Immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV in the Netherlands.

OBJECTIVE: We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH). DESIGN: Prospective observational cohort study. METHODS: PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those < 45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1:2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses, and cytokine responses up to 180 days post-vaccination. RESULTS: Forty PWH received mRNA-1273.214 (N = 35) or BNT162b2 (N = 5) following mRNA-based (N = 29) or vector-based (N = 11) primary vaccination. PWH were predominantly male (87% vs 26% of non-PWH) and median 57 years (interquartile range [IQR] 53-59). Their median CD4+ T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was < 50 copies/mL in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH (4.48, 95% confidence interval [CI] 3.24-6.19) and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. IFN-γ, IL-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH. CONCLUSION: A bivalent BA.1 booster vaccine was immunogenic in well-treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH.

Prognostic Scores for Ursodeoxycholic Acid-Treated Patients Predict Graft Loss and Mortality in Recurrent Primary Biliary Cholangitis after Liver Transplantation.

BACKGROUND/AIM: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of scores for PBC to predict the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centres across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2 - 62.6], and 298 patients (90%) were females. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3 - 12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (HR, 3.97, 95%CI 1.36-11.55, P=0.01), use of prednisone (HR 3.18, 95%CI 1.04-9.73, P=0.04), ALP xULN (HR 1.59, 95%CI 1.26-2.01, P<0.001), Paris-2 criteria (HR 4.14, 95%CI 1.57-10.92, P=0.004), GLOBE score (HR 2.82, 95%CI 1.71-4.66, P<0.001), and the UK-PBC score (HR 1.06, 95%CI 1.03-1.09, P<0.001) were associated with graft survival in the multivariate analysis. Similar results were found in the overall survival analysis. CONCLUSION: Patients with rPBC and disease activity as indicated by standard PBC risk scores have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who have liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid according to conventional prognostic scores have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results emphasized supporting efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

INTRODUCTION: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. RESULTS: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

Factors associated with knowledge and awareness of Hepatitis B in individuals of Chinese descent: Results from a mass point of care testing and outreach campaign in Toronto, Canada.

Background: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine. Methods: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants' level of HBV knowledge. Results: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% (N = 552), were female, and 73.6% (N = 656) have been in Canada for <30 years. The average questionnaire score was 70.7% correct, with 65.2% (N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of $50,000 to <$75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing. Conclusions: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups.

Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan.

BACKGROUND: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial). DESIGN: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved. TRIAL REGISTRATION: ClinicalTrials.gov NCT04373902 (registered April 2020).

Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study.

BACKGROUND & AIMS: Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. METHODS: We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. RESULTS: In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. CONCLUSION: In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. IMPACT AND IMPLICATIONS: Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study).

We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 µg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.

Hepatocellular carcinoma risk in sub-Saharan African and Afro-Surinamese individuals with chronic hepatitis B living in Europe.

BACKGROUND & AIMS: Sub-Saharan African (SSA) ethnicity has been associated with a higher risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis B in cross-sectional studies. However, the incidence of HCC and performance of HCC risk scores in this population are unknown. METHODS: We conducted an international multicenter retrospective cohort study of all consecutive HBV-monoinfected individuals of SSA or Afro-Surinamese (AS) ethnicity managed at sites in the Netherlands, the United Kingdom and Spain. We assessed the 5- and 10-year cumulative incidences of HCC in the overall study population, among different clinically relevant subgroups and across (m)PAGE-B subgroups. Next, we explored the different risk factors for HCC. RESULTS: During a median follow-up of 8 years, we analyzed 1,473 individuals of whom 34 developed HCC. The 5- and 10-year cumulative incidences of HCC were 1% and 2.4%. The 10-year cumulative incidence of HCC was 0.7% among individuals without advanced fibrosis at baseline, compared to 12.1% among individuals with advanced fibrosis (p <0.001). Higher age (adjusted hazard ratio [aHR] 1.05), lower platelet count (aHR 0.98), lower albumin level (aHR 0.90) and higher HBV DNA log10 (aHR 1.21) were significantly associated with HCC development. The 10-year cumulative incidence of HCC was 0.5% among individuals with a low PAGE-B score, compared to 2.9% in the intermediate- and 15.9% in the high-risk groups (p <0.001). CONCLUSIONS: In this unique international multicenter cohort of SSA and AS individuals with chronic hepatitis B, we observed 5- and 10-year cumulative HCC risks of 1% and 2.4%, respectively. The risk of HCC was negligible for individuals without advanced fibrosis at baseline, and among individuals with low baseline (m)PAGE-B scores. These findings can be used to guide HCC surveillance strategies. IMPACT AND IMPLICATIONS: Sub-Saharan African ethnicity has been associated with a higher risk of hepatocellular carcinoma among individuals with chronic hepatitis B. In this international multicenter cohort study of sub-Saharan African and Afro-Surinamese individuals living with chronic hepatitis B in Europe, we observed 5- and 10-year cumulative incidences of hepatocellular carcinoma of 1% and 2.4%, respectively. The risk was negligible among individuals without advanced fibrosis and a low baseline (m)PAGE-B score. These findings can be used to guide HCC surveillance strategies in this population.

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Validation and optimization of AFP-based biomarker panels for early HCC detection in Latin America and Europe.

BACKGROUND: HCC is a major cause of cancer death worldwide. Serum biomarkers such as alpha-fetoprotein (AFP), protein induced by vitamin K absence-II, and the Gender, Age, AFP-L3, AFP, Des-gamma-carboxy prothrombin (GALAD) score have been recommended for HCC surveillance. However, inconsistent recommendations in international guidelines limit their clinical utility. METHODS: In this multicenter study, over 2000 patient samples were collected in 6 Latin American and 2 European countries. The performance of the GALAD score was validated in cirrhotic cases, and optimized versions were tested for early-stage HCC and prediagnostic HCC detection. RESULTS: The GALAD score could distinguish between HCC and cirrhosis in Latin American patients with an AUC of 0.76, sensitivity of 70%, and specificity of 83% at the conventional cutoff value of -0.63. In a European cohort, GALAD had an AUC of 0.69, sensitivity of 66%, and specificity of 72%. Optimizing the score in the 2 large multicenter cohorts revealed that AFP-L3 contributed minimally to early-stage HCC detection. Thus, we developed a modified GALAD score without AFP-L3, the ASAP (age, sex, AFP, and protein induced by vitamin K absence-II), which showed promise for early-stage HCC detection upon validation. The ASAP score also identified patients with cirrhosis at high risk for advanced-stage HCC up to 15 months before diagnosis (p < 0.0001) and differentiated HCC from hemangiomas, with a specificity of 100% at 71% sensitivity. CONCLUSION: Our comprehensive analysis of large sample cohorts validates the GALAD score's utility in Latin American, Spanish, and Dutch patients for early-stage HCC detection. The optimized GALAD without AFP-L3, the ASAP score, is a good alternative and shows greater promise for HCC prediction.

Analysis of Time to Treatment and Survival Among Adults Younger Than 50 Years of Age With Colorectal Cancer in Canada.

Importance: Colorectal cancer (CRC) is uncommon in adults younger than 50 years of age, so this population may experience delays to treatment that contribute to advanced stage and poor survival. Objective: To investigate whether there is an association between time from presentation to treatment and survival in younger adults with CRC. Design, Setting, and Participants: This retrospective cohort study used linked population-based data in Ontario, Canada. Participants included patients with CRC aged younger than 50 years who were diagnosed in Ontario between 2007 and 2018. Analysis was performed between December 2019 and December 2022. Exposure: Administrative and billing codes were used to identify the number of days between the date of first presentation and treatment initiation (overall interval). Main Outcomes and Measures: The associations between increasing overall interval, overall survival (OS), and cause-specific survival (CSS) were explored with restricted cubic spline regression. Multivariable Cox proportional hazards models were also fit for OS and CSS, adjusted for confounders. Analyses were repeated in a subset of patients with lower urgency, defined as those who did not present emergently, did not have metastatic disease, did not have cross-sectional imaging or endoscopy within 14 days of first presentation, and had an overall interval of at least 28 days duration. Results: Among 5026 patients included, the median (IQR) age was 44.0 years (40.0-47.0 years); 2412 (48.0%) were female; 1266 (25.2%) had metastatic disease and 1570 (31.2%) had rectal cancer. The lower-urgency subset consisted of 2548 patients. The median (IQR) overall interval was 108 days (55-214 days) (15.4 weeks [7.9-30.6 weeks]). Patients with metastatic CRC had shorter median (IQR) overall intervals (83 days [39-183 days]) compared with those with less advanced disease. Five-year overall survival was 69.8% (95% CI, 68.4%-71.1%). Spline regression showed younger patients with shorter overall intervals (<108 days) had worse OS and CSS with no significant adverse outcomes of longer overall intervals. In adjusted Cox models, overall intervals longer than 18 weeks were not associated with significantly worse OS or CSS compared with those waiting 12 to 18 weeks (OS: HR, 0.83 [95% CI, 0.67-1.03]; CSS: HR, 0.90 [95% CI, 0.69-1.18]). Results were similar in the subset of lower-urgency patients, and when stratified by stage. Conclusions and relevance: In this cohort study of 5026 patients with CRC aged younger than 50 years of age in Ontario, time from presentation to treatment was not associated with advanced disease or poor survival. These results suggest that targeting postpresentation intervals may not translate to improved outcomes on a population level.

Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor.

BACKGROUND AND AIMS: Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor. APPROACH AND RESULTS: We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival. CONCLUSIONS: Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. METHODS: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. RESULTS: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. CONCLUSIONS: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.

Association Between the Presence of Metabolic Comorbidities and Liver-Related Events in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Patients with chronic hepatitis B (CHB) are at increased risk of hepatocellular carcinoma and (liver-related) mortality. In addition to hepatitis B-related factors, metabolic comorbidities may contribute to the progression of fibrosis. Therefore, we studied the association between metabolic comorbidities and adverse clinical outcomes in patients with CHB. METHODS: We conducted a retrospective cohort study of CHB patients attending the Erasmus MC University Medical Center (Rotterdam, The Netherlands) and CHB patients who underwent liver biopsy at the Toronto General Hospital (Toronto, Canada). The presence of metabolic comorbidities (ie, overweight, diabetes mellitus, hypertension, and dyslipidemia) was assessed based on chart review. The primary end point was liver-related events, defined as the first composite of hepatocellular carcinoma, liver transplantation, or liver-related mortality. RESULTS: We analyzed 1850 patients, of whom 926 (50.1%) were overweight, 161 (8.7%) had hypertension, 116 (6.3%) had dyslipidemia, and 82 (4.4%) had diabetes. During a median follow-up period of 7.3 years (interquartile range, 2.9-11.5 y), a total of 111 first events were recorded. Hypertension (hazard ratio [HR], 8.3; 95% CI, 5.5-12.7), diabetes (HR, 5.4; 95% CI, 3.2-9.1), dyslipidemia (HR, 2.8; 95% CI, 1.6-4.8), and overweight (HR, 1.7; 95% CI, 1.1-2.5) were associated with an increased risk for liver-related events. The presence of multiple comorbidities further increased the risk. Findings were consistent for patients with and without cirrhosis, among noncirrhotic hepatitis B e antigen-negative patients with hepatitis B virus DNA less than 2000 IU/mL and in multivariable analysis adjusting for age, sex, ethnicity, hepatitis B e antigen status, hepatitis B virus DNA, use of antiviral therapy, and the presence of cirrhosis. CONCLUSIONS: Metabolic comorbidities in CHB patients are associated with an increased risk for liver-related events, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in various clinically relevant subgroups, underscoring the need for thorough metabolic assessment in patients with CHB.

Survival in very preterm infants with congenital diaphragmatic hernia and association with prenatal imaging markers: A retrospective cohort study.

OBJECTIVES: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. DESIGN: Retrospective cohort study. SETTING: Multicentre study in large referral centres. POPULATION: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. METHODS: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). MAIN OUTCOME MEASURE: Survival to discharge. RESULTS: We included 53 infants born at 30+4 (interquartile range 29+1 -31+2 ) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07-1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88-1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). CONCLUSIONS: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival.

Outcomes of liver transplantation in non-alcoholic steatohepatitis (NASH) versus non-NASH associated hepatocellular carcinoma.

BACKGROUND: Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has potential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort. METHODS: Adults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria. RESULTS: 2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual proportional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87-1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89-1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34-0.98, p = 0.04). DISCUSSION: NASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.

Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection.

Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of "early recurrence" (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA. Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used. Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period. Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.

Comparing Time to Diagnosis and Treatment Between Younger and Older Adults With Colorectal Cancer: A Population-Based Study.

BACKGROUND & AIMS: Younger adults (aged <50 years) with colorectal cancer (CRC) may have prolonged delays to diagnosis and treatment that are associated with adverse outcomes. We compared delay intervals by age for patients with CRC in a large population. METHODS: This was a population-based study of adults diagnosed with CRC in Ontario, Canada, from 2003 to 2018. We measured the time between presentation and diagnosis (diagnostic interval), diagnosis and treatment start (treatment interval), and the time from presentation to treatment (overall interval). We compared interval lengths between adults aged <50 years, 50 to 74 years, and 75 to 89 years using multivariable quantile regression. RESULTS: Included were 90,225 patients with CRC. Of these, 6853 patients (7.6%) were aged <50 years. Younger patients were more likely to be women, present emergently, have stage IV disease, and have rectal cancer compared with middle-aged patients. Factors associated with significantly longer overall intervals included female sex (8.7 days; 95% confidence interval [CI], 6.6-10.9 days) and rectal cancer compared with proximal colon cancer (9.8 days; 95% CI, 7.4-2.2 days). After adjustment, adults aged <50 years had significantly longer diagnostic intervals (4.3 days; 95% CI. 1.3-7.3 days) and significantly shorter treatment intervals (-4.5 days; 95% CI, -5.3 to -3.7 days) compared with middle-aged patients. However, there was no significant difference in the overall interval (-0.6 days; 95% CI, -4.3 to 3.2 days). In stratified models, younger adults with stage IV disease who presented emergently and patients aged >75 years had longer overall intervals. CONCLUSIONS: Younger adults present more often with stage IV CRC but have overall similar times from presentation to treatment as screening-eligible older adults.