Jordan J. Feld’s research while affiliated with University Health Network and other places

The natural history and response to therapy in chronic hepatitis B (CHB) infection have been defined by a combination of serological and virological biomarkers along with liver biochemistry and/or histology. A number of novel biomarkers including HBV RNA, hepatitis B core-related antigen (HBcrAg), hepatitis B core antigen (HBcAg) and quantitative hepatitis B surface antigen (qHBsAg) have been developed and evaluated in different clinical settings. Novel immunological biomarkers have also been studied but have been less well characterized. In addition to providing insights into HBV biology, these novel biomarkers may significantly aid in the design, development and assessment of novel antiviral strategies aiming for cure of CHB. Biomarkers can be used to confirm the mechanism of action or target engagement of a novel agent but also may be used for patient selection for trials and clinical use. Ideally, biomarkers can be used to more accurately define stages of CHB, particularly degrees of virological control. In this review, the serological, virological and immunological biomarkers are described with a focus on how they can be used to guide development of HBV cure strategies. New terminology is proposed for clinical endpoints, including Sustained Control to replace the concept of partial cure and Resolved Chronic Infection to replace Functional Cure, reserving the term Cure for clearance or silencing of all cccDNA and integrated HBV DNA.

Background Hepatitis C virus (HCV) infection is associated with reduced quality of life and health utility. It is unclear whether this is primarily due to HCV infection itself or commonly co-occurring patient characteristics such as low income and mental health issues. This study aims to estimate and separate the effects of HCV infection on health utility from the effects of clinical and sociodemographic factors using real-world population-level data. Methods We conducted a cross-sectional retrospective cohort study to estimate health utilities in people with and without HCV infection in Ontario, Canada, from 2000 to 2014 using linked survey data from the Canadian Community Health Survey and health administrative data. Utilities were derived from the Health Utilities Index Mark 3 instrument. We used propensity score matching and multivariable linear regression to examine the impact of HCV infection on utility scores while adjusting for clinical and sociodemographic factors. Results There were 7,102 individuals with hepatitis C status and health utility data available (506 HCV-positive, 6,596 HCV-negative). Factors associated with marginalization were more prevalent in the HCV-positive cohort (e.g., household income <$20,000: 36% versus 15%). Propensity score matching resulted in 454 matched pairs of HCV-positive and HCV-negative individuals. HCV-positive individuals had substantially lower unadjusted utilities than HCV-negative individuals did (mean ± standard error: 0.662 ± 0.016 versus 0.734 ± 0.015). The regression model showed that HCV positivity (coefficient: −0.066), age, comorbidity, mental health history, and household income had large impacts on health utility. Conclusions HCV infection is associated with low health utility even after controlling for clinical and sociodemographic variables. Individuals with HCV infection may benefit from additional social services and supports alongside antiviral therapy to improve their quality of life. Highlights Hepatitis C virus (HCV) infection is associated with reduced quality of life and health utility. There is debate in the literature on whether this is primarily due to HCV infection itself or commonly co-occurring patient characteristics such as low income and mental health issues. We showed that individuals with HCV infection have substantially lower health utilities than uninfected individuals do even after controlling for clinical and sociodemographic variables, based on a large, real-world population-level dataset. Socioeconomically marginalized individuals with HCV infection had particularly low health utilities. In addition to improving access to HCV testing and treatment, it may be beneficial to provide social services such as mental health and financial supports to improve the quality of life and health utility of people living with HCV.

Resistance‐associated substitutions (RASs) are mutations within the hepatitis C (HCV) genome that may influence the likelihood of achieving a sustained virological response (SVR) with direct acting antiviral (DAA) treatment. Clinicians conduct RAS testing to adapt treatment regimens with the intent of improving the likelihood of cure. The Canadian Network Undertaking against Hepatitis C (CANUHC) prospective cohort consists of chronic HCV patients enrolled between 2015 and 2023 across 17 Canadian sites. Utilisation of RAS testing was assessed across demographics, clinical characteristics and years. SVR was described for the overall cohort and compared across populations of patients with historically negative predictors of SVR. The detection of key RASs and how this information influenced DAA selection were assessed. 2434 patients were identified with information on RAS testing. 98.3% achieved SVR. Out of the 227 patients tested for RAS, 147 (64.8%) had any detected RAS, and 84 (37.0%) had an NS5A RAS. The proportion of patients with SVR did not differ between RAS‐tested (98.3%) and non‐tested patients (98.3%; p = 0.99). SVR in those with an NS5a RAS was similar (98.6%) to the overall SVR proportion. Proportions with SVR did not differ between those with and without RAS testing in key subgroups (genotype 1a, genotype 3, prior treatment, cirrhosis). The specific DAA regimen and the addition of ribavirin were not associated with SVR outcome. RAS testing has a minimal influence on antiviral treatment selection. Going forward, there is a reduced role for RAS testing in most clinical scenarios.

Designing and carrying out a controlled human infection (CHI) model for hepatitis C virus (HCV) is critical for vaccine development. However, key considerations for a CHI model protocol include understanding of the earliest viral-host kinetic events during the acute phase and susceptibility of the viral isolate under consideration for use in the CHI model to antiviral treatment before any infections in human volunteers can take place. Humanized mouse models lack adaptive immune responses but provide a unique opportunity to obtain quantitative understanding of early HCV kinetics and develop mathematical models to further understand viral and innate immune response dynamics during acute HCV infection. We show that the models reproduce the measured HCV kinetics in humanized mice, which are consistent with early acute HCV-host dynamics in immunocompetent chimpanzees. Our findings suggest that humanized mice are well-suited to support development of a CHI model. In-silico and in-vivo modeling estimates provide a starting point to characterize candidate viruses for testing in CHI model studies.

Background Severe flares (ALT ≥ 10×ULN) are a well‐recognised adverse outcome after nucleos(t)ide analogue (NA) cessation and may lead to liver failure. Thus, identification of patients at risk for these flares is of major importance. Methods Data were used from two prospective studies on NA cessation conducted in the Netherlands and Canada. Patients were eligible based on EASL criteria. HBcrAg and anti‐HBc levels were measured at end of treatment (EOT) and week 6 (FUW6). Logistic regression was used to study the association with severe flares. Results Seventy‐eight patients were analysed with a mean age of 49 years, 16 (21%) Caucasian and a majority (65%) were treated with Tenofovir. Overall, 22 patients (28%) developed a severe flare, and 29 (37%) patients were retreated. At EOT, higher HBcrAg levels (aOR: 1.97, p = 0.05; ≥ 4log: 47% severe flare vs. < 3log: 19%, p = 0.036), lower anti‐HBc (aOR: 0.29, p = 0.036; < 2log: 50% vs. ≥ 3log: 11%, p = 0.029) and higher HBcrAg/anti‐HBc‐ratio (aOR: 3.17, p = 0.015; ≥ 2: 58% vs. < 1.5: 14%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBsAg. At FUW6, higher HBcrAg (aOR: 2.91, p = 0.035; ≥ 5log: 83%, < 3log: 4%, p < 0.001), lower anti‐HBc (aOR: 0.46, p = 0.29; < 2log: 50% vs. ≥ 3log: 0%, p = 0.003) and higher HBcrAg/anti‐HBc‐ratio (aOR: 2.19, p = 0.048; ≥ 1.75: 52% vs. < 1.75: 8%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBV DNA and ALT. Conclusion Higher HBcrAg, lower anti‐HBc and higher HBcrAg/anti‐HBc ratio at EOT and during the first weeks of post‐treatment follow‐up are associated with an increased risk of hepatic flares after NA withdrawal and could therefore potentially be used to select patients eligible for therapy cessation and to identify patients requiring retreatment. Trial Registration: This study was a post hoc and follow‐up study of two previously registered clinical trials (NCT01911156 & NTR7001). No new patients were prospectively included

Liver transplantation (LT) is a life-saving intervention for patients with end-stage liver disease (ESLD). However, 12-20% of patients listed for LT will die on the waitlist. Modern risk scores used for transplant prioritization cannot encompass the full statistical heterogeneity of patients awaiting LT, disadvantaging women and patients with cholestatic liver disease. Our study objective was to implement more equitable LT prioritization via a more expressive class of statistical models to individualize risk prediction. To do so, we created DynaMELD, a deep machine learning-based model of waitlist prioritization. DynaMELD leverages a neural network to model complex interactions between covariates, and leverages the rate-of-change (velocity) of time-varying laboratory biomarkers to predict a more personalized risk of mortality or dropout. Our study cohort comprised 53,046 patients with ESLD listed for LT from 2016-2023 from the U.S. Scientific Registry of Transplant Recipients. Using 90-day concordance to measure risk discrimination, DynaMELD achieves 90-day concordance 0.5% higher than MELD 3.0 (𝑝 < 0.001). Using pooled group concordance (PGCI) as a measure of fairness, DynaMELD achieves a PGCI 1.2% higher for female patients (𝑝 < 0.001), 8.3% higher for patients with primary biliary cholangitis (𝑝 < 0.001), 7.2% higher for patients with primary sclerosing cholangitis (𝑝 < 0.001), and 1.5% higher for patients with acute-on-chronic liver failure Grade 1 (𝑝 < 0.001) compared to MELD 3.0. DynaMELD reclassifies members of these sub- groups into higher risk tiers, suggesting it would improve their access to organ offers. Introspecting upon DynaMELD using the method of SHapley Additive exPlanations (SHAP) values provides an individualized degree of model interpretability. Overall, DynaMELD may provide more accurate, individualized predictions of waitlist mortality or dropout to reduce inequities and fairly prioritize patients for liver transplant.

Background Liver disease assessment is a key aspect of chronic hepatitis C virus (HCV) infection pre-treatment evaluation but guidelines differ on the optimal testing modality given trade-offs in availability and accuracy. We compared clinical outcomes and cost-effectiveness of common fibrosis staging strategies. Methods We simulated adults with chronic HCV receiving care at US health centers through a lifetime microsimulation across five strategies: (1) no staging or treatment (comparator), (2) indirect serum biomarker testing (Fibrosis-4 index [FIB-4]) only, (3) transient elastography (TE) only, (4) staged approach: FIB-4 for all, TE only for intermediate FIB-4 scores (1.45–3.25), and (5) both tests for all. Outcomes included infections cured, cirrhosis cases, liver-related deaths, costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We used literature-informed loss to follow-up (LTFU) rates and 2021 Medicaid perspective and costs. Results FIB-4 alone generated the best clinical outcomes: 87.7% cured, 8.7% developed cirrhosis, and 4.6% had liver-related deaths. TE strategies cured 58.5%–76.6%, 16.8%–29.4% developed cirrhosis, and 11.6%–22.6% had liver-related deaths. All TE strategies yielded worse clinical outcomes at higher costs per QALY than FIB-4 only, which had an ICER of $12 869 per QALY gained compared with no staging or treatment. LTFU drove these findings: TE strategies were only cost-effective with no LTFU. In a point-of-care HCV test-and-treat scenario, treatment without any staging was most clinically and cost-effective. Conclusions FIB-4 staging alone resulted in optimal clinical outcomes and was cost-effective. Treatment for chronic HCV should not be delayed while awaiting fibrosis staging with TE.