Faculty Bibliography

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.

BACKGROUND:JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B. METHODS:The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed. FINDINGS/RESULTS:Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths. INTERPRETATION/CONCLUSIONS:Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies. FUNDING/BACKGROUND:Janssen Research and Development.

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.

BACKGROUND & AIMS/OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSION/CONCLUSIONS: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.

Background: Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) for its replication. HDV infection leads to the most severe form of viral hepatitis, which is associated with an increased risk of liver-related morbidity and mortality. HDV prevalence and characteristics of patients with HDV infection are not well described. We aim to evaluate the epidemiology and characteristics of patients with HDV in a comprehensive claims dataset of commercially insured adults in the US.
Method(s): Commercially insured adults (>= 18 years of age) with HBV or HDV infection were identified with >= 1 inpatient claim or >= 2 outpatient claims (according to International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification diagnosis codes) >= 30 days apart for HBV monoinfection or HDV infection using the All-Payer Claims Database from 1/1/2014 to 12/31/2020 (study period). HDV prevalence was calculated as the proportion of patients with HDV among those with HBV over the study period; a subcohort was identified with the earliest HDV diagnosis defined as the index date from 1/1/2015 to 12/31/2019 and with >= 12 months continuous enrollment before and after the index date. Age, sex, race, income, education, and geographic region at the index date were collected. Comorbidities were assessed during the 12-month pre-index period. Continuous variables were summarized by mean 7plusmn; standard deviation, and categorical variables by frequencies and proportions.
Result(s): Among 105,509 adults with HBV, 4,694 (4.4%) had HDV infection. Among 2,871 adults with HDV identified in the subcohort, mean age was 47.5 (7plusmn; 12.1) years, and 53.0% were male. Among adults with HDV with available data on race and socioeconomic status, 47.1% were White, 33.6% were Black, and 18.0% were Asian; 65.5% reported high school as their highest education; mean annual household income was $44,756 (7plusmn; $47,829); and 35.9% and 33.3% lived in the northeast and north-central US regions, respectively. At baseline, 16.9% of patients had compensated cirrhosis, 10.1% had decompensated cirrhosis, 2.8% had liver cancer, and 1.9% had received a liver transplant. Mean Charlson Comorbidity Index score was 1.6 (7plusmn; 2.2). Hypertension (41.9%), diabetes (39.6%), history of smoking (25.9%), substance use disorder (25.9%), and HIV infection (24.9%) were the top five comorbidities.
Conclusion(s): HDV infection prevalence was 4.4% among commercially insured adults with HBV in the US. Patients with HDV infection have a high comorbidity burden. These findings underscore a need for earlier identification, diagnosis, and treatment of HDV infection among patients with HBV, which may mitigate future disease progression