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Background Evidence regarding the use of proton-pump inhibitors (PPIs) in COVID-19 patients remains elusive. We examined the impact of PPI use on clinical outcomes of COVID-19 patients in a territory-wide cohort. Methods We performed a retrospective cohort study using data from an electronic healthcare database managed by the Hospital Authority, Hong Kong. COVID-19 patients diagnosed virologically between 23 January 2020 and 1 January 2021 in Hong Kong were identified. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. PPI user was identified by PPI use within 12 months before the diagnosis of COVID-19. In subgroup analysis, current PPI users were defined as patients who used PPIs within 1 month before the diagnosis of COVID-19;past PPI users were defined as patients who used PPIs 1 to 12 months before COVID-19 diagnosis. We performed sensitivity analysis after excluding patients with short-term new NSAID use within 1 month before COVID-19 diagnosis to minimize reverse causation bias. Results We identified 8,675 COVID-19 patients (mean age 46 years, 49% male, 97.6% of all the reported cases in Hong Kong);579 (6.7%) patients had used PPI. PPI users were older, more likely to have comorbidities, concomitant medications and unfavorable laboratory parameters than non-users. Of 8,675 COVID-19 patients, 500 (5.8%) developed the primary endpoint. After propensity score (PS) balancing for patients' demographics, comorbidities, laboratory parameters, and use of medications, PPI use was not associated with the development of primary endpoint in PS weighting (weighted hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.83-1.47, P=0.482) (IDDF2021-ABS- 0122 Figure 1. Cumulative incidence of primary endpoint (a composite endpoint of intensive care unit [ICU] admission, use of invasive mechanical ventilation [IMV], and death) in COVID-19 patients who were and were not proton- pump inhibitor (PPI) users after propensity score (PS) weighting in a single multiple imputation data set.), and PS matching analysis (weighted HR 0.81, 95%CI 0.57-1.14, P=0.228) (IDDF2021-ABS-0122 Figure 2. Cumulative incidence of primary endpoint (a composite endpoint of intensive care unit [ICU] admission, use of invasive mechanical ventilation [IMV], and death) in COVID-19 patients who were and were not proton-pump inhibitor (PPI) users after propensity score (PS) matching in a single multiple imputation data set). Consistent non-association was observed after multivariable adjustment (adjusted HR 0.84, 95%CI 0.66- 1.07, P=0.151), in subgroups of current and past PPI users, and in sensitivity analysis after excluding short-term new NSAID users. Conclusions PPI use is not associated with adverse clinical outcomes in COVID-19 patients. The result remains robust after PS weighting, PS matching, multivariable adjustment, and subgroup analyses.

Background There is a major unmet need for accurate, readily available, noninvasive tests (NITs) to identify patients with advanced fibrosis due to NASH. Our goal was to evaluate sequential NIT algorithms to minimize the requirement for biopsy and improve accuracy overuse of single tests. Methods The STELLAR studies (NCT03053050, NCT03053063) enrolled NASH patients with bridging fibrosis (F3) or compensated cirrhosis (F4). Baseline liver biopsies were read using the NASH CRN fibrosis classification and noninvasive fibrosis markers: FIB-4 index, ELF test, and FibroScan® (FS). The performance of these tests to discriminate advanced fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Thresholds were obtained by maximizing specificity given ≥85% sensitivity. The cohort was divided (80%/20%) into evaluation/validation sets. The evaluation set was further stratified 250x into training and test sets (66%/33%). Optimal thresholds were derived as the average across training sets, and applied sequentially (FIB-4 followed by ELF and/or FS) to the validation set. Data are from an interim analysis on 26 July 2018. Results All patients with available liver histology (N=3202, 71% F3-F4) and NIT results were included. While single tests were able to discriminate advanced fibrosis (AUROCs of 0.78, 0.80, and 0.80 for FIB-4, ELF, and FS in validation cohort), up to 32% of patients had an indeterminate result. Using thresholds derived from STELLAR data, FIB-4 followed by FS or ELF in those with indeterminate FIB-4 values (1.23 to 2.1) reduced indeterminate results to as low as 13% (table 1). Published NIT thresholds yielded similar results (data not shown). Adding a third test (FIB-4 then ELF then FS) reduced the rate of indeterminate results to 8%. Misclassification occurred at rates similar to biopsy (15–21%). The majority of misclassifications (63–81%) were false negatives; among false positive cases (19–27% of misclassifications) up to 70% had F2 fibrosis. Conclusions FIB-4 followed by ELF and/or FS nearly eliminated the need for liver biopsy and accurately identified patients with advanced fibrosis due to NASH with misclassification rates similar to liver biopsy.

Background Liver biopsy is currently the reference standard for fibrosis staging, but is an invasive procedure with limitations. There are a major unmet need for accurate, readily available noninvasive tests (NITs) to identify patients with advanced fibrosis due to NASH. Our aim is to describe the performance of NITs using the baseline data from the Phase 3 STELLAR studies of the ASK1 inhibitor selonsertib (SEL). Methods The STELLAR studies (NCT03053050 and NCT03053063) enrolled patients with bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH (NAFLD Activity Score [NAS] ≥3). Baseline liver biopsies were centrally read according to the NASH CRN fibrosis classification and noninvasive markers of fibrosis, including the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness (LS) by transient elastography (TE; FibroScan®) were measured. The performance of these tests to discriminate advanced (F3-F4) fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Optimal thresholds for F3-F4 fibrosis were selected based on the literature. Data presented are from an interim analysis on 1 May 2018. Results A total of 4467 patients (median age 58 years, 55% women, 72% Caucasian, 59% with diabetes) were screened. In the 3220 with evaluable histology, median biopsy length was 2.0 cm, 8% F0, 9% F1, 13% F2, 31% F3, 40% F4, 59% with NAS ≥5. Median values of NFS, FIB-4, ELF, and LS by TE increased with worsening fibrosis (-0.962/1.19/9.21/8.8 kPa in F0-F2 vs 0.342/2.20/10.39/16.5 kPa in F3-F4 respectively). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis (table 1). When tests were combined, performance characteristics improved and PPVs ≥98% were possible. Conclusions In these large, global phase 3 trials of SEL, routinely available NITs demonstrated acceptable diagnostic performance for the discrimination of advanced fibrosis due to NASH.

Background We examined the interaction between severity of renal and liver impairment on the risk of metabolic acidosis in diabetic patients with chronic hepatitis B (CHB)-related cirrhosis. Methods This is a retrospective cohort study on diabetic patients with CHB-related cirrhosis between January 2000 and December 2017 using Clinical Data Analysis and Reporting System, which is a territory-wide electronic healthcare database that captures in-patient and out-patient data of all public hospitals and clinics and represents 90% of the 7.3 million Hong Kong population. Metabolic acidosis was defined by blood pH≤7.35 with arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L or lactate >5 mmol/L, and/or diagnosis codes. Renal and liver function were modelled by time-dependent estimated glomerular filtration rate (eGFR) category and Child-Pugh class. Time-dependent medication uses and comorbidities were included in Fine-Gray model adjusted for competing for death. We excluded patients with eGFR Results Of 4,431 diabetic patients with CHB-related cirrhosis, 3,216 (72.6%) were male; the mean age (SD) was 60.8 (10.8) years; 1,590 (35.9%), 2,029 (45.8%), 544 (12.3%) and 268 (6.0%) had baseline eGFR ≥90, 60–89, 45–59 and 30–44 mL/min/1.73 m2; 3,217 (72.6%), 1,028 (23.2%) and 186 (4.2%) were in Child-Pugh class A, B and C at baseline (figure 1). At a median (interquartile range) follow-up of 5.3 (2.0–9.7) years, 1,060 (23.9%) patients developed metabolic acidosis. In Child-Pugh class A, the risk of metabolic acidosis elevated in eGFR Conclusions The risk of metabolic acidosis increases with renal and liver impairment in diabetic patients with CHB-related cirrhosis.

Background We aimed to evaluate the impact of alanine aminotransferase (ALT) normalisation (ALTN) achieved at different time after the start of antiviral treatment on the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Methods We identified a territory-wide cohort of CHB patients who received entecavir and/or tenofovir disoproxil fumarate (TDF) for ≥1 year between 2005 and 2016 in Hong Kong. Serial on-treatment ALT levels were analysed. ALTN referred to ALT level lower than the upper limit of normal (ULN) (30 U/L in males and 19 U/L in females). Early ALTN was defined as ALTN within 12 months. The primary outcome was HCC based on ICD-9-CM diagnosis codes. Patients with cancers previously or during the first year of treatment were excluded. Results 21,182 CHB patients (10 437 with and 10 745 without ALTN at 12 months after antiviral treatment) were identified and followed for a median (interquartile range) of 4.1 (2.4–6.0) years. Patients with or without ALTN at 12 months differed in gender distribution (76.9% vs. 58.4% male), baseline ALT (58 vs. 61 U/L), baseline serum HBV DNA (4.9 vs. 5.1 log10IU/mL), proportion of positive hepatitis B e antigen (31.5% vs. 37.1%), and presence of cirrhosis (8.8% vs. 10.5%) and diabetes mellitus (8.1% vs. 9.1%); 509 (2.4%) patients developed HCC. ALTN at 3, 6, 9 and 12 months were associated with a reduced risk of HCC (Figure 1), with adjusted hazard ratios (aHR) (95% confidence interval [CI]) of 0.55 (0.42,0.71), 0.52 (0.41,0.64), 0.47 (0.38,0.58) and 0.46 (0.37,0.56), respectively (all p Conclusions Early on-treatment ALTN reduces the risk of HCC in CHB patients having entecavir/TDF treatment. On-treatment ALT above 1 and 2 times the ULN at 12 months were associated with higher risk of HCC.