Faculty Bibliography

AIM/OBJECTIVE:Primary sclerosing cholangitis (PSC) increases the risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients; however, there is a paucity of literature to suggest PSC alone as an independent risk factor for CRC. We aimed to determine if PSC is an independent risk factor for CRC in a large tertiary care medical center. Optimizing screening intervals is of great importance, given the burden and risks associated with a lifetime of colonoscopy screening. METHODS:This retrospective cohort study consists of patients diagnosed with PSC preceding IBD (PSC-IBD) and PSC-only before January 6, 2023 from a large, tertiary, academic medical center. Patients diagnosed with IBD concurrently or before PSC were excluded to reduce IBD's impact on CRC risk. Demographic data and colonoscopy findings were collected and assessed. RESULTS:Overall, 140 patients from all NYU Langone Health clinical settings were included. Patients with PSC-IBD were more likely to be diagnosed with CRC (23.3% vs. 1.8%, p < 0.01) and either low-grade or uncharacterized dysplasia (16.7% vs. 0.0%, p < 0.01) compared with those with PSC-only. Among PSC-only patients, the estimated CRC risk was significantly elevated compared with that expected of the standard NYU Langone population (SIR 9.2, 95% CI 1.1, 33.2). CONCLUSIONS:Our study revealed a significantly heightened CRC risk in PSC-IBD patients compared with those with PSC-only. Importantly, individuals with PSC-only also face a greater CRC risk compared with the general population. Individuals with PSC-alone may require extended screening and surveillance colonoscopy intervals compared with those with PSC-IBD, yet still require more frequent monitoring than screening guidelines recommend for the general population.

BACKGROUND AND AIMS/OBJECTIVE:Hepatitis delta virus (HDV) leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database (APCD), this study estimates the prevalence of HBV/HDV infection among the chronic hepatitis B (HBV) population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States (US). APPROACH AND RESULTS/RESULTS:Adults (≥ 18 y) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the APCD from 1/1/2014 to 12/31/2020 were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (e.g., cirrhosis, hepatocellular carcinoma), and comorbidities were assessed. A total of 6,719 -patients were diagnosed with HBV/HDV among 144,975 with HBV and 12-months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), HIV infection (30.9%), were the top three comorbidities. CONCLUSION/CONCLUSIONS:In a large database capturing approximately 80% of the US insured population, HBV/HDV infection prevalence was 4.6% among HBV-infected adults. HDV-infected patients had high rates of baseline liver complications and other comorbidities at time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the HBV population may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.

Hepatocellular carcinoma (HCC) has long been recognized as a complication in people with chronic liver disease, particularly those with cirrhosis. Two gene therapies for haemophilia A and B recently approved in Europe and the US utilize adeno-associated virus (AAV) vectors designed to target hepatocytes. A number of other AAV gene therapies are undergoing clinical investigation for both liver and extrahepatic diseases, many of which likely transduce hepatocytes as well. Although AAV vectors predominantly persist in episomal forms, concerns about insertional mutagenesis have arisen due to findings in pre-clinical models and in a small subset of human HCC cases featuring wild-type AAV integrations in proximity to potential oncogenes. Despite the absence of any causative link between AAV vector therapy and HCC in approved extrahepatic gene therapies or haemophilia gene therapy trials, the package inserts for the recently approved haemophilia gene therapies advise HCC screening in subsets of individuals with additional risk factors. In this review, we discuss HCC risk factors, compare various screening modalities, discuss optimal screening intervals, and consider when to initiate and possibly discontinue screening. At this early point in the evolution of gene therapy, we lack sufficient data to make evidence-based recommendations on HCC screening. While AAV vectors may eventually be shown to be unassociated with risk of HCC, we presently favour a cautious approach that entails regular surveillance until such time as it is hopefully proven to be unnecessary.

BACKGROUND & AIMS/UNASSIGNED:The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). METHODS/UNASSIGNED:Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. RESULTS/UNASSIGNED:Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. CONCLUSIONS/UNASSIGNED:Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. CLINICAL TRIAL NUMBER/UNASSIGNED:NCT03780543. IMPACT AND IMPLICATIONS/UNASSIGNED:Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

BACKGROUND & AIMS/OBJECTIVE:Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week PGBF treatment in patients with NASH with compensated cirrhosis. METHODS:FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10-, 20-, or 40-mg) or placebo was subcutaneously injected once weekly. The primary endpoint was ≥1 stage improvement in NASH CRN fibrosis score without NASH worsening at week 48; pegbelfermin dose-response was assessed using a Cochran-Armitage trend test across proportions (1-sided α=0.05). Additional endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS:Overall, 155 patients were randomized; 154 received treatment. At week 48, 24%-28% of the pegbelfermin arms had primary endpoint responses versus 31% of the placebo arm (P=.361). NAS improvements were more frequent with pegbelfermin versus placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (MRE) and steatosis (MRI-PDFF) improvements versus placebo; these differences were not statistically significant. Mean PRO-C3, ALT, and AST were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events (AEs) were more frequent with pegbelfermin versus placebo, though none were treatment-related. One patient (40-mg pegbelfermin) discontinued treatment due to a treatment-emergent AE (worsening ascites). CONCLUSIONS:FALCON 2 did not meet its primary endpoint, ≥1 stage improvement in NASH CRN fibrosis without NASH worsening assessed via biopsy. Pegbelfermin was generally well tolerated in this advanced NASH population.

The main aim of antiviral therapy in patients with chronic hepatitis B (CHB) is to prevent disease progression and reduce the risk of hepatocellular carcinoma (HCC). In general, treatment is recommended for select patient groups viewed as being at higher risk of developing adverse outcomes from CHB. However, patients who do not meet treatment criteria under current international guidelines may still benefit from antiviral therapy to reduce CHB-related complications. Moreover, well-tolerated antiviral drugs that are highly effective at suppressing viral replication are now widely available, and withholding therapy from patients with viremia is increasingly controversial. In this article, we review traditional treatment paradigms and argue the merits of expanding treatment eligibility to patients with CHB who do not meet current treatment criteria.