Lok, Anna S.

Background: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings. Methods: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of −1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology. Results: In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%–81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3–66.4), PALAD (55.1%, 95% CI: 50.0%–70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%–62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3–48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%–26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%–15.8%), PALAD (13.0%, 95% CI: 10.2%–14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%–12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%–23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged ≥65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC. Conclusions: Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.

Background and Aims: With rapid changes in the management landscape of chronic hepatitis B (CHB), this technical systematic review addresses 4 critical Population, Intervention, Comparator, Outcome (PICO) questions to provide guidance to the formulation of recommendations to the 2025 AASLD practice guideline for management of CHB. Approach: The review was reported in accordance with PRISMA guidelines. Outcomes were evaluated across 4 key PICOs: (1) antiviral therapy for prevention of horizontal HBV transmission in high-risk groups, (2) antiviral therapy versus observation for persons in the immune-tolerant phase, (3) discontinuation versus continuation of nucleos(t)ide analogue therapy in HBeAg-negative individuals with undetectable HBV DNA, and (4) hepatocellular carcinoma (HCC) surveillance in non-cirrhotic individuals with HBsAg clearance or co-infections with HCV, HDV, or HIV. Results: For PICO 1, limited evidence suggests antiviral therapy may reduce horizontal transmission risk, though with low certainty. PICO 2 analyses reveal uncertain benefits of treating persons in the immune-tolerant phase, with very low certainty due to heterogeneity and bias. PICO 3 analyses demonstrate that discontinuing antiviral therapy in persons who are HBeAg negative with undetectable HBV DNA increases HBsAg loss rates (OR: 12.65, 95% CI: 1.58–101.51) but carries moderate risks of virologic relapse (OR: 47.17, 95% CI: 2.79–797.35) and clinical flares. PICO 4 analyses on several cohort studies showed that in patients co-infected with HCV, HBV, or HIV, the annual incidence of HCC was higher than the level where screening becomes cost-effective, suggesting that regular liver cancer screening could be beneficial for these patients. Conclusions: Despite low certainty, the findings support shared decision-making in high-risk horizontal transmission scenarios or in treating individuals in the immune tolerance phase, caution in discontinuing antiviral therapy in virologically suppressed individuals without HBsAg loss, and tailored HCC surveillance for those with co-infection or cirrhosis.

Background and Aims: Accumulating data related to prevention, surveillance and treatment of chronic hepatitis B (CHB) provided the impetus for this updated guideline, using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Methods: The guideline was developed in compliance with the National Academy of Medicine standards. The guideline panel developed structured questions following the Population, Intervention Comparison, Outcomes (PICO) framework. The panel addressed 6 PICO questions covering prevention (maternal to infant transmission and horizontal transmission), surveillance for liver cancer (among hepatitis B surface antigen positive (HBsAg) persons co-infected with hepatitis C virus, hepatitis D virus and/or human immunodeficiency viruses and after HBsAg loss) and treatment (HBsAg positive persons in immune-tolerant or indeterminate phases as well as withdrawal of antiviral therapy), providing evidence-based recommendations on these topics. Four systematic reviews of the literature were conducted, and two existing systematic reviews were utilized to support the recommendations in this practice guideline. Conclusions: This evidence-based guideline provides updated recommendations to optimize the care of persons with CHB.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Abstract Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.

ImportanceDisparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited.ObjectiveTo examine whether HBV treatment initiation and outcomes differ among racial groups.Design, Setting, and ParticipantsFrom January 14, 2011, to January 28, 2018, hepatitis B surface antigen—positive adults (age ≥18 years) not receiving anti-HBV therapy were enrolled and followed up at weeks 12, 24, and every 24 weeks thereafter in a multicenter longitudinal cohort study (Hepatitis B Research Network [HBRN] adult cohort study) conducted in North America. The last study visit and data collection were completed January 28, 2019. Data were analyzed from August 27, 2021, to August 25, 2022. All HBRN participants were included unless they had acute HBV, HIV, hepatitis C or D, less than 24-weeks of follow-up after enrollment, initiated treatment at or immediately after enrollment, or had unknown race.ExposuresParticipants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment.Main Outcomes and MeasuresHepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death).ResultsOf 1550 participants, 193 (12%) were African American or Black, 1157 (75%) were Asian, 157 (10%) were White, and 43 (3%) were other races; 789 (51%) were women, and the median age was 41.2 (IQR, 32.9-51.6) years. Sociodemographic and virologic parameters differed between groups. During 5727 person-years of follow-up, 504 participants initiated treatment, with incidences of 4.8 per 100 person-years in African American or Black individuals, 9.9 per 100 person-years in Asian individuals, 6.6 per 100 person-years in White individuals, and 7.9 per 100 person-years in those of other races (P < .001). A lower proportion (14%) of African American or Black participants met treatment criteria compared with Asian (22%) and White (27%) individuals (P = .01). The cumulative probabilities of treatment initiation after meeting the criteria were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.38; White, 0.40 at 48 weeks and African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race.Conclusions and RelevanceIn this observational study of chronic HBV, African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, HBV treatment receipt did not differ significantly by race or socioeconomic factors. Not all eligible participants initiated treatment, but adverse liver outcomes were rare. These findings may not be generalizable to patients with chronic HBV receiving care in other settings.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.