TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism.

OBJECTIVE: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment. DESIGN: We identified TLR8-expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN's indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN's effect were validated using transcriptomic data from HBV-infected patients. RESULTS: Hepatic TLR8 expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg, S100A12) and downregulated genes associated with the KC identity (eg, SPIC). Treatment of hepatocytes with SLGN-CM downregulated NTCP and impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition. CONCLUSION: Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.

Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

Phase 1 Trial of the Safety, Pharmacokinetics, and Antiviral Activity of EDP-514 in Untreated Viremic Chronic Hepatitis B Patients.

Background & Aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics (PK), and antiviral activity of three doses of EDP-514 in treatment naïve viremic patients with HBeAg-positive or -negative chronic HBV infection. Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. Results: A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were 2.9, 3.3, 3.5 and 0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was 2.9, 2.4, 2.0, and 0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events (TEAEs) of mild or moderate severity with no discontinuations, serious AEs or deaths. Conclusions: In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.

Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

INTRODUCTION: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. RESULTS: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

Association between Cholecystectomy and the Incidence of Pancreaticobiliary Cancer after Endoscopic Choledocholithiasis Management.

(1) Background: Previous studies have raised concerns about a potential increase in pancreaticobiliary cancer risk after cholecystectomy, but few studies have focused on patients who undergo cholecystectomy after receiving endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. This study aims to clarify cancer risks in these patients, who usually require cholecystectomy, to reduce recurrent biliary events. (2) Methods: We conducted a nationwide cohort study linked to the National Health Insurance Research Database, the Cancer Registry Database, and the Death Registry Records to evaluate the risk of pancreaticobiliary cancers. All patients who underwent first-time therapeutic ERCP for choledocholithiasis from 2011 to 2017 in Taiwan were included. We collected the data of 13,413 patients who received cholecystectomy after endoscopic retrograde cholangiopancreatography and used propensity score matching to obtain the data of 13,330 patients in both the cholecystectomy and non-cholecystectomy groups with similar age, gender, and known pancreaticobiliary cancer risk factors. Pancreaticobiliary cancer incidences were further compared. (3) Results: In the cholecystectomy group, 60 patients had cholangiocarcinoma, 61 patients had pancreatic cancer, and 15 patients had ampullary cancer. In the non-cholecystectomy group, 168 cases had cholangiocarcinoma, 101 patients had pancreatic cancer, and 49 patients had ampullary cancer. The incidence rates of cholangiocarcinoma, pancreatic cancer, and ampullary cancer were 1.19, 1.21, and 0.3 per 1000 person-years in the cholecystectomy group, all significantly lower than 3.52 (p < 0.0001), 2.11 (p = 0.0007), and 1.02 (p < 0.0001) per 1000 person-years, respectively, in the non-cholecystectomy group. (4) Conclusions: In patients receiving ERCP for choledocholithiasis, cholecystectomy is associated with a significantly lower risk of developing pancreaticobiliary cancer.

Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma.

PURPOSE: There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. METHODS: This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). RESULTS: The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). CONCLUSION: Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

BACKGROUND: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. AIM: To evaluate the impact of HCV treatment on such disparities. METHODS: In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. RESULTS: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). CONCLUSION: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation.

BACKGROUND/AIMS: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). METHODS: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. RESULTS: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5-40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7-67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1-62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12-2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21-0.81). CONCLUSION: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study.

BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

Increased spine bone density in patients with chronic hepatitis B switched to tenofovir alafenamide: A prospective, multinational study.

BACKGROUND: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. AIMS: To assess the treatment and renal/bone safety outcomes following the switch to TAF. METHODS: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF. RESULTS: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). CONCLUSIONS: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable.

Long-Term Use of Immunosuppressive Agents Increased the Risk of Fractures in Patients with Autoimmune Diseases: An 18-Year Population-Based Cohort Study.

The risk of fractures is higher in patients with autoimmune diseases, but it is not clear whether the use of immunosuppressive agents can further increase this risk. To investigate this issue, a retrospective study was conducted using data from Taiwan's National Health Insurance Research Database. Patients diagnosed with autoimmune diseases between 2000 and 2014, including psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, were included in the study. A control group of patients without autoimmune diseases was selected from the same database during the same period. Patients with autoimmune diseases were divided into two sub-cohorts based on their use of immunosuppressive agents. This study found the risk of fractures was 1.14 times higher in patients with autoimmune diseases than in those without. Moreover, we found that patients in the immunosuppressant sub-cohort had a higher risk of fractures compared to those in the non-immunosuppressant sub-cohort. The adjusted sub-distribution hazard ratio for shoulder fractures was 1.27 (95% CI = 1.01-1.58), for spine fractures was 1.43 (95% CI = 1.26-1.62), for wrist fractures was 0.95 (95% CI = 0.75-1.22), and for hip fractures was 1.67 (95% CI = 1.38-2.03). In conclusion, the long-term use of immunosuppressive agents in patients with autoimmune diseases may increase the risk of fractures.