Sodium/bile acid co-transporter inhibitors currently in preclinical or early clinical development for the treatment of primary biliary cholangitis.

INTRODUCTION: Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC. AREAS COVERED: In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients. EXPERT OPINION: Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.

Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p < 0.001) but not healthy controls (r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02), emotional (u = 1374, p = 0.004), and itch (u = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001). Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

Seladelpar: an investigational drug for the treatment of early-stage primary biliary cholangitis (PBC).

INTRODUCTION: Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits. The recently developed fibrate, seladelpar, has shown promising results in clinical trials, but these outcomes have been previously marred by safety concerns. AREAS COVERED: We summarize existing treatment options in PBC and evaluate current trial data for seladelpar in relation to liver biochemistry, symptomology, and safety. EXPERT OPINION: Seladelpar leads to marked improvement in liver biochemistry and may improve symptoms. Safety concerns around liver toxicity appear to have been addressed. With likely increasing evidence compared to existing off-label fibrates, seladelpar has the potential as an attractive future second-line agent in PBC.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study.

BACKGROUND: Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice. METHODS: Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA. FINDINGS: Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level. INTERPRETATION: This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians. FUNDING: Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing.

Viral hepatitis in 2021: The challenges remaining and how we should tackle them.

Viral hepatitis results in 1.4 million deaths annually. The World Health Organization (WHO) set an ambitious target to eliminate viral hepatitis by 2030, but significant challenges remain. These include inequalities in access to healthcare, reaching at risk populations and providing access to screening and effective treatment. Stigma around viral hepatitis persists and must be addressed. The WHO goal of global elimination by 2030 is a worthy aim, but remains ambitious and the coronavirus 2019 pandemic undoubtedly has set back progress. This review article will focus on hepatitis A to E, highlighting problems that have been resolved in the field over the past decade, those that remain to be resolved and suggest directions for future problem solving and research.

Association of exercise participation levels with cardiometabolic health and quality of life in individuals with hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with an increased risk of cardiovascular disease (CVD) and reduced health-related quality of life (HRQoL). Although physical activity (PA)/exercise has been shown to reduce CVD risk and improve HRQoL in patients with liver disease, there is limited data in HCV. We aimed to explore the association between PA/exercise levels, CVD risk and HRQoL in patients with HCV and assess individuals' attitudes to PA/exercise. DESIGN: Cross-sectional observational study recruiting consecutive patients with HCV from viral hepatitis clinics. Data were collected on CVD risk factors, anthropometry, HRQoL and the Exercise Benefits and Barriers Scale (EBBS). RESULTS: 86 patients were recruited (71% men, 94% white, age 52±13 years); 49% of the cohort self-reported to be currently active. Although HRQoL was reduced across the cohort, patients that were regularly 'active' reported significantly higher HRQoL scores across Short-Form 36v2 domains compared with their inactive counterparts (p<0.05). Metabolic and cardiovascular characteristics were no different between groups stratified by PA/exercise status (p>0.05). EBBS scores were similar in the 'active' versus 'inactive' groups, however, patients categorised as 'active' scored significantly higher on the psychological outlook and social interaction subscales (p<0.05) than those that were 'inactive'. There were significant associations between EBBS scores and HRQoL (p<0.05). CONCLUSIONS: PA/exercise is associated with increased HRQoL in patients with HCV irrespective of clinical parameters. Addressing specific motivators/barriers to exercise for patients will be key to designing effective PA/exercise interventions in this patient population to ensure maximum uptake and adherence.

Increased cardiovascular risk and reduced quality of life are highly prevalent among individuals with hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is common. Although treatment is effective, with oral antivirals curing >95% of patients, most individuals have comorbidities that persist long term. Therefore, our aim was to determine the prevalence of potentially modifiable health problems in patients with HCV and develop an HCV care bundle to identify and target comorbidities. DESIGN: Cross-sectional, observational single-centre study that recruited consecutive patients with HCV from our viral hepatitis clinics. Data were collected on cardiovascular (CV) risk factors, lifestyle behaviours, anthropometry and health-related quality of life (HRQoL). QRISK 3 was used to predict 10-year CV event risk. RESULTS: 100 patients were recruited (67% male, 93% white, median age 52 years (range 24-80); 71% were treated for HCV; 34% had cirrhosis; 14% had diabetes; 61% had hypertension; 31% had metabolic syndrome; and 54% were smokers). The median 10-year CV event risk was 8.3% (range 0.3%-63%). 45% had a predicted 10-year CV event risk of >10%. Only 10% of individuals were treated with statins and 27% with antihypertensives. 92% had a predicted 'heart age' greater than their chronological age (median difference +7 (-4 to +26) years). HRQoL was reduced in all SF36v2 domains in the cohort. Factors independently associated with HRQoL included cirrhosis, metabolic syndrome, history of mental health disorder, sedentary behaviour and HCV viraemia. CONCLUSION: A large proportion of patients with HCV presented with increased risk of CV events, and rates of smoking and sedentary behaviour were high, while prescribing of primary prophylaxis was infrequent. HRQoL was also reduced in the cohort. A 'care bundle' was developed to provide a structured approach to treating potentially modifiable health problems.