Hepatitis C virus RNA functionally sequesters miR-122.

Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.

Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database.

BACKGROUND AND AIMS: 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, this study estimates the prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States. APPROACH AND RESULTS: Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 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 (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 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%), and HIV infection (30.9%) were the top 3 comorbidities. CONCLUSIONS: In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

BACKGROUND & AIMS: 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 pegbelfermin treatment in patients with nonalcoholic steatohepatitis (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 injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P = .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). CONCLUSIONS: FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Monitoring for liver cancer post-gene therapy-How much and how often?

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.

Risk of colorectal cancer in patients with primary sclerosing cholangitis and concomitant inflammatory bowel disease compared with primary sclerosing cholangitis only.

AIM: 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.

The tolerability of sofosbuvir/velpatasvir for 12 weeks in patients treated in the ASTRAL 1, 2 and 3 studies: A pooled safety analysis.

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

Expert Panel Consensus on Clinical Assertion Statements Describing Noninvasive Tools for Diagnosing Nonalcoholic Steatohepatitis.

GOALS AND BACKGROUND: A panel of 9 experts in nonalcoholic steatohepatitis gathered to assess multiple components of the diagnostic process. MATERIALS AND METHODS: The Clinical Assertion Statements covered screening of patients with type 2 diabetes for high-risk nonalcoholic fatty liver disease, which-if any-noninvasive tests could determine whether to delay or defer biopsy, whether primary care providers and endocrinologists should routinely calculate Fibrosis-4 (FIB-4) scores in patients with nonalcoholic fatty liver disease or those at risk for it, optimal noninvasive tests to stage fibrosis, the need to consider fibrosis in patients with normal transaminase levels, periodic monitoring for progressive fibrosis, whether patients should undergo biopsy before pharmacotherapy, and the clinical utility of genetic testing. RESULTS AND CONCLUSIONS: Evidence was presented to support or refute each Clinical Assertion Statement; the panel voted on the nature of the evidence, level of support, and level of agreement with each Statement. Panel level of agreement and rationale of each Clinical Assertion Statement are reported here.

Diagnosis and Management of Hepatitis Delta Virus Infection.

Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.