 participants. The cohort was 55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had markers of psychiatric illness. The median number of medical comorbidities was 4 (range: 0-15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being present in 20-50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were present in over 60% and gastrointestinal symptoms in 40-50%. In multivariable validation models, the strongest and most frequent predictors of worse PROs were disability, unemployment, and use of psychiatric medications, while liver markers generally were not. This large multi-center cohort study provides a comprehensive and contemporary assessment of the symptom burden and comorbid medical conditions in patients with HCV treated in real world settings. Pain, fatigue, and sleep disturbance were common and often severe. Sociodemographic and psychiatric markers were the most robust predictors of PROs. Future research that includes a rapidly changing population of HCV-infected individuals needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve with viral eradication. (Clinicaltrial.gov: NCT02601820).

Fecal transplant is associated with reduction in the expression of antibiotic‐resistance genes in patients with decompensated cirrhosis. Genes focused on beta‐lactamase and vancomycin resistance reduced after fecal transplant regardless of pre‐procedure antibiotics and concurrent use of lactulose, rifaximin or PPIs. Antibiotic resistance leads to poor outcomes in cirrhosis. Fecal microbiota transplant (FMT) is associated with reduction in antibiotic resistance gene (ARG) burden in patients without cirrhosis; however, the impact in cirrhosis is unclear. We aimed to study the effect of capsule and enema FMT on ARG abundance in fecal samples, which were collected during two published FMT trials in patients with cirrhosis on rifaximin, lactulose, and proton pump inhibitors. ARGs were identified using metagenomics and mapped against the Comprehensive Antibiotic Resistance Database. Changes in ARG abundance were studied within/between groups. The capsule FMT trial involved a one‐time FMT or placebo capsule administration with stool collection at baseline and week 4 postintervention. Antibiotics+enema FMT included preprocedure antibiotics followed by FMT enema versus standard‐of‐care (SOC). Stool was collected at baseline, postantibiotics, and day 7/15 postintervention. Both trials included 20 patients each. There was no safety/infection signal linked to FMT. In the capsule trial, beta‐lactamase (OXY/LEN) expression decreased post‐FMT versus baseline. Compared to placebo, patients who were post‐FMT had lower abundance of vancomycin (VanH), beta‐lactamase (ACT), and rifamycin ARGs; the latter was associated with cognitive improvement. No changes were seen within patients treated with placebo. In the antibiotics+enema trial for postantibiotics at day 7 versus baseline, there was an increase in vancomycin and beta‐lactamase ARGs, which decreased at day 15. However, quinolone resistance increased at day 15 versus baseline. Between SOC and FMT, day 7 had largely lower ARG (CfxA beta‐lactamase, VanW, and VanX) that continued at day 15 (cepA beta‐lactamase, VanW). No changes were seen within the SOC group. Conclusion: Despite differences in routes of administration and preintervention antibiotics, we found that ARG abundance is largely reduced after FMT compared to pre‐FMT baseline and non‐FMT groups in decompensated cirrhosis.

(1) Background: Direct-acting antiviral therapy for chronic hepatitis C virus (HCV) infection is associated with high sustained virologic response (SVR) and overcomes negative predictive factors, including steatosis, in patients without human immunodeficiency virus (HIV) coinfection. The impact of steatosis on SVR in patients with HIV–HCV coinfection is unknown. (2) Methods: A retrospective analysis of patients treated with direct-acting antivirals was performed. Demographic, laboratory and direct-acting antiviral regimen data were prospectively collected. Metabolic syndrome and its components—diabetes mellitus, hypertension, dyslipidemia and obesity—were assessed. Hepatic steatosis (≥5%) was defined by liver biopsy or controlled attenuation parameter (CAP) measurement during vibration-controlled transient elastography (VCTE). (3) Results: A total of 151 HIV–HCV-coinfected patients on combined antiretroviral therapy and direct-acting antiviral therapy were included in this analysis. Prevalence of steatosis by liver biopsy (n = 34) or CAP (≥263 db/m) during VCTE (n = 92) was 27% and was independently associated with obesity (OR 3.11; 95% CI 1.43–6.82; p = 0.004) and the metabolic syndrome (OR 1.08; 95% CI 1.01–0.15; p = 0.01). The overall SVR rate (n = 148) was 95% and was not impacted by the presence of steatosis (p = 0.42). (4) Conclusions: Hepatic steatosis is common in HIV–HCV coinfection, correlates with obesity and the metabolic syndrome and does not impact SVR.