Evaluating gender bias in ML-based clinical risk prediction models: A study on multiple use cases at different hospitals.

BACKGROUND: An inherent difference exists between male and female bodies, the historical under-representation of females in clinical trials widened this gap in existing healthcare data. The fairness of clinical decision-support tools is at risk when developed based on biased data. This paper aims to quantitatively assess the gender bias in risk prediction models. We aim to generalize our findings by performing this investigation on multiple use cases at different hospitals. METHODS: First, we conduct a thorough analysis of the source data to find gender-based disparities. Secondly, we assess the model performance on different gender groups at different hospitals and on different use cases. Performance evaluation is quantified using the area under the receiver-operating characteristic curve (AUROC). Lastly, we investigate the clinical implications of these biases by analyzing the underdiagnosis and overdiagnosis rate, and the decision curve analysis (DCA). We also investigate the influence of model calibration on mitigating gender-related disparities in decision-making processes. RESULTS: Our data analysis reveals notable variations in incidence rates, AUROC, and over-diagnosis rates across different genders, hospitals and clinical use cases. However, it is also observed the underdiagnosis rate is consistently higher in the female population. In general, the female population exhibits lower incidence rates and the models perform worse when applied to this group. Furthermore, the decision curve analysis demonstrates there is no statistically significant difference between the model's clinical utility across gender groups within the interested range of thresholds. CONCLUSION: The presence of gender bias within risk prediction models varies across different clinical use cases and healthcare institutions. Although inherent difference is observed between male and female populations at the data source level, this variance does not affect the parity of clinical utility. In conclusion, the evaluations conducted in this study highlight the significance of continuous monitoring of gender-based disparities in various perspectives for clinical risk prediction models.

Cooperative nucleic acid binding by Poly ADP-ribose polymerase 1.

Poly (ADP)-ribose polymerase 1 (PARP1) is an abundant nuclear protein well-known for its role in DNA repair yet also participates in DNA replication, transcription, and co-transcriptional splicing, where DNA is undamaged. Thus, binding to undamaged regions in DNA and RNA is likely a part of PARP1's normal repertoire. Here we describe analyses of PARP1 binding to two short single-stranded DNAs, a single-stranded RNA, and a double stranded DNA. The investigations involved comparing the wild-type (WT) full-length enzyme with mutants lacking the catalytic domain (∆CAT) or zinc fingers 1 and 2 (∆Zn1∆Zn2). All three protein types exhibited monomeric characteristics in solution and formed saturated 2:1 complexes with single-stranded T20 and U20 oligonucleotides. These complexes formed without accumulation of 1:1 intermediates, a pattern suggestive of positive binding cooperativity. The retention of binding activities by ∆CAT and ∆Zn1∆Zn2 enzymes suggests that neither the catalytic domain nor zinc fingers 1 and 2 are indispensable for cooperative binding. In contrast, when a double stranded 19mer DNA was tested, WT PARP1 formed a 4:1 complex while the ∆Zn1Zn2 mutant binding saturated at 1:1 stoichiometry. These deviations from the 2:1 pattern observed with T20 and U20 oligonucleotides show that PARP's binding mechanism can be influenced by the secondary structure of the nucleic acid. Our studies show that PARP1:nucleic acid interactions are strongly dependent on the nucleic acid type and properties, perhaps reflecting PARP1's ability to respond differently to different nucleic acid ligands in cells. These findings lay a platform for understanding how the functionally versatile PARP1 recognizes diverse oligonucleotides within the realms of chromatin and RNA biology.

Review article: New developments in biomarkers and clinical drug development in alpha-1 antitrypsin deficiency-related liver disease.

BACKGROUND: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD. AIMS: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments. METHODS: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic. RESULTS: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies. CONCLUSIONS: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.

Outcomes of early vs late treatment initiation in solid organ transplantation from hepatitis C virus nucleic acid test-positive donors to hepatitis C virus-uninfected recipients: Results from the HCV-TARGET study.

Curative hepatitis C virus (HCV) therapy has increased transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients (D+/R-). We evaluated outcomes of early and late HCV treatment among D+/R- nonliver organ transplants. Patients received HCV regimens per local standard (n = 10 sites). Outcomes were compared between early and late treatments. Early treatment regimens (ETR) (n = 56) were initiated pretransplantation to day 7 posttransplant. Late treatment regimens (LTRs) (n = 102) began median 31 (range, 8-114) days posttransplant. There were 79 kidney, 50 lung, 23 heart, and 6 mixed transplants, similar between groups. HCV RNA was quantifiable in 98% of LTR versus 44.6% of ETR recipients (P < .001). Mean (range) days on treatment were 28 (7-93) ETR and 81 (51-111) LTR (P < .0001). There were no virological failures with ETR, but relapse (n = 3) and nonresponse (n = 2) in LTR (P = .16), including fibrosing cholestatic hepatitis postrelapse (n = 1). Sustained virological response was 100% (95% confidence interval, 93.4-100.0) in ETR (n = 54) and 94.9% (95% confidence interval, 88.5-98.3) in LTR (n = 98). Acute rejection occurred in 11 (19.6%) ETR and 25 (24.5%) LTR. In total, 11 HCV-unrelated deaths occurred: 8 ETR and 3 LTR. Organ transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients was safe. ETR led to fewer virological failures with shorter treatment duration, supporting recommendations to initiate treatment promptly posttransplant.

Patient-reported symptoms and interest in symptom monitoring in HCC treated with locoregional therapies: A qualitative study.

BACKGROUND: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system. METHODS: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes. RESULTS: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring. CONCLUSIONS: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC.

Validation of a Clinical Risk-based Classification System in a Large Nonalcoholic Fatty Liver Disease Real-world Cohort.

BACKGROUND & AIMS: There is an unmet need to validate simple and easily available methods that can be used in routine practice to identify those at risk of adverse outcomes from nonalcoholic fatty liver disease (NAFLD). A retrospective-prospective analysis of NAFLD patients enrolled in a longitudinal noninterventional study (TARGET-NASH) was performed to validate the prognostic utility of the following risk-categories: (A) Fibrosis-4 (FIB-4) <1.3 and/or liver-stiffness measurement (LSM) measured by Fibroscan <8 kp, (B) FIB-4 1.31‒2.6 and/or LSM 8.1-12.5 kp, and (C) FIB-4 >2.6 and/or LSM >12.5 kp. METHODS: Those in class A with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3, or class B with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3 were upstaged by one class. Fine-Gray competing risk analyses were performed for all outcomes. RESULTS: A total of 2523 individuals (class A = 555, B = 879, C = 1089) were followed for a median duration of 3.74 years. Adverse outcomes increased from class A to C in all-cause mortality (0.07 vs 0.3 vs 2.5/100 person-years [PY], hazard ratio [HR], 3.0 and 16.3 class B and C vs A), liver-associated clinical events (0.2 vs 1 vs 8/100 PY, HR, 4.3 and 36.6 B and C vs A), major adverse cardiovascular events (0.69 vs 0.87 vs 2.02/100 PY, HR, 0.78 and 1.55 B and C vs A), hepatocellular carcinoma (0 vs 0.09 vs 0.88/100 PY, HR, 8.32 C vs B), and chronic kidney disease (1.24 vs 2.48 vs 3.51/100 PY). Those who were upstaged had outcome rates similar to the lower class defined by their FIB-4. CONCLUSIONS: These data support a FIB-4-based risk-stratification of NAFLD that can be used in routine clinical practice. CLINICALTRIALS: gov Identifier: NCT02815891.

Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial.

INTRODUCTION: Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn. METHODS: Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <10 3 IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria. RESULTS: Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal. DISCUSSION: Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.

Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

Effectiveness of Remdesivir Treatment Protocols Among Patients Hospitalized with COVID-19: A Target Trial Emulation.

BACKGROUND: Remdesivir is recommended for certain hospitalized patients with COVID-19. However, these recommendations are based on evidence from small randomized trials, early observational studies, or expert opinion. Further investigation is needed to better inform treatment guidelines with regard to the effectiveness of remdesivir among these patients. METHODS: We emulated a randomized target trial using chargemaster data from 333 US hospitals from 1 May 2020 to 31 December 2021. We compared three treatment protocols: remdesivir within 2 days of hospital admission, no remdesivir within the first 2 days of admission, and no remdesivir ever. We used baseline comorbidities recorded from encounters up to 12 months before admission and identified the use of in-hospital medications, procedures, and oxygen supplementation from charges. We estimated the cumulative incidence of mortality or mechanical ventilation/extracorporeal membrane oxygenation with an inverse probability of censoring weighted estimator. We conducted analyses in the total population as well as in subgroups stratified by level of oxygen supplementation. RESULTS: A total of 274,319 adult patients met the eligibility criteria for the study. Thirty-day in-hospital mortality risk differences for patients adhering to the early remdesivir protocol were -3.1% (95% confidence interval = -3.5%, -2.7%) compared to no early remdesivir and -3.7% (95% confidence interval -4.2%, -3.2%) compared to never remdesivir, with the strongest effect in patients needing high-flow oxygen. For mechanical ventilation/extracorporeal membrane oxygenation, risk differences were minimal. CONCLUSIONS: We estimate that, among hospitalized patients with COVID-19, remdesivir treatment within 2 days of admission reduced 30-day in-hospital mortality, particularly for patients receiving supplemental oxygen on the day of admission.

Speech patterns and enunciation for encephalopathy determination-A prospective study of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complication of cirrhosis that benefits from early diagnosis and treatment. We aimed to characterize speech patterns of individuals with HE to investigate its potential to diagnose and monitor HE. This was a single-center prospective cohort study that included participants with cirrhosis with HE (minimal HE [MHE] and overt HE [OHE]), cirrhosis without HE, and participants without liver disease. Audio recordings of reading, sentence repetition, and picture description tasks were obtained from these groups. Two certified speech-language pathologists assessed speech rate (words per minute) and articulatory precision. An overall severity metric was derived from these measures. Cross-sectional analyses were performed using nonparametric Wilcoxon statistics to evaluate group differences. Change over time in speech measures was analyzed descriptively for individuals with HE. The study included 43 total participants. Speech results differed by task, but the overall pattern showed slower speech rate and less precise articulation in participants with OHE compared to other groups. When speech rate and precision ratings were combined into a single speech severity metric, the impairment of participants with OHE was more severe than all other groups, and MHE had greater speech impairment than non-liver disease controls. As OHE improved clinically, participants showed notable improvement in speech rate. Participants with OHE demonstrated impaired speech rate, precision, and speech severity compared with non-liver disease and non-HE cirrhosis. Participants with MHE had less pronounced impairments. Speech parameters improved as HE clinically improved. Conclusion: These data identify speech patterns that could improve HE diagnosis, grading, and remote monitoring.

Machine Learning-Based Prediction Models for Different Clinical Risks in Different Hospitals: Evaluation of Live Performance.

BACKGROUND: Machine learning algorithms are currently used in a wide array of clinical domains to produce models that can predict clinical risk events. Most models are developed and evaluated with retrospective data, very few are evaluated in a clinical workflow, and even fewer report performances in different hospitals. In this study, we provide detailed evaluations of clinical risk prediction models in live clinical workflows for three different use cases in three different hospitals. OBJECTIVE: The main objective of this study was to evaluate clinical risk prediction models in live clinical workflows and compare their performance in these setting with their performance when using retrospective data. We also aimed at generalizing the results by applying our investigation to three different use cases in three different hospitals. METHODS: We trained clinical risk prediction models for three use cases (ie, delirium, sepsis, and acute kidney injury) in three different hospitals with retrospective data. We used machine learning and, specifically, deep learning to train models that were based on the Transformer model. The models were trained using a calibration tool that is common for all hospitals and use cases. The models had a common design but were calibrated using each hospital's specific data. The models were deployed in these three hospitals and used in daily clinical practice. The predictions made by these models were logged and correlated with the diagnosis at discharge. We compared their performance with evaluations on retrospective data and conducted cross-hospital evaluations. RESULTS: The performance of the prediction models with data from live clinical workflows was similar to the performance with retrospective data. The average value of the area under the receiver operating characteristic curve (AUROC) decreased slightly by 0.6 percentage points (from 94.8% to 94.2% at discharge). The cross-hospital evaluations exhibited severely reduced performance: the average AUROC decreased by 8 percentage points (from 94.2% to 86.3% at discharge), which indicates the importance of model calibration with data from the deployment hospital. CONCLUSIONS: Calibrating the prediction model with data from different deployment hospitals led to good performance in live settings. The performance degradation in the cross-hospital evaluation identified limitations in developing a generic model for different hospitals. Designing a generic process for model development to generate specialized prediction models for each hospital guarantees model performance in different hospitals.

"If I Get Cured, My Whole Quality of Life Will Change": Patients' Anticipated and Actualized Benefits Following Cure from Chronic Hepatitis C.

BACKGROUND: Patients' motivations for undergoing direct-acting antiviral (DAA) therapy for chronic hepatitis C may include anticipation of treatment benefits not well described in the literature. AIMS: Evaluate patients' anticipated and actualized improvements in several domains of functioning before and after viral cure. METHODS: Pre-post-study utilizing in-depth interviews with 28 patients prior to, and several months after, DAA therapy. Interviews were audio-recorded, transcribed, coded, and analyzed by two qualitative experts. RESULTS: Patients had a median age of 54 years, 43% were male, 57% white, 25% had cirrhosis, and 71% were treated with sofosbuvir/ledipasvir. Pre-treatment, patients hoped for improvements in several domains including psychological, emotional, physical, social, and occupational functioning. After viral cure, increased energy and less fear of transmission were pathways to better quality of life. Psychological and emotional improvements positively affected physical, social, and occupational functioning. Social improvements were due to better mood and motivation, fewer symptoms, and reduced fear of stigma and transmission. Occupational benefits were linked to increased stamina, self-confidence, and less pain, anxiety, and stigma. Reduced fear of stigma had a pervasive impact on all life improvements after cure. Patient characteristics such as the presence of cirrhosis or psychiatric issues influence treatment motivations. Qualitative data correspond with change in pre-post-survey scores. CONCLUSIONS: Tremendous hope is placed on the ability of DAA therapy to bring about substantial improvements in life functioning after viral cure. Highly interconnected effects on quality of life worked synergistically through improved physical and psychological well-being. Stakeholders should appreciate the multi-dimensional benefits that viral eradication bestows upon individuals and society.

Factors Associated With Readmission in the United States Following Hospitalization With Coronavirus Disease 2019.

BACKGROUND: Patients hospitalized for coronavirus disease 2019 (COVID-19) may experience complications following hospitalization and require readmission. In this analysis, we estimated the rate and risk factors associated with COVID-19-related readmission and inpatient mortality. METHODS: In this retrospective cohort study, we used deidentified chargemaster data from 297 hospitals across 40 US states on patients hospitalized with COVID-19 from 15 February 2020 through 9 June 2020. Demographics, comorbidities, acute conditions, and clinical characteristics of first hospitalization are summarized. Multivariable logistic regression was used to measure risk factor associations with 30-day readmission and in-hospital mortality. RESULTS: Among 29 659 patients, 1070 (3.6%) were readmitted. Readmitted patients were more likely to have diabetes, hypertension, cardiovascular disease (CVD), or chronic kidney disease (CKD) vs those not readmitted (P < .0001) and to present on first admission with acute kidney injury (15.6% vs 9.2%), congestive heart failure (6.4% vs 2.4%), or cardiomyopathy (2.1% vs 0.8%) (P < .0001). Higher odds of readmission were observed in patients aged >60 vs 18-40 years (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.48-2.50) and those admitted in the Northeast vs West (OR, 1.43; 95% CI, 1.14-1.79) or South (OR, 1.28; 95% CI, 1.11-1.49). Comorbidities including diabetes (OR, 1.34; 95% CI, 1.12-1.60), CVD (OR, 1.46; 95% CI, 1.23-1.72), CKD stage 1-5 (OR, 1.51; 95% CI, 1.25-1.81), and CKD stage 5 (OR, 2.27; 95% CI, 1.81-2.86) were associated with higher odds of readmission; 12.3% of readmitted patients died during second hospitalization. CONCLUSIONS: Among this large US population of patients hospitalized with COVID-19, readmission was associated with certain comorbidities and acute conditions during first hospitalization. These findings may inform strategies to mitigate risks of readmission due to COVID-19 complications.

Prevalence and Factors Associated With Statin Use Among Patients With Nonalcoholic Fatty Liver Disease in the TARGET-NASH Study.

Patients with nonalcoholic fatty liver disease (NAFLD) are at an increased risk of cardiovascular disease. Hydoxy-3-methyglutaryl-coenzyme reductase inhibitors, statins, reduce the risk of cardiovascular events.1 Studies have shown that statins are safe among patients with liver disease, including those with compensated cirrhosis,2 and their use is associated with lower mortality, hepatic decompensation, and possibly hepatocellular carcinoma.3,4 Despite these data, statins are under prescribed among patients with liver disease due to concerns about hepatotoxicity.5 This study aimed to assess prevalence and patient factors associated with indicated statin use in patients with NAFLD in a real-world cohort.

Safety and Effectiveness of Tenofovir Alafenamide in Usual Clinical Practice Confirms Results of Clinical Trials: TARGET-HBV.

BACKGROUND: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option. AIMS: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice. METHODS: Retrospective data from electronic health records was obtained from those enrolled in TARGET-HBV, a longitudinal observational cohort study of patients with chronic hepatitis B managed according to local practice standards at community and academic medical centers throughout the U.S. RESULTS: Of 500 patients enrolled, most were male (66%) and of Asian race (66%) with median age of 55 years. Cirrhosis was evident in 15%. Most patients (82%) had switched to TAF after treatment with other antivirals. The perceived safety profile of TAF was cited as the primary reason for changing therapy (32%). TAF was well tolerated and only 4 patients discontinued therapy due to adverse event during a median duration of TAF dosing of 74 weeks. Among those with paired laboratory data 12-18 months after switching to TAF, biochemical response and HBV DNA suppression was maintained. Most patients had normal renal function which was essentially unchanged throughout follow-up. CONCLUSIONS: TAF is frequently utilized in routine clinical practice due to the perception of its improved safety profile. The current study supports the growing body of evidence regarding the safety and effectiveness of TAF. Trial Registration ClinicalTrials.gov identifier: NCT03692897, https://clinicaltrials.gov/ct2/show/NCT03692897 .

Liver biopsy in the real world-reporting, expert concordance and correlation with a pragmatic clinical diagnosis.

BACKGROUND: Patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage ≥2 comprise a target population for pharmacotherapy. Liver biopsy, the reference standard for identifying this population, requires complete and accurate assessment of steatohepatitis and fibrosis. Aims To investigate the completeness of real-world NASH-related pathology reports, assess concordance between site pathologists and central expert interpretation of the histologic elements of NASH, and determine concordance between biopsy-diagnosed NASH and a pragmatic clinical definition of NASH. METHODS: Liver pathology reports from 222 patients across 38 TARGET-NASH sites were analysed for documentation of the histologic features of NASH. Biopsy slides were over-read by a blinded central expert pathologist. Concordance of histologic scores and interpretation was assessed. Histologic concordance with a clinical definition of NASH was determined. TARGET-NASH clinically defined NASH: elevated ALT, hepatic steatosis on biopsy or imaging and ≥1 of the following: BMI ≥30 kg/m2 , type 2 diabetes mellitus and dyslipidaemia. RESULTS: Documentation of steatosis, lobular inflammation, portal inflammation and ballooning were missing from 21%, 35%, 46% and 40% of reports, respectively. There was slight-to-fair concordance (weighted kappa 0.01-0.35) between site and central pathologists for inflammatory features, and moderate concordance (weighted kappa 0.56-0.57) for fibrosis staging. Clinical definition of NASH was 75%-91% concordant (94%-95% sensitive) with biopsy-diagnosed NASH. CONCLUSIONS: There is substantial variability in reporting and grading NASH and fibrosis staging in clinical practice. This heterogeneity may adversely impact patient assessment and translation of practice guidelines into reality. The TARGET-NASH pragmatic clinical definition may serve as a valuable tool to accurately identify NASH patients in clinical practice.

Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: A prospective cohort study.

Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co-infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24-48 weeks. HBeAg loss was defined as first HBeAg-negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg-negative values ≥24 weeks apart. During a median follow-up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8-13.3) per 100 person-years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre-core mutations versus wild type. Additionally, during follow-up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.