Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease.

Background & Aims: Fibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. Methods: Cohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin-bilirubin (ALBI) scores. Results: In cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6-4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9-14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8-3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0-13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. Conclusions: PRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and Implications: We tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Clinical and occupational health management of healthcare workers living with chronic hepatitis B: UK policy and international comparisons.

Hepatitis B virus (HBV) is a highly infectious bloodborne virus, which remains endemic in large geographic areas and represents a major global healthcare challenge. HBV transmission from healthcare workers, who perform exposure prone procedures (EPP), to patients is a recognized transmission risk, which varies widely globally. Although the risk is small in developed countries, it increases significantly in high-prevalent, low-resource countries, representing a major challenge to these healthcare systems and underlining the necessity for robust guidance to be in place. The HBV landscape has evolved as a result of global vaccination programs, implementation of standard precautions and the advent of new generation antiviral agents (3rd generation nucleos(t)ide analogues). In light of the progress in the field, the UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP) recently issued updated guidance, which essentially removes past barriers, restricting healthcare workers from performing EPPs solely on the basis of HBV DNA level, regardless of hepatitis B 'e' antigen and/or treatment status. Although the current recommendations remain conservative compared to those of other developed healthcare systems, UK practice is now in line with other high-income countries, while ensuring patient safety remains paramount, without unduly restricting HCWs from clinical practice. The current article presents the latest UKAP guidance, considers its implications for HCWs and compares it with the guidance from major international scientific societies and governing bodies.

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.

Hepatitis B virus reactivation in patients treated with immunosuppressive drugs: a practical guide for clinicians.

Hepatitis B virus reactivation (HBVr) is emerging as an important clinical entity, with the advent of highly potent immunosuppression licensed for use as the treatment of a widening range of clinical indications. HBVr can lead to severe acute liver failure and death. Risk can be minimised through appropriate screening, monitoring and antiviral prophylaxis. Screening for serological markers at the -earliest opportunity is recommended. Risk stratification should then be performed on the basis of characteristics of the -underlying disease, markers of viral activity and the potency of proposed immunosuppression. In this review, we summarise the most recent recommendations from the relevant international societies. We also provide suggestions on how a robust multidisciplinary service can be delivered to prevent HBVr in UK clinical practice through optimisation of resources and introduction of checkpoints to prevent the inappropriate administration of immunosuppression to those at significant risk of HBVr.

Why, who and when to start treatment for chronic hepatitis B infection.

Chronic hepatitis B remains a major global health challenge due to morbidity and mortality from hepatocellular carcinoma and complications of liver cirrhosis. Current treatment regimens are non-curative and, once initiated, treatment is of indefinite duration for the majority. The decision to initiate treatment decisions is based on risk stratification. Advances in our understanding of the natural history of chronic hepatitis B have led to a paradigm shift in recommendations for treatment. Emerging non-invasive biomarkers of disease activity will further enhance disease stratification. In this review, we summarise the guidance from major international societies on treatment for chronic hepatitis B and explore some of the novel approaches to disease assessment.

Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease.

AIMS: The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus-related chronic liver disease. METHODS AND RESULTS: Elastin contents in liver biopsies were determined by image analysis, technically validated in an independent centre, and correlated with outcome in patients with advanced (Ishak stage ≥5) chronic hepatitis C virus-related chronic liver disease. Elastin was robustly quantified in an operator-independent and laboratory-independent manner, with very strong correlation of elastin staining measured with two methods of image classification (rs = 0.873, P < 0.00001). Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virological response, the median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with a hepatic elastin content of >3.4% progressed to a clinical outcome, as compared with only six of 15 (40%) with an elastin content of <3.4%. The difference in time to outcome was significant. CONCLUSIONS: We describe a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.

Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks.

Chronic infection with hepatitis B virus (HBV) progresses through multiple phases, including immune tolerant, immune active, immune control, and, in a subset of patients who achieve immune control, reactivation. The first, the immune tolerant phase, is considered to be prolonged in duration but essentially benign in nature, lacking long-term consequences, and thus not recommended for antiviral therapy. This review challenges the notion that the immune tolerant phase is truly benign and considers the possibility that events during this phase may contribute significantly to cirrhosis, hepatocellular carcinoma (HCC), and the premature death of 25% of HBV carriers worldwide. Thus, earlier treatment than recommended by current guidelines should be considered. Low therapeutic coverage exacerbated by restrictive treatment guidelines may facilitate disease progression in many patients but also increase the risk of neonatal and horizontal transmission from untreated mothers to their children. While a prophylactic vaccine exists, there are many areas worldwide where the treatment of adults and the delivery of an effective vaccination course to newborns present difficult challenges.

The performance of transient elastography compared to clinical acumen and routine tests - what is the incremental diagnostic value?

BACKGROUND/AIMS: There is substantial evidence suggesting transient elastography (TE) is a useful tool in assessing liver fibrosis. We aimed to determine whether TE has incremental diagnostic value over clinical acumen and routinely available tests. METHODS: We performed a retrospective study of 130 patients to assess the ability of hepatologists to predict severity of fibrosis using clinical acumen; clinical acumen with routine tests; and elastography in patients with chronic liver disease. The incremental diagnostic benefit was assessed using the area under the ROC curve (AUC) and the Net Reclassification Index (NRI). RESULTS: Using universally available tests, including clinical acumen, the AUCs for detection of cirrhosis ranged from 0.70 to 0.80 for the four hepatologists. Elastography led to statistically non-significant improvements in AUC statistics (range 0.83-0.89; P > 0.01). The detection of significant fibrosis using clinical acumen and routine tests was less accurate, with AUCs of 0.52-0.59. Elastography had incremental diagnostic value (AUC performance range 0.76-0.82; P < 0.01). The NRI indicated that 39-58% were correctly reclassified using elastography, especially with respect to sensitivity. CONCLUSIONS: Our study suggests that the diagnostic value of clinical acumen and routine tests is acceptable for detection of cirrhosis, but not significant fibrosis. Elastography detects significant fibrosis or cirrhosis with acceptable accuracy and offered incremental diagnostic value in detecting significant fibrosis, but not cirrhosis. These findings have implications for determining the diagnostic value of tests over and above routine clinical assessment, which will aid incorporation of novel tests into clinical algorithms.