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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.)

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.)

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.)

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., (© 2021 John Wiley & Sons Ltd.)

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy., (© 2019 John Wiley & Sons Ltd.)

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., (© 2017 John Wiley & Sons Ltd.)

Approximately 3.2 million people in the United States have chronic hepatitis C virus (HCV) infection; the primary cause for adult liver transplantation and a significant burden on healthcare resources. The role of HCV and other risk factors in development of HCC in patients with chronic kidney disease is not well defined. We studied predictors of hepatocellular carcinoma (HCC) in dialysis patients with chronic HCV by analyzing factors associated with its development. Data were extracted from the United States Renal Database System (USRDS) using ICD-9 codes. Variables included were gender, race, duration on dialysis and co-morbidities (alcohol abuse, drug abuse, HIV, hepatitis B, diabetes and/or presence of cirrhosis). Among the 32 806 HCV infected subjects, 262 cases had HCC. HCC was 12 times more likely in subjects with cirrhosis (P < 0.001), three times more likely in subjects with alcohol abuse (P < 0.001), and 1.3 times more likely in subjects with diabetes (P = 0.04). Asians were three times more likely (P < 0.001) to have HCC. Females were less likely to have HCC compared to males (P = 0.002). The likelihood of having HCC increased with age (P =0.001). This population-based study demonstrates that among subjects with HCV on dialysis, those with cirrhosis, Asian race and history of alcohol abuse are at highest risk for development of HCC. Furthermore, these findings indicate links between HCV and HCC which are valuable in case management for identifying; monitoring, and managing dialysis patients with HCC.

Simple, rapid and accurate assays for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) are helpful for clinical diagnosis and field epidemiological surveys. A commercially developed, rapid immunochromatographic test for simultaneous detection of HBsAg and HBeAg was evaluated using a total of 2463 selected samples (827 frozen sera, 1011 fresh sera, and 625 whole blood samples). Results of the rapid test were compared with standard enzyme immunoassay (EIA) methods for HBsAg and HBeAg detection. The accuracy of the rapid test was excellent and was similar for frozen sera, fresh sera and whole blood. The overall sensitivity and specificity for the detection of HBsAg were 95 and 100%, and the corresponding positive and negative predictive values were 100 and 99.7%, respectively. The sensitivity and specificity for the detection of HBeAg were slightly less than that for HBsAg, and were 80 and 98%, with positive and negative predictive values of 91 and 94%, respectively. Thus, compared with the EIA method, the rapid test was highly sensitive and accurate for the detection of HBsAg although somewhat less sensitive and specific for detection of HBeAg. Because of its speed, simplicity and flexibility, the rapid test is ideally suited for HBsAg and HBeAg screening in population-based epidemiological studies and in low risk populations, particularly in regions of the world where hepatitis B is endemic.

In a previously reported randomized controlled trial of interferon-alpha (IFN-alpha) for chronic hepatitis B, we found a significant difference in response between Chinese adults with elevated vs normal pretreatment aminotransferase (ALT) levels. The aim of this study was to determine the correlation between serum hepatitis B virus (HBV) DNA levels and response to IFN therapy. HBV DNA levels in residual stored sera from patients who participated in the above trial were quantified by a branched DNA (bDNA) assay. Nominal logistic regression was used to estimate the probability of response to IFN treatment as a function of pretreatment ALT and/or HBV DNA levels. We found a significant (P < 0.01) correlation between the HBV DNA levels at midtreatment and response to IFN therapy. Response was achieved in 53% of patients who had undetectable HBV DNA levels at midtreatment but in only 17% of those who remained HBV DNA positive (P < 0.01). In contrast, the probabilities of response for patients with baseline HBV DNA levels over the range 10 to 10000 million equivalents (MEq) ml-1 were almost identical. We also found a significant correlation between the pretreatment ALT levels and response to IFN therapy. The probabilities of response for patients with pretreatment ALT levels of 500 and 100 IU l-1 were higher than for patients with normal ALT levels by two and onefold, respectively. Our findings may help to improve the cost-effectiveness of IFN therapy for chronic hepatitis B by guiding the selection of patients for therapy and in optimizing the duration of treatment for the individual patient.