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Background Hepatitis B virus (HBV) and fatty liver disease (FLD) are common in human immunodeficiency virus (HIV). Correlates of FLD and its relationship with alanine aminotransferase (ALT) were examined longitudinally in HIV-HBV coinfection. Methods From 28/4/2014–7/11/2018, 114 HIV-HBV adults had liver biopsy and were followed for a median of 3 years (ancillary study of Hepatitis B Research Network). Steatohepatitis was based on presence of steatosis, ballooning, and perisinusoidal fibrosis. FLD was defined as ≥5% steatosis and/or steatohepatitis. Results Median age was 49 years, 93% were male, 51% black, 93% had HIV RNA <400 copies/mL and 83% HBV DNA <1000 IU/mL. Thirty percent had FLD (20% steatosis, 10% steatohepatitis). Those with FLD had higher median triglyceride (171 vs 100 mg/dL, P < .01) and small, dense LDL (44 vs 29 mg/dL, P < .01) and lower HDL-2-C (9 vs 12 mg/dL, P  = .001). After adjusting for age, sex, and alcohol use, white and other versus black race (ORs, 8.49 and 16.54, respectively), ALT (OR, 3.13/doubling), hypertension (OR, 10.93), hyperlipidemia (OR, 4.36), and diabetes family history (OR, 5.38) were associated with having FLD (all P <.05). Steatohepatitis or steatosis alone (vs none) was associated with higher ALT over time (1.93 and 1.34 times higher, respectively; P < .001), with adjustment for age, sex, and HBV DNA. Conclusions About 30% with HIV-HBV coinfection had FLD including 10% with steatohepatitis. FLD was associated with non-black race, metabolic risks, an atherogenic lipid profile, and elevated ALT over time. Thus, identification of FLD and management of adverse metabolic profiles are critically important in HIV-HBV coinfection. Clinical Trial Registration. NCT 01924455. [ABSTRACT FROM AUTHOR]

Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co‐infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24–48 weeks. HBeAg loss was defined as first HBeAg‐negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg‐negative values ≥24 weeks apart. During a median follow‐up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8–13.3) per 100 person‐years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre‐core mutations versus wild type. Additionally, during follow‐up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies. [ABSTRACT FROM AUTHOR]

Background: In chronic hepatitis B (CHB) viral infection, e antigen positivity (HBeAg+) is associated with high levels of viral replication and infectivity. Furthermore, HBeAg‐positive CHB is associated with a liver disease spectrum ranging from none to severe. Aim: To assess whether the level of circulating HBeAg is associated with different clinical presentations of HBeAg‐positive CHB. Methods: A cross‐sectional analysis was conducted among HBV mono‐infected participants enrolled in Hepatitis B Research Network (HBRN) cohorts to explore clinical and virological associations with quantitative HBeAg (qHBeAg). Results: Among 763 HBeAg+ participants (56% female; 85% Asian; median age 26 years), multivariable median regression modelling significantly associated qHBeAg with liver injury (inverse qHBeAg association with ALT p<.001 and APRI p<.001), and with both race and age (p=0.01). Among Asians, qHBeAg was inversely related to age; a relationship less clear among Blacks and Whites. Among Asians also, median qHBeAg levels were higher among those infected with HBV genotype C versus B (p<0.001), suggesting causal virologic differences. Across all races, median qHBeAg was higher in women (p=.01). Independent of sex, age, race and HBV genotype, qHBeAg was higher in participants with predominant wild‐type versus basal core promoter and/or precore 'stop' viral variants (p<0.001). Conclusion: Lower qHBeAg was observed among HBRN participants with the greatest degree of liver injury independent of demographics and HBV genotype. These data support longitudinal studies to examine the role of qHBeAg in modulating the host immune response and predicting the outcomes of chronic HBV infection. [ABSTRACT FROM AUTHOR]

Antiviral drug resistance hepatitis B virus (HBV) variants ( HBV- DR) occur spontaneously in chronic hepatitis B ( CHB) patients and after exposure to nucleos(t)ide analogues ( NUCs). We determined the prevalence of HBV- DR variants among participants of the Hepatitis B Research Network ( HBRN) Cohort Study conducted at 21 sites in the United States ( US) and Canada. Samples obtained from 1342 CHB participants aged ≥18 years, and who were currently not receiving NUCs, were tested for HBV- DR variants by Sanger sequencing. In addition, next generation sequencing ( NGS) was used to characterize HBV- DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg positive. Primary HBV- DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV- DR variants in a higher proportion of participants: primary variants in 18 (13.6%) (8 [12.1%] with, and 10 [15.2%] without prior NUC therapy) and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV- DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV- DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon. [ABSTRACT FROM AUTHOR]

Background and Aims: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear., Approach and Results: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log 10 IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg + and 58% of HBeAg - participants; HBcrAg was quantifiable in 20% of HBeAg + (above linear range in the other 80%) and 51% of HBeAg - participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg + and HBeAg - immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg + and HBeAg - phases (HBV RNA: e + ρ = 0.84; e - ρ = 0.78; HBcrAg: e + ρ = 0.66; e - ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg + phases only (HBV RNA: e + ρ = 0.71; P < 0.001; e - ρ = 0.18; P = 0.56; HBcrAg: e + ρ = 0.51; P < 0.001; e - ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg - , but not HBeAg + , phases., Conclusions: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background and Aims: Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined., Approach and Results: Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm 3 and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58)., Conclusions: In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon., (© 2021 by the American Association for the Study of Liver Diseases.)

Introduction: Fatty liver disease (FLD) influences liver disease progression and liver cancer risk. We investigated the impact of FLD on liver disease severity in a large North American cohort with chronic hepatitis B virus (HBV)., Methods: Liver biopsies from 420 hepatitis B surface antigen-positive adults enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning ± Mallory-Denk bodies, and perisinusoidal fibrosis. Models evaluated factors associated with steatohepatitis, and the associations of steatohepatitis with fibrosis, and longitudinal alanine aminotransferase, aspartate aminotransferase, and Fibrosis-4., Results: The median age was 42 years, 62.5% were male, and 79.5% were Asian. One hundred thirty-two (31.4%) patients had FLD (77 [18.3%] steatosis only, 55 [13.1%] steatohepatitis). Older age, overweight/obesity, and diabetes were associated with steatohepatitis. Steatohepatitis (vs no FLD) was associated with 1.68 times higher risk of advanced fibrosis at baseline (95% confidence interval, 1.12-2.51), and there was an indication of higher incident cirrhosis rate during follow-up. Steatohepatitis vs no FLD was also independently associated with, on average, 1.39 times higher alanine aminotransferase (P < 0.01) and 1.25 times higher Fibrosis-4 (P = 0.04) across 4 years., Discussion: Coexisting steatosis occurred in nearly a third of adults (13% had steatohepatitis) with chronic HBV in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. Therefore, in addition to viral suppression, screening for and managing metabolic abnormalities is important to prevent disease progression in HBV., (Copyright © 2021 by The American College of Gastroenterology.)

Background and Aims: Hepatitis B virus (HBV) precore (PC) and dual basal core promoter (BCP) mutations halt and down-regulate hepatitis B e antigen (HBeAg) production respectively. PC mutation is rarely associated with HBV genotype A. We sought to examine the association of these variants with HBV genotypes, age, and HBeAg status in a racially diverse population in North America. Prospective study included 1,036 (808 adults, 228 children) participants in the Hepatitis B Research Network. PC and BCP variants were determined by Sanger sequencing, and dominant HBV species (>50%) were reported., Approach and Results: Median age was 36.3 years (range, 2-80), 44.6% HBeAg(+), 74.2% Asians, 13.3% black, and 9.7% white. The dominant PC variant was present in 29.4% participants, including 20 with subgenotype A1 or A2. Seventeen of 20 participants with genotype A and PC had a compensatory C1858T mutation. In the HBeAg(+) cohort, the prevalence of PC and/or BCP variants increased from 14.4% in the first two decades to 51% after 40 years of age. Among those aged 2-18, 52% and 83% with dominant PC and BCP variants were HBeAg(+) compared to 3.8% and 29% in the >40 years age group. HBeAg clearance rates were significantly higher for those with dominant PC or BCP variants: 24.4 and 15.0 per 100 person-years compared to 6.0 in wild-type HBV (P < 0.0001)., Conclusions: PC variants can be present in HBV genotype A and are usually associated with C1858T, which preserves the pregenome encapsidation sequence. Selection of PC and BCP variants occurred at a young age, with increasing prevalence across age groups. HBeAg(+) participants with dominant PC and BCP variants progressed to the HBeAg(-) phase of chronic HBV infection significantly faster. This finding has potential clinical and therapeutic implications., (© 2020 by the American Association for the Study of Liver Diseases.)

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confirmed two previously reported significant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fine-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe.