Search

BACKGROUND: The factors predictive of the presence or the absence of esophageal varices in hepatitis C virus (HCV) and advanced fibrosis have not been defined. OBJECTIVES: To define the prevalence of esophageal varices and the factors that are positively and negatively with such varices in hepatitis C and advanced fibrosis. DESIGN: A prospective study of esophageal varices and associated risk factors in subjects with hepatitis C and advanced fibrosis. SETTING: Prerandomization data from the HALT-C (hepatitis C long-term antiviral treatment against cirrhosis) clinical trial. PATIENTS AND INTERVENTION: Subjects with bridging fibrosis or cirrhosis, who were virologic nonresponders to treatment with pegylated interferon alpha 2a and ribavirin, underwent endoscopy. RESULTS: Sixteen percent of subjects with bridging fibrosis (95/598) and 39% of subjects with cirrhosis (164/418) had varices (P < .0001); 2% of subjects with bridging fibrosis (13/598) and 11% of those with cirrhosis (48/418) had medium or large varices. Subjects with bridging fibrosis and varices had a significantly lower platelet count and higher bilirubin and international normalized ratio (INR) compared with those without varices, suggesting that the biopsy may have underestimated the severity of fibrosis. A platelet count >150,000/mm(3) was associated with a negative predictive value of 99% for esophageal varices. By logistic regression modeling, African American race and female sex were protective, whereas a lower platelet count and higher bilirubin and INR predicted varices (c statistic, 0.758). CONCLUSIONS: The risk of having varices increases with decreasing platelet counts, increasing bilirubin, and INR. The probability of having medium or large varices at platelet counts >150,000/mm(3) is negligible in this population. [ABSTRACT FROM AUTHOR]

Background: Incidence of hepatocellular carcinoma (HCC) had been increasing steadily among older Americans but plateaued in 2015-2017. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are important causes of HCC. The impact of improved treatments for these infections on recent trends in HCC incidence is unclear., Aims: To examine the relationship between use of antiviral therapy for chronic viral hepatis and HCC incidence in older Americans., Methods: We used 2007-2017 data from the Surveillance, Epidemiology, and End Results-Medicare database to estimate age-standardized incidence rates and average annual percent changes (AAPCs) for viral hepatitis-attributable HCC among individuals ≥66 years. We analyzed data from Medicare Part D to determine the frequency of HBV and HCV treatment utilization in this population., Results: Overall HCC incidence increased 10.5%, from 22.2/100,000 in 2007 to 24.5/100,000 in 2017 (AAPC, 1.3%). During that time, HBV-attributable HCC rates decreased from 2.5 to 2.0/100,000 (AAPC, -1.6%), while HCV-attributable HCC rose from 6.6 to 8.0/100,000 (AAPC, 2.0%). HBV treatment among patients with HBV infection increased by 66% (2007, 7.4%; 2015, 12.3%). Treatment for HCV was stable at <2% during 2006-2013 but rose to 6.9% in 2014 and 12.7% in 2015, coinciding with the introduction of direct acting antiviral agents for HCV., Conclusions: A decreased incidence of HBV-attributable HCC corresponded with an increased uptake in treatment for that infection. Despite a marked increase in the effectiveness and frequency of HCV treatment in 2014 and 2015, HCV-attributable HCC had not begun to fall as of 2017., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Introduction: Withdrawal of nucleos(t)ide analog (NA) therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained, off-therapy partial cure (normal ALT [≤30 U/L males, ≤20 U/L females) with HBV DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBVRNA may be useful for risk stratification., Methods: The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir (TDF) for 192 weeks ± peginterferon-α (PegIFN) for initial 24 weeks followed by protocolized withdrawal of TDF amongst eligible participants (NCT01369212). HBV RNA was evaluated as predictor of ALT flares and sustained partial cure (HBV DNA<2000 IU/mL) 48 weeks after TDF withdrawal., Results: Of 93 participants discontinuing TDF (52 in TDF+PegIFN and 41 in TDF alone), 52 (55.9%) had unquantifiable HBVRNA at end-of-treatment. ALT flares (>5xULN) at 48 weeks off-therapy occurred in 33.3%, with pre-treatment age (≥35 years) and quantifiable HBV RNA at end-of-treatment, the best predictors (AUROC 0.74 and 0.85, training and test set) of ALT flare. A total of 26 (28.3%) had sustained partial cure; 3 (11.5%) with ALT flare. Non-quantifiable HBVRNA and qHBsAg <100 IU/mL at end-of-treatment were the best predictors of sustained partial cure (AUROC 0.84 and 0.93, training and test set). If HBVRNA was quantifiable at end-of-treatment, the likelihood of sustained partial cure was only 3% whereas if HBV RNA was unquantifiable and qHBsAg <100 IU/mL, this likelihood was 73%., Conclusions: HBVRNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of NAs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose of Review: Advancements in our understanding of the hepatitis B viral (HBV) life cycle have paved the way for novel approaches to treat HBV infection. This review summarizes the various strategies being pursued to achieve a functional cure, defined as loss of hepatitis B surface antigen (HBsAg) and absence of viral replication 6 months off-therapy., Recent Findings: Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection., Summary: Novel treatments are being developed in pursuit of a cure for HBV. Current evidence suggests a single therapeutic agent alone may be insufficient, necessitating the need for combination therapy targeting HBV and the host immune response. Ongoing research focused on identifying the best therapeutic combination holds promise in achieving functional cure for HBV., Competing Interests: Competing Interests The authors declare no competing interests.

The current multiday diagnosis and treatment paradigm for hepatitis C virus (HCV) infection results in far fewer patients receiving treatment with direct-acting antiviral agents than those with diagnosed HCV infection. To achieve HCV elimination, a paradigm shift in access to HCV treatment is needed from multiday testing and treatment algorithms to same-day diagnosis and treatment. This shift will require new tools, such as point-of-care (POC) antigen tests or nucleic acid tests for HCV and hepatitis B virus (HBV) and nucleic acid tests for human immunodeficiency virus (HIV) that do not require venous blood. This shift will also require better use of existing resources, including expanded access to HCV treatment and available POC tests, novel monitoring approaches, and removal of barriers to approval. A same-day diagnosis and treatment paradigm will substantially contribute to HCV elimination by improving HCV treatment rates and expanding access to treatment in settings where patients have brief encounters with healthcare., Competing Interests: Potential conflicts of interest. J. M. reports research grants outside the submitted work from AbbVie, Gilead, and Merck. B. A. P. reports research contracts outside the submitted work with Abbott Diagnostics, Altona Diagnostics, and Hologic. J. W. W. reports that the Task Force for Global Health, for which he serves as director of the Coalition for Global Hepatitis Elimination, receives funds for the support of the Coalition for Global Hepatitis Elimination from Abbott, Gilead, AbbVie, Merck, Siemens, Roche, Pharco, VBI Vaccines, Zydus-Cadila, governmental agencies, and philanthropic organizations. R. T. C. reports grants outside the submitted work from AbbVie, Gilead, Merck, BMS, Janssen, Roche, Boehringer, and GSK. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Hepatitis B virus is a substantial contributor to cirrhosis and hepatocellular carcinoma (HCC) globally. Vaccination is the most effective method for prevention of hepatitis B and its associated morbidity and mortality, and the only method to prevent infection with hepatitis D virus. The hepatitis B vaccine has been used worldwide for more than four decades; it is available in a single- or triple-antigen form and in combination with vaccines against other infections. Introduction of the vaccine and administration at birth led to sustained decline in mother-to-child transmission, chronic hepatitis B, and HCC, however, global birth dose coverage remains suboptimal. In this review we will discuss different hepatitis B vaccine formulations and schedules, vaccination guidelines, durability of the response, and vaccine escape mutants, as well as the clinical and economic benefits of vaccination.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100 IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs., (Copyright © 2023 American Association for the Study of Liver Diseases and European Association for the Study of the Liver. Published by Wolters Kluwer/Elsevier B.V. All Rights Reserved.)

Introduction: We aimed to determine whether the intensity of alanine aminotransferase (ALT) flares during antiviral therapy is associated with the level of hepatitis B surface antigen (HBsAg) decline., Methods: Quantitative HBsAg was determined during tenofovir monotherapy or tenofovir plus peginterferon alfa-2a in 201 participants with hepatitis B e antigen-positive or -negative chronic hepatitis B. A multivariable analysis identified factors associated with a shorter time to reduction in HBsAg., Results: Fifty flares occurred during treatment of which 74% were moderate (ALT >5-10 × upper limit of normal) or severe (ALT >10 × upper limit of normal). These flares were associated with greater HBsAg decline compared with no flares. Significantly faster times to HBsAg decline >1 log 10 IU ( P = 0.04) and to HBsAg level <100 IU/mL ( P = 0.01) were observed with severe flares., Discussions: Flare severity is a potentially important factor associated with shorter time to HBsAg reduction. These findings can be useful when evaluating HBsAg response to evolving hepatitis B virus therapies., (Copyright © 2023 by The American College of Gastroenterology.)

Background and Aims: Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss., Approach and Results: Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability., Conclusion: Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB., (Copyright © 2023 American Association for the Study of Liver Diseases.)

The design of a clinical trial for a controlled human infection model (CHIM) to accelerate hepatitis C virus (HCV) vaccine development requires careful consideration. The design of a potential approach to HCV CHIM is outlined, involving initial sentinel cohorts to establish the safety and curability of the viral inoculum followed by larger cohorts to establish the spontaneous clearance rate for each inoculum. The primary endpoint would be HCV clearance by 24 weeks post-inoculation, recognizing that the prevention of chronic infection would be the primary goal of HCV vaccine candidates. Additional considerations are discussed, including the populations to be enrolled, the required monitoring approach, indications for antiviral therapy, and the required sample size for different CHIM approaches. Finally, safety considerations for CHIM participants are discussed., Competing Interests: Potential conflicts of interest . J. B. reports funding through the Canadian Institutes of Health Research and Gilead Sciences. They also report honoraria payment for giving a presentation from Gilead Sciences. They report participation in a Data and Safety Monitoring Board (DSMB) with AbbVie, Gilead Sciences, and Cepheid Sciences and a board role with the International Network on Hepatitis and Health for Substance Abusers. D. L. T. reports research funding support from the National Institutes of Health (NIH) and National Institute on Drug Abuse (NIDA); royalties or licenses with UpToDate; consulting fees from Merck and Co, Excision Bio, and Evrys; honoraria payments from Masur et al Infectious Diseases Board Review; and participation on a DSMB with Merck and Co; and holds a leadership role with the Conference on Retroviruses and Opportunistic Infections (CROI) Program Committee and the African Mission Healthcare. G. J. D. reports clinical trial grants from Gilead Sciences, AbbVie, and Merck. They also report being an associate editor with the Journal of Hepatology. J. J. F. reports receiving a Canadian Institutes of Health Research Planning and Dissemination Grant (1183426). They report receiving grants and consulting fees from AbbVie and Gilead and is the past president of the Canadian Association for the Study of the Liver. M. S. reports receiving the NIH midcareer mentoring award, K24DA034621. They report receiving research grants to Johns Hopkins University from Janssen, Vir, Assembly Bio, and AbbVie, and also received consulting fee payments from AbbVie, Assembly Bio, Aligos Antios, Arbutus, Gilead, Precision Bio, and GSK for participation in a Scientific Advisory Board related to hepatitis V virus (HBV) and HCV. They also participated in a DSMB related to HIV and HBV with Gilead and Immunocore and is the American editor for the Journal of Viral Hepatitis. B. H. and M. G. G. report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), reflecting transcriptional activity of covalently closed circular DNA, are gaining traction as important markers to assess viral activity. Whether their expression differs under viral suppression by HIV co-infection status is unknown. Among adults with chronic HBV on antiviral therapy, we sought to determine if the expression of HBV markers (specialized and well-established) differs between HBV-HIV co-infection vs. HBV mono-infection. We compared HBV marker levels among 105 participants in the Hepatitis B Research Network (HBRN) HBV-HIV Ancillary Study and 105 participants in the HBRN mono-infected Cohort Study, matched for HBeAg status and HBV DNA suppression on therapy. Among HBeAg+ participants (N = 58 per group), after adjusting for age, sex, race, ALT and HBV DNA, viral markers were higher (p < .05) in the HBV-HIV versus the HBV-only sample (HBeAg: 1.05 vs. 0.51 log 10 IU/mL; HBsAg: 3.85 vs. 3.17 log 10 IU/mL; HBV RNA: 5.60 vs. 3.70 log 10 U/mL; HBcrAg: 6.59 vs. 5.51 log 10 U/mL). Conversely, among HBeAg(-) participants (N = 47 per group), HBsAg (2.00 vs. 3.04 log10 IU/mL) and HBV RNA (1.87 vs. 2.66 log 10 U/mL) were lower (p < .05) in HBV-HIV vs. HBV-only; HBcrAg levels were similar (4.14 vs. 3.64 log 10 U/mL; p = .27). Among adults with chronic HBV with suppressed viremia on antiviral therapy, viral markers tracked with HIV co-infection status and associations differed inversely by HBeAg status. The greater sensitivity and specificity of HBV RNA compared to HBcrAg allows for better discrimination of transcriptional activity regardless of HBeAg status., (© 2023 John Wiley & Sons Ltd.)

Background and Aims: Hepatitis B virus (HBV) reactivation has been reported in patients co-infected with hepatitis C virus (HCV) during direct acting antiviral (DAA) therapy, leading the United States Food and Drug Administration (U.S. FDA) to issue a black box warning on all DAA drug labels recommending monitoring for HBV reactivation. We conducted a comprehensive evaluation to assess the rate of HBV reactivation among patients with chronic hepatitis C (CHC) during DAA therapy., Methods: Patients with CHC and recovered HBV infection (hepatitis B surface antigen negative (HBsAg)/anti-hepatitis B core positive), treated with DAAs were included if stored sera were available. Samples were tested for HBV DNA, HBsAg, and ALT. HBV reactivation was considered if (1) HBV DNA was undetectable pre-DAA therapy and became detectable post-therapy, or (2) HBV DNA was detectable pre-treatment, but not quantifiable (< 20 IU/mL) and became quantifiable post-treatment., Result: 79 patients with median age of 62 years were included. 68% were male and Caucasian. Various DAA regimens were administered for 12-24 weeks. Reactivation occurred in 8/79 (10%) of patients and occurred more frequently in men compared to women: 6 during treatment and 2 after treatment. Neither an ALT flare nor HBsAg seroreversion were observed. Detectable HBV DNA was transient in 5/8 and could not be determined in 3/8 but ALT flares were not observed in follow-up of these patients., Conclusion: The risk of HBV reactivation was low in CHC patients with resolved HBV during DAA therapy. Our data support testing for HBV DNA only in selected patients with ALT flares or failure of ALT normalization during DAA treatment., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (Copyright © 2022 by The American College of Gastroenterology.)

Introduction: Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn., Methods: Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <10 3 IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria., Results: Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal., Discussion: Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

In chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) clearance are important milestones toward immune control. 1 A drop in HBV DNA is an established correlate of both HBeAg and HBsAg clearance. 2 We evaluated changes in HBV RNA and hepatitis B core-related antigen (HBcrAg) levels, markers of transcriptional activity of covalently closed circular DNA (cccDNA), 3,4 with HBeAg and HBsAg clearance, and compared them with changes in HBV DNA level among adult participants in the Hepatitis B Research Network (HBRN)., (Copyright © 2023 AGA Institute. All rights reserved.)

Background and Aim: Staining for hepatitis B viral antigens is often done in liver biopsies from patients with chronic hepatitis B, but its correlates with clinical phenotypes are not well described., Methods: Biopsies were collected from a large cohort of adults and children with chronic hepatitis B viral infection through the Hepatitis B Research Network. Immunohistochemical staining of sections was done for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and then centrally read by the pathology committee. The degree of liver injury and pattern of staining were then correlated with clinical characteristics, including the clinical phenotype of hepatitis B., Results: Biopsies from 467 subjects were studied, including 46 from children. Immunostaining for HBsAg was positive in 417 (90%) with scattered hepatocyte staining being the most common pattern. HBsAg staining correlated best with serum levels of HBsAg and hepatitis B viral DNA; the absence of HBsAg staining was often a prelude to loss of HBsAg from serum. HBcAg staining was positive in 225 (49%), and, while cytoplasmic staining was more frequent than nuclear staining, both nuclear and cytoplasmic positivity were often seen in the same specimen. Staining for HBcAg correlated with both level of viremia and liver injury. No biopsies from inactive carriers had stainable HBcAg, while 91% of the biopsies from those with hepatitis B e antigen-positive chronic hepatitis B stained positively for HBcAg., Conclusion: Immunostaining for hepatitis B viral antigens may yield helpful insights into liver disease pathogenesis but appears to add little to commonly used serological and biochemical blood tests., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: Most patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years., Methods: Demographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA >10 7 IU/mL) were compared by age category, and to those with IA-HBeAg+ CHB in cross-sectional analysis. This study received institutional review board approval at all participating centers., Results: Of 107 adult IT participants, 52 (48%) were <30, 33 (31%) were 30 to 39, and 22 (21%) were ≥40 years old (maximum, 71 years). Among IT groups, the proportion born in Asia and duration of CHB were greater in older IT groups, but virologic and liver disease characteristics were similar. Compared with IA-HBeAg+ participants (n = 192), IT participants were younger, fewer were men, more were Asian, and platelets, qHBsAg, and qHBeAg levels were higher. Similar differences were observed when comparisons were made with the ≥40 years IT group. Among IT participants, 60 (56%) transitioned during 206 person-years of follow-up. The phase transition rate per 100 person-years was highest in the <30 years group (33.0 [95% confidence interval [CI], 23.4-46.7]) vs the 30 to 39 years group (24.8 [95% CI, 15.6-39.4]) and ≥40 group (27.4 [95% CI, 14.8-50.9]), but 95% CIs overlapped., Conclusions: In a large North American population, over 50% of adults in the IT phase of CHB were ≥30 years and 20% were ≥40 years old, but older IT patients had similar characteristics and rates of transition as younger IT patients., (Copyright © 2023. Published by Elsevier Inc.)

Background: Prospective data regarding the safety and yield of liver biopsy in both adults and children with chronic hepatitis B are limited. The aim of this study is to report safety, yield, and complication rates among adults and children with chronic hepatitis B undergoing percutaneous liver biopsy., Methods: Data on the indication for procedural characteristics and complication rate for liver biopsies performed as part of the Hepatitis B Research Network were prospectively recorded on a study case report form and analyzed in aggregate., Results: Among 2506 adult and pediatric subjects enrolled in the Hepatitis B Research Network between 2011 and 2018, 465 (19%) underwent 491 liver biopsies for clinical or research reasons. Adequate liver tissue was obtained in 98% of the procedures. In total, there were 32 complications reported for 24 biopsies: 23 biopsies with 30 complications in adults and 1 biopsy with 2 complications in children. Pain (n=19) and vasovagal reaction (n=6) were the most common complications. There were 7 serious adverse events, including an arterioportal venous fistula, a pneumothorax, 4 cases of bleeding, and severe pain with no associated condition. There were no deaths., Conclusions: These data demonstrate that percutaneous liver biopsy is associated with a high yield of tissue (98%) and a rate of serious complications of 1.4% in both children and adults with chronic HBV. These results support the focused use of liver biopsy in the evaluation of novel treatments in development for chronic hepatitis B., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Importance: Disparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited., Objective: To examine whether HBV treatment initiation and outcomes differ among racial groups., Design, Setting, and Participants: From 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., Exposures: Participants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment., Main Outcomes and Measures: Hepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death)., Results: Of 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 Relevance: In 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.

Background and Aims: Liver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV., Methods: This is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg., Results: Participants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p < 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels., Conclusion: HBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Objective: Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)-HIV co-infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF., Methods: Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors., Results: A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non-Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow-up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m 2 ) decreased from 87.1 to 79.9 over 192 weeks (p < 0.001); however, the prevalence of eGFR <60 ml/min/1.73m 2 did not appear to differ over time (always <16%; p = 0.43). From baseline to week 192, procollagen type I N-terminal propeptide (P1NP) (146.7 to 130.5 ng/ml; p = 0.001), osteocalcin (14.4 to 10.2 ng/ml; p < 0.001) and C-terminal telopeptides of type I collagen (CTX-1) (373 to 273 pg/ml; p < 0.001) decreased. Younger age, male sex and overweight/obesity versus normal weight predicted a decrease in eGRF. Black race, healthy weight versus underweight, advanced fibrosis, undetectable HBV DNA, and lower parathyroid hormone level predicted worsening bone turnover., Conclusion: In this HBV-HIV cohort with high prevalence of TDF use, several biomarkers of renal function and bone turnover indicated worsening status over approximately 4 years, highlighting the importance of clinical awareness in co-infected adults., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure., (Published by Elsevier Inc.)

Background & Aims: The contribution of the novel biomarkers, hepatitis B virus (HBV) RNA and HBV core-related antigen (HBcrAg), to characterization of HBV-human immunodeficiency virus (HIV) coinfection is unclear. We evaluated the longitudinal dynamics of HBV RNA and HBcrAg and their association with classical HBV serum biomarkers and liver histology and viral staining., Methods: HBV-HIV co-infected adults from 8 North American centers entered a National Institutes of Health-funded prospective cohort study. Demographic, clinical, serological, and virological data were collected at entry and every 24 to 48 weeks for up to 192 weeks. Participants with HBV RNA and HBcrAg measured ≥2 times (N = 95) were evaluated; 56 had paired liver biopsies obtained at study entry and end of follow-up., Results: Participants had a median age of 50 years; 97% were on combination anti-viral therapy. In hepatitis B e antigen (HBeAg)+ participants, there were significant declines in HBV RNA and HBcrAg over 192 weeks that tracked with declines in HBeAg, hepatitis B surface antigen, HBV DNA, and hepatitis B core antigen (HBcAg) hepatocyte staining grade (all P < .05). In HBeAg- participants, there were not significant declines in HBV RNA (P = .49) and HBcrAg (P = .63), despite modest reductions in hepatitis B surface antigen (P < .01) and HBV DNA (P = .03). HBV serum biomarkers were not significantly related to change in hepatic activity index, Ishak fibrosis score, or hepatocyte HBcAg loss (all P > .05)., Conclusions: In HBV-HIV coinfected adults on suppressive dually active antiviral therapy, the use of novel HBV markers reveals continued improvement in suppression of HBV transcription and translation over time. The lack of further improvement in HBV serum biomarkers among HBeAg- patients suggests limits to the benefit of combination anti-viral therapy and provide rationale for additional agents with distinct mechanisms of action., (Copyright © 2023. Published by Elsevier Inc.)

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An increased risk for HEV infection has been reported in organ-transplant recipients, mainly from Europe. Prospective data on HEV prevalence in the United States (U.S.) organ transplant population are limited. To determine the prevalence and factors associated with HEV infection among solid organ transplant-recipients, we conducted a prospective, cross-sectional, multicentre study among transplant-recipients and age- and organ-matched waitlist patients. Participants answered a risk-exposure questionnaire and were tested for HEV-RNA (in-house PCR), HEV-IgG, and IgM (ELISA, Wantai). Among 456 participants, 224 were transplant-recipients, and 232 were waitlist patients. The mean age was 58 years, 35% female, and 74% White. HEV seroprevalence of the entire cohort was 20.2% and associated with older age (p < 0.0001) and organ transplantation (p = 0.02). The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%, p = 0.042). Among transplant recipients, relative-risk of being HEV seropositive increased with older age (RR = 3.4 [1.07-10.74] in patients >70 years compared with ≤50 years, p = 0.037); history of graft hepatitis (2.2 [1.27-3.72], p = 0.005); calcineurin inhibitor use (RR = 1.9 [1.03-3.34], p = 0.02); and kidney transplantation (2.4 [1.15-5.16], p = 0.02). HEV-RNA, genotype 3 was detected in only two patients (0.4%), both transplant-recipients. HEV seroprevalence was higher among transplant-recipients than waitlist patients. HEV should be considered in transplant-recipients presenting with graft hepatitis. Detection of HEV-RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S., (© 2022 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Chronic hepatitis B virus (HBV) infection remains a major global health problem. Hepatitis B surface antigen (HBsAg) loss has been accepted as the definition of a functional HBV cure. Recent studies found that while covalently closed circular DNA (cccDNA) is the predominant source of HBsAg in hepatitis B e antigen-positive (HBeAg-positive) patients, integrated HBV DNA (iDNA) is the main source in HBeAg-negative patients. Consequently, achieving a functional HBV cure will require not only silencing of cccDNA but also iDNA. Assays that distinguish the source of HBsAg are needed to evaluate emerging therapies. In this issue of the JCI, Grudda et al. developed a PCR-based assay that differentiated the source of HBsAg and explored the contributing sources of HBsAg in patients on nucleos(t)ide analog antivirals. These findings provide a tool for understanding the contribution of iDNA in HBV infection and may guide therapies toward a functional HBV cure.

Background: Fatty liver disease (FLD) and hepatitis B virus (HBV) infection occur commonly in human immunodeficiency virus (HIV). FLD resolution is associated with improvement in lipoproteins in HIV-uninfected patients. We evaluated changes in FLD in an HBV/HIV-coinfected cohort., Methods: One hundred eight HBV/HIV-coinfected adults with baseline liver biopsies were followed every 24 weeks (median, 166 weeks) and 60 had follow-up biopsies. Baseline FLD categories (none, ≥5% steatosis, steatohepatitis), their change, and relationships with clinical and lipid/lipoprotein parameters were explored using multivariable modeling., Results: Median age was 50 years, and 93% were male. At baseline 30% had FLD. With control for lipid-lowering medications and body mass index, low-density lipoprotein (LDL) cholesterol (LDL-C), LDL particle concentration (LDL-P), and apolipoprotein B (apoB) decreased and adiponectin increased over time (all P < .05); On follow-up (vs baseline), there was no significant difference in FLD category (P = .85); 60% remained without FLD, 17% had unchanged, 12% worsening, and 12% improved FLD. Baseline low-density lipoproteins (LDL-C, LDL-P, small LDL-P) and apoB appeared highest in those with unchanged FLD status (all P < .05). No associations between changes in FLD across follow-up (worsening/improvement vs unchanged) and lipid/lipoproteins changes were identified., Conclusions: In this cohort, there was no significant change in FLD prevalence over a relatively short timeframe. Baseline atherogenic lipids appeared highest in those with persistent steatosis or steatohepatitis, suggesting potentially increased cardiovascular risk in this group, but an independent relationship between individual-level change in FLD status and lipid/lipoprotein levels across follow-up was not observed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The hepatitis B virus (HBV) affects an estimated 290 million individuals worldwide and is responsible for approximately 900 000 deaths annually, mostly from complications of cirrhosis and hepatocellular carcinoma. Although current treatment is effective at preventing complications of chronic hepatitis B, it is not curative, and often must be administered long term. There is a need for safe, effective, finite duration curative therapy., Aim: Our aim was to provide a concise, up to date review of all currently available and emerging treatment options for chronic hepatitis B., Methods: We conducted a search of PubMed, clinicaltrials.gov, major meeting abstracts and pharmaceutical websites for publications and communications on current and emerging therapies for HBV., Results: Currently approved treatment options for chronic hepatitis B include peginterferon alpha-2a and nucleos(t)ide analogues. Both options do not offer a 'complete cure' (clearance of covalently closed circular DNA (cccDNA) and integrated HBV DNA) and rarely achieve a 'functional cure' (hepatitis B surface antigen (HBsAg) loss). An improved understanding of the viral lifecycle, immunopathogenesis and recent advances in drug delivery technologies have led to many novel therapeutic approaches that are currently being evaluated in clinical trials including targeting of viral entry, cccDNA, viral transcription, core protein, and release of HBsAg and HBV polymerase. Additionally, novel immunological approaches that include targeting the innate and adaptive immune system and therapeutic vaccination are being pursued., Conclusion: The breadth and scope of novel therapies in development hold promise for regimen/s that will achieve functional cure., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background and Aims: Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics., Methods: The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated., Results: Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively., Conclusion: HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling., (© 2021 American Association for the Study of Liver Diseases.)

Background: There are limited data on noninvasive methods to identify hepatic steatosis in coexisting hepatitis B virus (HBV) infection., Aims: To evaluate the diagnostic performance of noninvasive serum-based scores to detect steatosis using two distinct chronic HBV cohorts with liver histology evaluation., Methods: Chronic HBV cohorts with untreated HBV mono-infection (N = 302) and with treated HBV-HIV (N = 92) were included. Liver histology was scored centrally. Four serum-based scores were calculated: hepatic steatosis index (HSI), nonalcoholic fatty liver disease Liver Fat Score (NAFLD-LFS), visceral adiposity index (VAI), and triglyceride glucose (TyG) index. Optimal cutoffs (highest sensitivity + specificity) to detect ≥ 5% HS, stratified by cohort, were evaluated., Results: HBV-HIV (vs. HBV mono-infected) patients were older (median 50 vs. 43 years), and a higher proportion were male (92% vs. 60%), were black (51% vs. 8%), had the metabolic syndrome (41% vs. 25%), and suppressed HBV DNA (< 1000 IU/mL; 82% vs. 9%). Applying optimal cutoffs, the area under the receiver operator curve for detecting ≥ 5% steatosis in HBV-only and HBV-HIV, respectively, was 0.69 and 0.61 for HSI, 0.70 and 0.76 for NAFLD-LFS, 0.68 and 0.64 for TyG, and 0.68 and 0.69 for VAI. The accuracy of optimal cutoffs ranged from 61% (NAFLD-LFS) to 67% (TyG) among HBV-only and 56% (HSI) to 76% (NAFLD-LFS) among HBV-HIV. Negative predictive values were higher than positive predictive values for all scores in both groups., Conclusion: The relative utility of scores to identify steatosis in chronic HBV differs by co-infection/anti-HBV medication status. However, even with population-specific cutoffs, several common serum-based scores have only moderate utility. ClinicalTrials.gov NCT01924455., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: Although hepatitis B surface antigen (HBsAg) loss is considered the ideal therapeutic endpoint for the treatment of chronic hepatitis B virus (HBV) infection, its impact on clinical outcomes remains uncertain., Aim: To assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment-related HBsAg loss., Methods: We searched PUBMED, Embase, the Cochrane library, and published abstracts through to May 2021 for studies that reported HBsAg loss, had >1 year of follow-up and reported at least one clinical outcome in adults with chronic HBV infection., Results: We identified 57 studies (258 744 HBsAg-positive patients, 63 270 with HBsAg loss). Based on 24 studies including 160 598 patients with and without HBsAg loss, HBsAg loss was associated with a non-significant 23% relative risk reduction of developing hepatocellular carcinoma (HCC) compared to those who remained HBsAg-positive (RR = 0.77; 95% CI: 0.38-1.57). In subgroup meta-analysis of 10 studies, treatment-related HBsAg loss was associated with a non-significant higher pooled proportion of HCC (0.94%) compared to spontaneous HBsAg loss (0.45%). HCC development after HBsAg loss was significantly higher in males, those with underlying cirrhosis, and those with a family history of HCC. HBsAg loss was associated with lower pooled proportions of incident cirrhosis, hepatic decompensation, overall and liver-related mortality compared to no HBsAg loss. Substantial heterogeneity was noted across studies for all outcomes., Conclusion: HBsAg loss is associated with a reduced risk of clinical outcomes. However, several shortcomings in the published studies prevent a more definitive conclusion on the potential benefits of HBsAg loss., (© 2021 John Wiley & Sons Ltd.)

Nucleoside analogue (NA) therapy for chronic hepatitis B (CHB) is associated with improved clinical outcomes, but usually requires long-term use. Whether treatment can be safely withdrawn and the factors associated with post-withdrawal outcome are not well defined. To assess long-term outcomes after stopping antiviral therapy, patients with hepatitis B e antigen (HBeAg)-negative CHB who had received antiviral therapy for 4 or more years with hepatitis B virus (HBV) DNA (≤100 IU/mL) were prospectively withdrawn from antiviral therapy and monitored monthly for the initial 6 months and every 3 months thereafter. Those with clinical relapse were retreated according to severity of relapse. Fifteen patients were withdrawn from lamivudine (4), adefovir (5), or a combination of the two (6) after a mean treatment duration of 8.4 years. The mean age was 45 years, 13 were male, and 8 were initially HBeAg-positive before treatment. After a mean follow-up of 6.6 years, outcomes differed by pretreatment HBeAg status. All patients who were HBeAg+ before treatment experienced virological relapse (8 of 8); 6 of 8 experienced clinical relapse; 4 of 8 had ALT flares; 5 of 8 required re-initiation of treatment, one of whom cleared hepatitis B surface antigen (HBsAg); and 3 of 8 remained off treatment, one of whom cleared HBsAg. In contrast, 4 of 7 patients who were HBeAg-negative before treatment experienced virological relapse, 3 of 7 experienced clinical relapse, and 1 of 7 had an alanine aminotransferase (ALT) flare. None restarted treatment, and 4 of 7 cleared HBsAg. Low pre-withdrawal HBsAg level was predictive of HBsAg loss. Conclusion: NA therapy can be safely withdrawn with long-term remission and high rates of HBsAg loss in most HBeAg-negative patients without cirrhosis. Patients who were initially HBeAg+ should not be withdrawn from treatment, because clinical relapse was frequent and often severe., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

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.)

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., (© 2021 John Wiley & Sons Ltd.)

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton, and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV). Their achievements represent a remarkable triumph of biomedical science which allowed the development of curative therapy for HCV, that will save countless lives. This tribute provides a historical perspective of the laureates' seminal work leading to the discovery of the HCV and a synopsis of a forum hosted by the American Association for the Study of Liver Diseases to honor the laureates in which they offered their perspectives, advice for young investigators and what's left to accomplish in the field. Finally, others in the research community who have worked closely with one or more of the laureates, share some of their personal reflections and anecdotes., (© 2021 by the American Association for the Study of Liver Diseases.)

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.)