Racial discrimination, knowledge, and health outcomes: The mediating role of hepatitis B-related stigma among patients with chronic hepatitis B.

It is well described in current literature that Hepatitis B virus (HBV) affects Asian Americans more than any other racial group in the United States and that there is a stigma attached to this condition. The effects of stigma can be lasting, penetrating physiologically and psychologically, yet few studies have focused on the consequences of this phenomenon. The purpose of this study was to examine the mediating role of stigma in the effect of racial discrimination and knowledge (of HBV sequelae) on health status of Korean Americans with chronic hepatitis B (CHB). Three hundred sixty-five CHB patients were recruited and enrolled from two clinics in Philadelphia and Los Angeles. Depressive symptoms were measured using the Patient Health Question-9 (PHQ-9), physical health via self-rated health survey and stigma via hepatitis B quality of life (HBQOL)-stigma survey. Perceived racial discrimination and knowledge of CHB sequelae were independent variables. The cohort had an average age of 60.1 years (range 19-84, SD 10.7), 56% were male and 94% were born in South Korea. Mediational analysis found that stigma was a significant mediator between both racial discrimination (indirect effect = .037, Bootstrap 95% CI = [.010-.064]) and sequelae knowledge (indirect effect = .097, Bootstrap 95% CI = [.018-.176]) and depressive symptoms. Stigma also had a direct effect on depressive symptoms (ß = .136, p < .01) and self-rated health (ß = .018, p < .05). In addition, age, gender, education and employment were related to health outcomes. The findings of this study indicate that HBV-related stigma is an important mediator of mental health outcomes in this population. Future studies should identify other psychosocial factors to develop effective intervention programs to reduce stigma and improve quality of life among CHB patients.

Urine DNA biomarkers for hepatocellular carcinoma screening.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test. METHODS: Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test. RESULTS: Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A). CONCLUSION: Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.

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.

Hepatitis B Virus-Associated Hepatocellular Carcinoma and Chronic Stress.

The Hepatitis B virus is one of the most significant hepatocarcinogens globally. The carcinogenic mechanisms of this virus are complex, and may include interactions with the host's immune system. Certain factors, such as stress on the body, can also potentiate these mechanisms. Stress, although adaptive in an acute form, is deleterious to health when chronic and can both suppress and activate the host's defense system. In hepatocellular carcinoma, this can lead to tumor initiation and progression. Those that are more prone to stress, or exposed to situations that incite stress, may be at higher risk of developing cancer. Racial disparities, for example, are a source of chronic psychosocial stress in America and predispose minorities to poorer outcomes. As it remains perplexing why some individuals with chronic hepatitis B develop feared complications while others do not, it is important to recognize as many risk factors as possible, including those often overlooked such as chronic stress.

Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries.

BACKGROUND & AIMS: Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. METHODS: Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n = 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n = 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. RESULTS: There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. CONCLUSIONS: In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.

Prospective and longitudinal evaluations of telomere length of circulating DNA as a risk predictor of hepatocellular carcinoma in HBV patients.

Prospective and longitudinal epidemiological evidence is needed to assess the association between telomere length and risk of hepatocellular carcinoma (HCC). In 323 cancer-free Korean-American HBV patients with 1-year exclusion window (followed for >1 year and did not develop HCC within 1 year), we measured the relative telomere length (RTL) in baseline serum DNAs and conducted extensive prospective and longitudinal analyses to assess RTL-HCC relationship. We found that long baseline RTL conferred an increased HCC risk compared to short RTL [hazard ratio (HR) = 4.93, P = 0.0005). The association remained prominent when the analysis was restricted to patients with a more stringent 5-year exclusion window (HR = 7.51, P = 0.012), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Adding baseline RTL to demographic variables increased the discrimination accuracy of the time-dependent receiver operating characteristic analysis from 0.769 to 0.868 (P = 1.0 × 10-5). In a nested longitudinal subcohort of 16 matched cases-control pairs, using a mixed effects model, we observed a trend of increased RTL in cases and decreased RTL in controls along 5 years of follow-up, with a significant interaction of case/control status with time (P for interaction=0.002) and confirmed the association between long RTL and HCC risk [odds ratio [OR] = 3.63, P = 0.016]. In summary, serum DNA RTL may be a novel non-invasive prospective marker of HBV-related HCC. Independent studies are necessary to validate and generalize this finding in diverse populations and assess the clinical applicability of RTL in HCC prediction.

Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study.

BACKGROUND & AIMS: Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). METHODS: LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. RESULTS: Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. CONCLUSIONS: TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. LAY SUMMARY: The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.

Lower Observed Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients Treated With Entecavir: Results of the ENUMERATE Study.

OBJECTIVES: Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence. METHODS: The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases. RESULTS: Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166-0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35-0.905). CONCLUSIONS: Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is active against lamivudine-resistant hepatitis B virus (HBV) infection, but data to support its clinical efficacy in this setting are limited. METHODS: In a prospective, double-blind, 96-week trial, patients were randomly assigned (1:1) to groups given TDF (300 mg, n = 141) or a combination of emtricitabine (FTC, 200 mg; n = 139) and TDF (300 mg, FTC/TDF). Patients were hepatitis B e antigen (HBeAg)-positive or HBeAg-negative, with levels of HBV DNA ≥3 log10 IU/mL and lamivudine resistance mutations (HBV polymerase or reverse transcriptase amino acid substitutions rtM204I/V ± rtL180M by INNO-LiPA Multi-DR v3; Innogenetics, Inc, Alpharetta, GA). The primary end point was proportion with HBV DNA <69 IU/mL (Roche COBAS Taqman assay; Roche Molecular Systems, Inc, Pleasanton, CA). RESULTS: Patient groups were well matched for demographic and disease characteristics, including region (60% from Europe), HBV genotype (45% genotype D), HBeAg status (47% HBeAg-positive), and duration of lamivudine treatment (mean, 3.8 years). At week 96 of treatment, 89.4% of patients in the TDF group and 86.3% in the FTC/TDF group had levels of HBV DNA <69 IU/mL (P = .43). HBeAg loss and seroconversion did not differ between groups; only 1 patient (0.7%) in the FTC/TDF group lost hepatitis B surface antigen. Treatment was well tolerated; confirmed renal events (creatinine increase of ≥0.5 mg/dL [>44 umol/L], creatinine clearance <50 mL/min, or level of PO4 <2 mg/dL [<0.65 mmol/L]) were generally mild and infrequent (<1%). Small reductions (<2%) in mean bone mineral density of hip and spine were detected by dual-energy x-ray absorptiometry in both groups. No TDF resistance developed through 96 weeks of treatment. CONCLUSIONS: TDF alone is safe and effective for treatment of patients with lamivudine-resistant, chronic HBV infection. Clinical Trials.gov No, NCT00737568.

Aspartate aminotransferase to platelet ratio index as a prospective predictor of hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection.

BACKGROUND AND AIM: APRI (aspartate aminotransferase [AST] to platelet ratio index) is widely used to assess fibrosis and cirrhosis risk, especially in hepatitis C virus (HCV)-infected patients. Few studies have evaluated APRI and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) risk. Prospective evidence is needed to assess whether APRI predicts HCC risk in HBV patients. METHOD: In a prospectively enrolled clinical cohort of 855 HBV patients with a 1-year exclusion window (followed for > 1 year and did not develop HCC within 1 year), the predictive value of APRI in HCC risk was evaluated by Cox proportional hazards model using univariate and multivariate analyses and longitudinal analysis. RESULTS: Higher APRI prospectively conferred a significantly increased risk of HCC in univariate analysis (quartile analysis, P trend = 2.9 × 10(-7) ). This effect remained highly significant after adjusting for common host characteristics but not cirrhosis (P trend = 7.1 × 10(-5) ), and attenuated when cirrhosis is adjusted (P trend = 0.021). The effect remained prominent when the analysis was restricted to patients with a more stringent 2-year exclusion window (P trend = 0.008 in quartile analysis adjusting all characteristics including cirrhosis), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Longitudinal comparison demonstrated a persistently higher APRI value in HBV patients who developed HCC during follow-up than those remaining cancer free. CONCLUSION: APRI might be a marker of HCC risk in HBV patients in cirrhosis-dependent and -independent manners. Further studies are warranted to validate this finding and test its clinical applicability in HCC prevention.

Circulating mitochondrial DNA content associated with the risk of liver cirrhosis: a nested case-control study.

BACKGROUND AND AIMS: Accumulating evidence has indicated that variations of mitochondrial DNA (mtDNA) content may affect the susceptibility to hepatocellular carcinoma (HCC). However, no study has been conducted to evaluate the association of circulating mtDNA content and the risk of liver cirrhosis, a leading cause of HCC. METHODS: We conducted a nested case-control study including 136 cirrhotic hepatitis B virus (HBV) cases and 136 frequency-matched non-cirrhotic HBV controls. We determined mtDNA content in serum DNA using quantitative real-time PCR and analyzed its association with cirrhosis risk. RESULTS: We found that cirrhotic HBV patients had significantly lower levels of mtDNA content than non-cirrhotic HBV controls (P = 0.0184). Compared to patients with high mtDNA content, those with low mtDNA content had a 2.25-fold increased risk of cirrhosis [odds ratio (OR) 2.25, 95 % confidence interval (CI) 1.26-4.02]. This association exhibited a significant dose relationship as evidenced in both tertile and quartile analyses (P for trend = 0.0018 and 0.0008, respectively). Stratified analyses showed that the association was prominent in younger patients (P = 0.0122), males (P = 0.0069), never smokers (P = 0.0063), never drinkers (P = 0.0078), patients with a family history of HBV infection (P = 0.0062), and patients with low values of aspartate aminotransferase to platelet ratio index (APRI), a commonly used noninvasive marker for cirrhosis (P = 0.0109). Moreover, a joint effect was observed between low mtDNA content and high APRI values on cirrhosis risk (OR 24.07, 95 % CI 6.72-86.24). CONCLUSIONS: Low circulating mtDNA content may confer an increased cirrhosis risk in HBV patients. Further prospective studies are warranted to validate these findings and explore the clinical significance.

HBV-related health behaviors in a socio-cultural context: perspectives from Khmers and Koreans.

PURPOSE: The aim of this study is to explore factors influencing health and health care within the sociocultural context of Cambodian Americans (CAs or Khmers) and Korean Americans (KA) and to examine intergroup similarities and differences between CAs and KAs, focusing on hepatitis B virus (HBV) and liver cancer prevention behaviors. METHODS: The study used a qualitative design guided by the revised Network Episode Model (NEM) and informed by ethnographic analysis. Focus group interviews with key informants among CA community health leaders (CHLs, n=14) and individual interviews with key informants of KA CHLs (n=9) were audiotaped and transcribed. RESULTS: Three categories that influenced HBV and liver cancer prevention emerged from both CAs and KAs: the socio-cultural, individual, and behavioral. Four additional subcategories (sub-themes) of sociocultural were identified as socio-history, socio-medicine, socio-linguistic, and socio-health resources. Both CAs and KAs, however, have low levels of knowledge and significant misunderstandings about HBV infection. CONCLUSIONS: The study identifies and compares the social-cultural determinant for HBV and liver cancer and highlights the factors of education, intercultural communication, and interactions within socio-cultural contexts of CA and KA subgroups. In general, conceptual overlaps are apparent between Khmers (from now on, the terms, CA and Khmer, will be used interchangeably) and Koreans except for the sub-theme of socio-history. However, differences in concept-specific attributes point to the need to account for differing conceptualizations and implications of specific ethnic groups' sociocultural contexts, and to design contextually-relevant outreach and educational interventions for targeted AAPI subgroups.

Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.

Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks.

BACKGROUND: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. AIM: To evaluate how these changes affect cardiovascular risk. METHODS: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. RESULTS: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. CONCLUSION: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: 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: 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: 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: 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: NCT03780543. Impact and implications: 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.

Single-center comparison of three chemoembolization regimens for hepatocellular carcinoma.

PURPOSE: Transarterial chemoembolization regimens for hepatocellular carcinoma (HCC) vary, without a gold-standard method. The present study was performed to evaluate outcomes in patients with HCC treated with doxorubicin/ethiodized oil (DE), cisplatin/doxorubicin/mitomycin-c/ethiodized oil (CDM), or doxorubicin drug-eluting beads (DEBs). MATERIALS AND METHODS: Patients received the same regimen at all visits, without crossover. Groups were compared based on Child-Pugh disease status, tumor/node/metastasis stage, and Barcelona Clinic Liver Cancer stage. Imaging outcomes were assessed based on modified Response Evaluation Criteria in Solid Tumors to calculate tumor response (ie, sum of complete and partial response), progressive disease (PD), and time to progression (TTP). RESULTS: A total of 228 infusions were performed in 122 patients: 59 with DE, 30 with CDM, and 33 with DEBs. The groups had similar Child-Pugh status (P = .45), tumor/node/metastasis stages (P = .5), and Barcelona Clinic Liver Cancer scores (P = .22). Follow-up duration was similar among groups (P = .24). Patients treated with DE underwent significantly more treatments (2.3 ± 1.4) than those treated with CDM (1.6 ± 0.7; P = .004) or DEBs (1.4 ± 0.6; P<.0001). Compared with DE (51%), tumor response was significantly more common with CDM (84%; P = .003) or DEBs (82%; P = .004). PD was significantly more likely with DE (37%) than with CDM (13%; P = .02) or DEBs (9%; P = .004). TTP was similar between groups (P = .07). CDM and DEBs were similar in regard to disease progression (P = .6) and response (P = .83). CONCLUSIONS: During a similar follow-up period, patients treated with CDM or DEB chemoembolization showed a significantly higher response rate and a lower incidence of tumor progression, with fewer required treatment sessions, than those treated with DE chemoembolization.

The Role of Host in the Spectrum of Outcomes in Family Clusters of Hepatitis Infection: From Asymptomatic to Hepatocellular Carcinoma.

Hepatitis B virus infections are prevalent worldwide, but the outcomes of infection vary greatly from host to host. In many endemic regions, vertical transmission from mother to child is most common. In this transmission setting, virus genotype and shared patient genetics make for an interesting comparison of outcome of chronic hepatitis B infection. This case series demonstrates four family clusters which display disparate outcomes among family members with hepatitis B virus infections, further stressing the role of host and non-genetic factors in the natural history of the disease. Many host factors have been theorized, from epigenetic mechanisms to the role of chronic stress, but more research is needed to better understand those at higher risk of feared complications such as hepatocellular carcinoma and cirrhosis.

Persistently Elevated HBV Viral-Host Junction DNA in Urine as a Biomarker for Hepatocellular Carcinoma Minimum Residual Disease and Recurrence: A Pilot Study.

Hepatitis B virus (HBV)-host junction sequences (HBV-JSs) has been detected in the urine of patients with HBV infection. This study evaluated HBV-JSs as a marker of minimum residual disease (MRD) and tumor recurrence after treatment in HBV-hepatocellular carcinoma (HCC) patients. Archived serial urine DNA from two HBV-HCC with recurrence as confirmed by MRI and four HBV-related cirrhosis (LC) patients were used. Urinary HBV-JSs were identified by an HBV-targeted NGS assay. Quantitative junction-specific PCR assays were developed to investigate dynamic changes of the most abundant urinary HBV-JS. Abundant urinary HBV-JSs were identified in two cases of tumor recurrence. In case 1, a 78-year-old female with HBV- HCC underwent a follow-up MRI following microwave ablation. While MRI results were variable, the unique HBV-JS DNA, HBV-Chr17, steadily increased from initial diagnosis to HCC recurrence. In case 2, a 74-year-old male with HBV-HCC contained two HBV-JS DNA, HBV-Chr11 and HBV-TERT, that steadily increased after initial HCC diagnosis till recurrence. One LC examined had HBV-TERT DNA detected, but transiently in 3.5 years during HCC surveillance. HBV-JS DNA was persistently elevated prior to the diagnosis of recurrent HCC, suggesting the potential of urinary HBV-JS DNA to detect MRD and HCC recurrence after treatment.

Genomic characterization of early-stage hepatocellular carcinoma patients with Hepatitis B using circulating tumor DNA.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology worldwide. Effective early detection strategies may facilitate curative therapies and improve survival. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as potential diagnostic markers of HCC in HBV-infected patients. METHODS: We identified early stage (BCLC 0-A) HCC cases (n = 21) and patients without HCC (n = 14) from a cohort of Asian patients with HBV, undergoing surveillance between 2013 and 2017. Circulating cell-free DNA was isolated from blood samples, and assayed by next-generation sequencing of 23 genes implicated in HCC pathogenesis. Somatic mutations were identified using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic (ROC) analysis, we evaluated gene alterations and clinical factors in an exploratory early HCC detection model. RESULTS: Mutant ARID1A, CTNNB1, TP53 genes were increased in HCC cases vs. non-HCC patients (85.7% vs 42.9%, P = 0.011; 42.9% vs 0%, P = 0.005; 100% vs 71.4%, P = 0.019, respectively). Using these three genes, AUC for discriminating HCC from non-HCC patients was 0.844 (95% confidence interval [CI]: 0.7317-0.9553). When combining these genes with clinical factors in an exploratory early HCC detection model, AUC increased from 0.7415 (using clinical factors alone) to 0.9354 (P = 0.041). CONCLUSION: Genomic aberrations in ctDNA were more prevalent in HBV-infected HCC patients compared with patients without HCC. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant validation in future studies.