Electronic Health Informatics Data To Describe Clearance Dynamics of Hepatitis B Surface Antigen (HBsAg) and e Antigen (HBeAg) in Chronic Hepatitis B Virus Infection.
ABSTRACT: HBsAg and HBeAg have gained traction as biomarkers of control and clearance during chronic hepatitis B virus infection (CHB). Improved understanding of the clearance correlates of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC), adopting an unbiased approach to the generation of a robust longitudinal data set for adults testing HBsAg positive from a large UK teaching hospital over a 6-year period (2011 to 2016 inclusive). Of 553 individuals with CHB, longitudinal data were available for 319, representing >107,000?weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. Among these 13, the HBsAg clearance rate in individuals on nucleos(t)ide analogue (NA) therapy (n?=?4 [31%]; median clearance time,150?weeks) was similar to that in individuals not on NA therapy (n?=?9 [69%]; median clearance time, 157?weeks). Those who cleared HBsAg were significantly older and less likely to be on NA therapy than nonclearers (P?=?0.003 and P?=?0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (P?=?0.025). HBeAg clearance occurred in individuals both on NA therapy (n?=?24; median time, 49?weeks) and off NA therapy (n?=?19; median time, 52?weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematized approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and support improvements in clinical care.IMPORTANCE Advances in the diagnosis, monitoring, and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical data sets that can help to inform advances in patient care and provide insights that may help to inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been underrepresented in the literature. By tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualized clinical care and may provide important clues into the immune events that underpin disease control.
Project description:The study was designed to investigate whether serum hepatitis B virus (HBV) RNA is a strong surrogate marker for intrahepatic HBV covalently closed circular DNA (cccDNA) compared with serum HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) in HBeAg-positive chronic hepatitis B (CHB) patients. Serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA were quantitatively detected at baseline (n = 82) and 96 weeks (n = 62) after treatment with nucleos(t)ide analogue (NUC) in HBeAg-positive CHB patients. The correlations among serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA levels were then statistically analyzed. The results showed that pretreatment intrahepatic cccDNA levels correlated better with serum HBV DNA levels (r = 0.36, P < 0.01) than with serum HBV RNA levels (r = 0.25, P = 0.02), whereas no correlations were found between pretreatment intrahepatic cccDNA levels and HBsAg (r = 0.15, P = 0.17) or HBeAg (r = 0.07, P = 0.56) levels. At 96 weeks after NUC treatment, intrahepatic cccDNA levels correlated well with HBsAg levels (r = 0.39, P < 0.01) but not with serum HBV RNA, HBV DNA, and HBeAg levels (all P > 0.05). Besides, the decline in the intrahepatic cccDNA level from baseline to week 96 correlated better with the reduction in the serum HBsAg levels than with the decreases in the levels of the other markers (for the HBsAg decline, r = 0.38, P < 0.01; for the HBV DNA decline, r = 0.35, P = 0.01; for the HBV RNA decline, r = 0.28, P < 0.05; for the HBeAg decline, r = 0.18, P = 0.19). In conclusion, the baseline serum HBV RNA level or its decline after 96 weeks of NUC therapy correlated with the corresponding intrahepatic cccDNA level, while it was less than that seen with serum HBV DNA at baseline and HBsAg (or its decline) at 96 weeks after treatment, respectively.
Project description:The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ?1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.
Project description:Patients with low hepatitis B surface antigen (HBsAg) levels and hepatitis B virus (HBV) DNA suppression by nucleos(t)ide analogues (NAs) achieve high rate of HBsAg loss through switching to PegIFNα in pre-registration study. The aim of this study was to achieve higher rate of HBsAg loss through extended PegIFN treatment. 98 patients with HBsAg < 2,000 IU/ml and HBV DNA < 20 IU/ml were randomized to receive PegIFNα-2b or continuing NA therapy for 60 weeks. At the end of treatment (EOT) and end of follow-up (EOF), only patients who switched to PegIFNα-2b achieved HBsAg loss (32.6%) and HBsAg seroconversion (27.9% and 25.6%). Patients who switched to PegIFNα-2b also achieved higher HBeAg seroconversion rates (65.1%) and HBeAg loss (81.4% and 90.7%) than those who continued NAs treatment. On-treatment HBsAg declines predicted the responses at EOT, and HBsAg declines at post-baseline times predicted the responses at EOF. The rates of responses were not increased through extended PegIFNα treatment. For patients with low HBsAg and HBV suppression with NAs, switching to PegIFNα-2b significantly increased the rates of HBsAg loss and HBsAg seroconversion. HBsAg decline can predict the response of switching to PegIFNα-2b following from NAs.
Project description:The clinical efficacy of nucleos(t)ide analogues (NAs) combined with interferon (IFN) therapy vs. NAs monotherapy for chronic hepatitis B (CHB) remains inconclusive. The aim of this meta-analysis was to determine whether the NAs plus IFN regimen offers synergistic efficacy that justifies the cost and burden of such a combination therapy in CHB patients.Related publications covering the period of 1966 to July 2014 were identified through searching MEDLINE, EMBASE, Cochrane library, Chinese Biomedical Literature Database, WANFANG, and CNKI database. A total of 17 studies were enrolled, including 6 in English and 11 in Chinese. Then, we established a final list of studies for the meta-analysis by systematically grading the quality and eligibility of the identified individual studies. We used hepatitis B antigen (HBeAg) loss, HBV-DNA undetectable rate, HBeAg seroconversion, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, and histological score at the end of treatment for efficacy evaluation. A quantitative meta-analysis (Review Manager, Version 5.1.0) was performed to assess the differences between NAs and IFN combination therapy and NAs monotherapy.Our analysis demonstrated that HBeAg loss (RR = 1.73, 95% CI = 1.32-2.26, p < 0.001), HBV-DNA undetectable rate (RR = 1.58, 95% CI = 1.22-2.04, p < 0.001), HBeAg seroconversion (RR = 1.68, 95% CI = 1.36-2.07, p < 0.001), and HBsAg loss (RR = 2.51, 95% CI = 1.32-4.75, p < 0.001) in the combination therapy group were significantly higher than those in the monotherapy group. However, there were no significant differences in HBsAg seroconversion (RR = 4.25, 95% CI = 0.62-29.13, p = 0.14), sustained virological response rates, and biochemical response rates observed between the two groups. The results showed that the combination therapy group had more improved HBV histology than the NAs monotherapy group (RR = 1.14, 95% CI = 0.93-1.39, p = 0.22).NAs and IFN or Peg-IFN combination therapy had a better efficacy in terms of HBeAg loss, HBV-DNA undetectable rate, HBeAg seroconversion, and HBsAg loss, compared to the NA monotherapy group at the end of treatment; however, there was no significant difference in HBsAg seroconversion between the two regimens.
Project description:Chronic hepatitis B (CHB) remains a global health dilemma with high morbidity and mortality. Human males absent on the first (hMOF) (a histone acetyltransferase) is responsible for DNA damage repair, tumorigenesis and cell cycle regulation. Persistence of HBV DNA contributes to cirrhosis and hepatocellular carcinoma (HCC) in CHB patients. Histone acetyltransferase enhances HBV replication, however the precise underlying mechanism of hMOF in HBV replication in CHB patients remains to be explored. This study aims to investigate the correlation between hepatic hMOF and HBV DNA replication in CHB patients, and may provide new insights towards the treatment of CHB patients.hMOF in liver biopsy (CHB, n = 33 HBeAg+; n = 20 HBeAg-, and three healthy controls) was determined, using immunohistochemistry, qPCR and Western blot. The correlation between hMOF and HBsAg, as well as, HBeAg were determined.A positive correlation between hMOF and HBV DNA in overall CHB patients was observed. A distinct positive correlation between hMOF and HBsAg and/or HBeAg in HBeAg+ CHB patients was also detected, however not observed between hMOF and HBsAg in HBeAg- CHB patients. No correlation was observed between hMOF and hepatic inflammation severity and fibrotic stage in CHB patients.Hepatic hMOF might contribute to host HBV clearance in CHB patients and possible pathogenesis.
Project description:BACKGROUND:As an important anti-HBV drug, pegylated interferon ? (PegIFN?) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. METHODS:We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFN?-2a or PegIFN?-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. RESULTS:HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value?<?0.05). HBV RNA???1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%). CONCLUSION:HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.
Project description:The purpose of this study was to explore the correlations of serum hepatitis B core-related antigen (HBcrAg) with intrahepatic Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and HBV total DNA in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. Serum HBcrAg and other parameters, including HBV DNA, HBV RNA, HBeAg, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were quantitatively measured at baseline and follow-up time points. Intrahepatic HBV cccDNA and total DNA were quantitatively detected at baseline and 96 weeks. Grading of liver necroinflammation and staging of hepatic fibrosis were assessed at baseline and 96 weeks. Correlations between serum HBcrAg and other parameters were analyzed by Pearson's correlation analysis. The results showed that pretreatment HBcrAg correlated significantly with HBV total DNA levels (r = 0.328, P = 0.003) in 82 CHB patients, and, after removing three outliers, with intrahepatic HBV cccDNA (r = 0.323, P = 0.004; n = 79). Serum HBcrAg correlated better with HBV cccDNA in patients with lower levels of serum HBV DNA (stratified by 7 log IU/ml of HBV DNA; r = 0.656, P = 0.003 versus r = -0.02, P = 0.866). Significant inverse correlations were found between HBcrAg and grade of liver necroinflammation (r = -0.245, P = 0.037), stage of hepatic fibrosis (r = -0.360, P = 0.002) at baseline. Serum HBcrAg presented significant correlation with intrahepatic HBV cccDNA in patients with HBeAg seroconversion at 96 weeks (r = 0.622, P = 0.006). The decrease in HBcrAg showed significant correlation with the decrease in HBV cccDNA after 96-week NA therapy (r = 0.282, P = 0.043). Serum HBcrAg also correlated significantly with other serum markers at baseline and 96 weeks of NA therapy. In conclusion, baseline HBcrAg and its decreased value were significantly correlated with the corresponding intrahepatic HBV cccDNA.
Project description:To examine hepatitis B (HBV) serological markers and plasma DNA concentrations in a large group of untreated HBV/HIV-coinfected individuals in two sub-Saharan settings.Baseline analysis of a randomized controlled trial.DART was a large trial of treatment monitoring practices in HIV-infected adults with advanced disease starting antiretroviral therapy at centres in Kampala or Entebbe, Uganda (n?=?2317) and Harare, Zimbabwe (n?=?999). HBV serological markers [antibody to HBV core antigen, HBV surface antigen (HBsAg), antibody to HBV surface antigen, HBV 'e' antigen (HBeAg), and antibody to hepatitis B 'e' antigen] and plasma HBV DNA viral load were measured retrospectively on stored baseline samples. Logistic regression was used to examine associations with baseline demographic and clinical factors.The rate of HBsAg positivity was significantly higher in Zimbabwe than Uganda (12.2 vs. 7.7%, adjusted odds ratio?=?1.54, P?<?0.001) despite a similar prevalence of antibody to HBV core antigen (56.3 vs. 52.4%) in the two settings. Overall, HBsAg positivity was associated with male sex (adjusted odds ratio?=?1.54, P?<?0.001) but not with age, WHO disease stage, or CD4 cell count. HBeAg was detected among 37% of HBsAg-positive patients, with higher rates among those with advanced WHO stage (P?=?0.02). Also in HBsAg-positive patients, HBV DNA was undetectable in 21%, detectable but below the level of quantification in 14%, and quantifiable in 65%. A total of 96% of HBeAg-positive and 70% of HBeAg-negative patients had detectable HBV DNA; 92 and 28% of patients, respectively, had HBV DNA viral load more than 2000?IU/ml.High rates of HBV coinfection were observed, highlighting the importance of ensuring that coinfected patients receive an antiretroviral regimen, whether first-line or not, that is active against both viruses.
Project description:Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem. HBV e antigen (HBeAg)-negative strains have become prevalent. Previously, no animal model mimicked the clinical course of HBeAg-negative HBV infection. To establish an HBeAg-negative HBV infection model, the 3.2-kb full-length genome of HBeAg-negative HBV was cloned from a clinical sample and then circularized to form covalently closed circular (cccDNA). The resulting cccDNA was introduced into the liver of C57BL/6J mice through hydrodynamic injection. Persistence of the HBeAg-negative infection was monitored at predetermined time points using HBV-specific markers including HBV surface antigen (HBsAg), HBeAg, and HBV core antigen (HBcAg) as well as DNA copies. Throughout the study, pAAV-HBV1.2 was used as a control. In mice injected with HBeAg-negative cccDNA, the HBV infection rate was 100% at the initial stage. HBsAg levels increased up to 1 week, at which point levels peaked and dropped quickly thereafter. In 60% of injected mice, HBsAg and HBcAg persisted for more than 10 weeks. High numbers of HBV DNA copies were detected in the serum and liver. Moreover, cccDNA persisted in the liver tissue of HBeAg-negative mice. In contrast to the pAAV-HBV 1.2 injected mice, no HBeAg was found in mice injected with HBeAg-negative HBV throughout the study period. These results demonstrate the first successful establishment of a model of HBeAg-negative HBV-persistent infection in immunocompetent mice. Compared to pAAV-HBV1.2-injected mice, the infection persistence and levels of serum virological and biochemical markers were approximately equal in the model mice. This model will be useful for mechanistic studies on HBeAg-negative HBV infection and will facilitate the evaluation of new antiviral drugs.
Project description:Background and Aims:We aimed to ascertain the feasibility and safety of NA cessation, the status of patients after cessation, and the predictive factors for relapse and subsequent retreatment. Methods:A total of 92 patients were enrolled in this prospective study. Patients were monitored every month for the first 3 months after cessation and every 3 months thereafter. Results:Sixty-two patients finished 48 weeks of follow-up. None died or developed liver failure, cirrhosis, or HCC. The 62 patients could be divided into 4 categories according to the 48-week clinical development of relapse. Virologic relapses occurred in 39 (62.9%) patients, with 72.7% occurring in the first 24 weeks in origin HBeAg positive patients and 82.4% in the first 12 weeks in origin HBeAg negative patients. Age (OR = 1.06, 95% CI = 1.02-1.10; p = 0.003), the HBsAg level (OR = 2.21, 95% CI = 1.47-3.32; p < 0.001), and positive origin HBeAg status (OR = 0.32, 95% CI = 0.14-0.74; p = 0.008) were predictive factors to virologic relapse. HBV DNA level (OR = 1.34, 95% CI = 1.13-1.58; p < 0.001) was predictive factor to retreatment. Conclusions:NA cessation is safe under supervision. Age, HBsAg level, and origin HBeAg status can be predictive factors for virologic relapse. The study was submitted to ClinicalTrials.gov Protocol Registration and Results System with the assigned NCT ID NCT02883647.