HBeAg-negative Hepatitis B Virus Research Articles

Large spontaneous HBV DNA fluctuations and potential usefulness of a single-point measurement of combined HBV DNA and quantitative HBsAg for the exclusion of HBeAg-negative chronic hepatitis B: A prospective Tunisian cohort study

Background and study aimDuring the natural course of HBeAg-negative chronic hepatitis B (CHB), fluctuations in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels are often observed, making the classification of patients difficult. We aimed to describe spontaneous short-term HBV DNA level fluctuations and to assess the usefulness of qHBsAg in Tunisian patients with HBeAg-negative chronic HBV infection. Patients and methodsWe included 174 treatment-naive Tunisian patients with HBeAg-negative chronic HBeAg-negative HBV infection. A prospective 1-year follow-up was conducted with serial determinations of HBV DNA, ALT levels, and qHBsAg. The patients were classified into three groups: inactive carriers (G1), patients with negative HBeAg CHB (G2), and patients with an “indeterminate state” (G3). For the latter group, a liver biopsy was indicated. ResultsOnly genotype D was detected. During follow-up, 21.6% and 19.5% of patients with a low initial (<2,000 IU/ml) and intermediate viral load (2,000–20,000 IU/ml) experienced a subsequent increase in their HBV DNA levels above 2,000 and 20,000 IU/ml, respectively. Significant variations in viral load were observed in 61.1% of patients at 6-month intervals. Among the 174 patients, 89 (51.1%) belonged to G1, 33 (19%) to G2, and 52 (29.9%) to G3. Fourteen patients have undergone a liver biopsy, of whom seven showed moderate to severe liver disease. Combination of HBV DNA < 2,000 IU/ml and qHBsAg < 832 IU/ml excluded CHB in 98.4% of cases. A cutoff point for qHBsAg < 100 IU/ml associated with an annual decline of > 0.5 log 10 IU/ml is a good predictor marker of functional cure for hepatitis B. ConclusionsThis study highlights the large short-term fluctuations in HBV DNA in patients with HBeAg-negative chronic HBeAg-negative HBV infection with genotype D. Thus, using the cutoff value of 832 for qHBsAg combined with that of 2,000 for HBV DNA makes it possible to exclude CHB for most patients.

Total serum bile acids predict therapy for HBeAg-negative chronic hepatitis B patients with borderline ALT and high HBV DNA.

The introduction of antiviral therapy in chronic hepatitis B (CHB) infection depends on precise evaluation of hepatic lesions. Total serum bile acids (TSBAs) are highly sensitive in monitoring liver dysfunction. We evaluated the predictive role of TSBAs for hepatic lesions in CHB patients with borderline alanine aminotransferase (ALT) and high level of hepatitis B virus (HBV) DNA copies. 328 CHB patients were enrolled, 241 were hepatitis B e antigen (HBeAg)-positive and 87 were HBeAg-negative. Patients were further divided into two entities according to inflammation/fibrosis evaluated by liver biopsy, low-grade (inflammation grade < 2 and fibrosis stage < 2) and high-grade (inflammation grade ≥ 2 or/and fibrosis stage ≥ 2) cohorts. TSBAs were compared with noninvasive tools including aspartate aminnotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) and red cell distribution width (RDW)-to-platelet ratio (RPR) to predict high-grade hepatic lesions in CHB subgroups. TSBAs, APRI, FIB-4 and RPR were statistically different between low- and high-grade patients in HBeAg-positive cohort. Only TSBAs showed significant difference between low and high grade in HBeAg-negative patients. Similarly, APRI, FIB-4 and RPR were correlated with different division of inflammation/fibrosis only in HBeAg-positive while TSBAs were correlated with inflammation/fibrosis levels in both HBeAg-positive and HBeAg-negative groups. Of the four indicators, the receiver operating characteristic (ROC) curve analysis showed that TSBAs have the maximum AUC (area under the curve) in HBeAg-negative group but the minimum in HBeAg-positive cohort. TSBAs can be used for predicting antiviral therapy in CHB patients with HBeAg-negative, borderline ALT and high HBV DNA.

Immunogenicity and Antiviral Response of Therapeutic Hepatitis B Vaccination in a Mouse Model of HBeAg-Negative, Persistent HBV Infection.

During the natural course of chronic hepatitis B virus (HBV) infection, the hepatitis B e antigen (HBeAg) is typically lost, while the direct transmission of HBeAg-negative HBV may result in fulminant hepatitis B. While the induction of HBV-specific immune responses by therapeutic vaccination is a promising, novel treatment option for chronic hepatitis B, it remains unclear whether a loss of HBeAg may influence its efficacy or tolerability. We therefore generated an adeno-associated virus (AAV)-vector that carries a 1.3-fold overlength HBV genome with a typical stop-codon mutation in the pre-core region and initiates the replication of HBeAg(−) HBV in mouse livers. Infection of C57BL/6 mice established persistent HBeAg(−) HBV-replication without any detectable anti-HBV immunity or liver damage. HBV-carrier mice were immunized with TherVacB, a therapeutic hepatitis B vaccine that uses a particulate HBV S and a core protein for prime vaccination, and a modified vaccinia Ankara (MVA) for boost vaccination. The TherVacB immunization of HBeAg(+) and HBeAg(−) HBV carrier mice resulted in the effective induction of HBV-specific antibodies and the loss of HBsAg but only mild liver damage. Intrahepatic, HBV-specific CD8 T cells induced in HBeAg(−) mice expressed more IFNγ but showed similar cytolytic activity. This indicates that the loss of HBeAg improves the performance of therapeutic vaccination by enhancing non-cytolytic effector functions.

Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load.

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication. To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19999IU/mL) due to their moderate risk of disease progression. A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load. Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20000IU/mL after 3years of follow-up. In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10KU/mL defines a low-risk group for disease progression.

Evaluation of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients

ObjectivesMany studies have investigated the utility of hepatitis B virus (HBV) serological markers in HBV-infected patients. However, only a few studies have examined HBV serological markers in HBV-human immunodeficiency virus (HIV) co-infected patients. Here, we conducted a cross-sectional study to evaluate correlations of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients. MethodsHBsAg, HBV DNA, HBV RNA, and HBcrAg were quantified in 51 HBV mono-infected patients and 33 HBV-HIV co-infected patients recruited at Tianjin Second People’s Hospital from 2016 to 2019. ResultsThere was no significant difference in serum levels of HBV DNA (P = 0.056), HBV RNA (P = 0.387), HBcrAg (P = 0.714) and HBsAg (P = 0.165) between the patient groups. In HBV mono-infected patients, strong positive correlations were confirmed between HBV RNA and HBV DNA (r=0.620, P < 0.01), HBcrAg and HBV DNA (r=0.802, P < 0.001), and HBcrAg and HBV RNA (r=0.727, P < 0.01). In HBV-HIV co-infected patients, serum HBsAg was very strongly correlated with HBcrAg (r=0.838, P < 0.001). In HBeAg-positive HBV mono-infected patients, all HBV serological markers correlated with each other, whereas only HBV RNA correlated with HBcrAg in HBeAg-negative HBV mono-infected patients (r=0.688, P = 0.007). In HBeAg-positive HBV-HIV co-infected patients, only HBsAg correlated with HBcrAg (r=0.725, P<0.001), whereas HBcrAg and HBV RNA correlated with each other in HBeAg-negative patients (r = 0.683, P=0.010). Moreover, CD4 T-cell counts were not significantly associated with HBsAg, HBV DNA, HBV RNA, and HBcrAg levels. ConclusionCompared with HBsAg and HBV DNA, which are widely used in clinical settings, our study confirmed that new HBV serological markers, such as HBV RNA and HBcrAg, have some utility in HBV mono-infected patients and HBV-HIV co-infected patients for monitoring the progression of liver disease.

Evaluation of Point Shear Wave Elastography Using Acoustic Radiation Force Impulse Imaging for Longitudinal Fibrosis Assessment in Patients with HBeAg-Negative HBV Infection.

Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection. Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L). Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05). Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.

Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses

Shrews, insectivorous small mammals, pertain to an ancient mammalian order. We screened 693 European and African shrews for hepatitis B virus (HBV) homologs to elucidate the enigmatic genealogy of HBV. Shrews host HBVs at low prevalence (2.5%) across a broad geographic and host range. The phylogenetically divergent shrew HBVs comprise separate species termed crowned shrew HBV (CSHBV) and musk shrew HBV (MSHBV), each containing distinct genotypes. Recombination events across host orders, evolutionary reconstructions, and antigenic divergence of shrew HBVs corroborated ancient origins of mammalian HBVs dating back about 80 million years. Resurrected CSHBV replicated in human hepatoma cells, but human- and tupaia-derived primary hepatocytes were resistant to hepatitis D viruses pseudotyped with CSHBV surface proteins. Functional characterization of the shrew sodium taurocholate cotransporting polypeptide (Ntcp), CSHBV/MSHBV surface peptide binding patterns, and infection experiments revealed lack of Ntcp-mediated entry of shrew HBV. Contrastingly, HBV entry was enabled by the shrew Ntcp. Shrew HBVs universally showed mutations in their genomic preCore domains impeding hepatitis B e antigen (HBeAg) production and resembling those observed in HBeAg-negative human HBV. Deep sequencing and in situ hybridization suggest that HBeAg-negative shrew HBVs cause intense hepatotropic monoinfections and low within-host genomic heterogeneity. Geographical clustering and low MSHBV/CSHBV-specific seroprevalence suggest focal transmission and high virulence of shrew HBVs. HBeAg negativity is thus an ancient HBV infection pattern, whereas Ntcp usage for entry is not evolutionarily conserved. Shrew infection models relying on CSHBV/MSHBV revertants and human HBV will allow comparative assessments of HBeAg-mediated HBV pathogenesis, entry, and species barriers.

Hepatitis B e Antigen Inhibits NF-κB Activity by Interrupting K63-Linked Ubiquitination of NEMO.

Viruses have adopted diverse strategies to suppress antiviral responses. Hepatitis B virus (HBV), a virus that is prevalent worldwide, manipulates the host's innate immune system to evade scavenging. It is reported that the hepatitis B e antigen (HBeAg) can interfere with NF-κB activity, which then leads to high viral loads, while HBV with the G1896A mutation remains infectious without the production of HBeAg but can induce more severe proinflammatory response and liver damage. The aim of current work was to study the molecular mechanism by which HBeAg suppresses interleukin-1β (IL-1β)-stimulated NF-κB activity, which leads to the suppression of the innate immune responses to HBV infection. Our study revealed that HBeAg could interact with NEMO, a regulatory subunit associated with IκB kinase, which regulates the activation of NF-κB. HBeAg suppressed the IL-1β-induced tumor necrosis factor (TNF)-associated factor 6 (TRAF6)-dependent K63-linked ubiquitination of NEMO, thereby downregulating NF-κB activity and promoting virus replication. We further demonstrated the inhibitory effect of HBeAg on the NF-κB signaling pathway using primary human hepatocytes, HBV-infected HepG2-NTCP cells, and clinical liver samples. Our study reveals a molecular mechanism whereby HBeAg suppresses IL-1β-induced NF-κB activation by decreasing the TRAF6-dependent K63-linked ubiquitination of NEMO, which may thereby enhance HBV replication and promote a persistent infection.IMPORTANCE The role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-κB pathway are controversial. In this study, we showed that HBeAg could suppress both Toll-like receptor 2 (TLR2)- and IL-1β-induced activation of NF-κB in cells and clinical samples, and we further revealed novel molecular mechanisms. We found that HBeAg can associate with NEMO, the regulatory subunit for IκB kinase (IKK) that controls the NF-κB signaling pathway, and thereby inhibits TRAF6-mediated K63-linked ubiquitination of NEMO, resulting in downregulation of NF-κB activity and promotion of virus replication. In contrast, the HBeAg-negative HBV mutant can induce higher levels of NF-κB activity. These results are important for understanding the HBV-induced pathogenesis of chronic hepatitis and indicate that different clinical measures should be considered to treat HBeAg-positive and HBeAg-negative infections. Our findings represent a conceptual advance in HBV-related suppression of NF-κB signaling.

Chronic hepatitis B virus infection is associated with decreased serum 25(OH)D concentration in non-cirrhotic patients.

Aim of the studyRecent reports provide evidence for the immunomodulatory properties of vitamin D. Decreased vitamin D levels may contribute to the progression of liver disease in hepatitis B virus (HBV) infection. This study aims to assess serum 25(OH)D in patients with chronic HBeAg-negative HBV (CHB) infection at different phases of disease.Material and methodsFifty-eighty patients with CHB, 10 with a history of HBsAg/anti-HBs seroconversion, were enrolled. The control group consisted of 9 healthy volunteers. Serum 25(OH)D concentration was assessed by ELISA.ResultsSerum 25(OH)D concentration was significantly lower in the CHB group in comparison to the HC group. It did not differ across the consecutive phases of the HBeAg-negative HBV infection. Negative correlations between serum 25(OH)D and alanine aminotransferase (ALT) as well as frequency of peripheral blood monocytes were observed. Serum 25(OH)D in samples collected in winter was significantly lower in comparison to the pool of samples collected in the summer. Serum 25(OH)D concentration was not associated with the phases of HBV-infection, HBV viral load, APRI or liver histology.ConclusionsSerum 25(OH)D is significantly decreased in HBV infection irrespectively of the phase of the infection and negatively correlates with serum ALT level, which may reflect the deterioration of liver function. Based on our results, we can conclude that the role of vitamin D in the immune control of HBV infection is probably irrelevant.

Evaluation of IgG4 Levels as a Fibrosis Marker On Disease Activity in the Course of Hepatitis B Infection

Aim: Understanding immunopathogenesis of hepatitis-B virus (HBV) infection is pivotal in the management of complications. The aim of the study is to investigate the association of IgG4 levels with the liver fibrosis. Methods: Histological evaluation of the liver biopsy and laboratory analyses including IgG4 were performed. Results: A total of 130 patients fulfilling the criteria for a diagnosis of HBV infection were enrolled in the study. Of these patients, 14 had HBeAg positive and 116 had HBeAg negative HBV infection. In HBeAg-positive patients serum IgG4 levels were significantly higher than HBeAg-negative patients (p = 0.038). Conclusion: There is an association of IgG4 level and higher rates of viral replication and enhanced infectivity.

Hepatitis B surface antigen levels in hepatitis B virus-related hepatocellular carcinoma: a retrospective cross-sectional study

Objective To investigate the distribution of serum hepatitis B surface antigen (HBsAg) levels in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods A total of 226 cases of HBV-related HCC were collected from June 2009 to December 2013. Demographic characteristics of patients with different barcelona clinica liver cancer (BCLC) stages, the status of cirrhosis and HBsAg levels with different virological indicators were compared. HBsAg quantification was tested by chemiluminescence. The statistical analysis was conducted by t test, χ2 test, Kruskal-Wallis H rank sum test and Mann-Whitney U rank sum test. Results A total of 226 cases were included with 201 male patients and 25 female patients. HBsAg levels in HBV-related HCC patients with different ages were significantly different (χ2=12.30, P=0.015), but with no statistical difference in those with different gender (Z=-0.35, P>0.05). The HBsAg levels were not significantly different between patients with or without liver cirrhosis (Z=-0.80, P=0.419). HBsAg levels in liver cirrhosis cases with different liver function stages were not significant different (χ2=2.15, P=0.341). HBsAg levels in HBeAg-positive group or HBV DNA positive group were significantly higher than those in HBeAg-negative group or HBV DNA negative group, respectively (Z=-3.67 and -4.80, respectively, both P 0.05). The constituent ratios of patients with different HBsAg levels in different BCLC stages were statistically different (χ2=28.17, P=0.005). Conclusions There are no significant differences of HBsAg levels in patients with different BCLC stages, indicating that HBsAg may not be a contributor for disease progression after emergence of HCC. Key words: Hepatitis B surface antigens; Carcinoma, hepatocellular; Liver cirrhosis; Barcelona clinical liver cancer

A new model mimicking persistent HBV e antigen-negative infection using covalently closed circular DNA in immunocompetent mice.

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.

Differences in the availability of diagnostics and treatment modalities for chronic hepatitis B across Europe

The prevalence and management of chronic hepatitis B virus (HBV) infection differ among European countries. The availability and reimbursement of diagnostics and drugs may also vary, determining distinct treatment outcomes. Herein, we analyse differences in medical facilities for the care of patients with chronic HBV infection across Europe. A survey was sent to the members of the ESCMID Study Group for Viral Hepatitis, all of whom are experts in chronic HBV infection management. The comprehensive survey asked questions regarding hepatitis B surface antigen (HBsAg) prevalence, the availability of diagnostics and drugs marketed, and distinct clinical practice behaviours in the management of chronic HBV infection. World Bank data were used to assess the economic status of the countries. With 16 expert physicians responding (69%), the HBsAg prevalence rates were <1% in France, Hungary, Italy, The Netherlands, Portugal, Spain, and the UK, intermediate (1–5%) in Turkey, Romania, and Serbia, and high (>5%) in Albania and Iran. Regarding the availability and reimbursement of HBV diagnostics (HBV DNA and liver stiffness measurement), HBV drugs (interferon, lamivudine, tenofovir, and entecavir), HBV prophylaxis, and duration of HBeAg-positive and HBeAg-negative HBV infection, the majority of high-income and middle-income countries had no restrictions; Albania, Iran and Serbia had several restrictions in diagnostics and HBV drugs. The countries in the high-income group were also the ones with no restrictions in medical facilities, whereas the upper-middle-income countries had some restrictions. The prevalence of chronic HBV infection is much higher in southern and eastern than in western European countries. Despite the availability of European guidelines, policies for diagnostics and treatment vary significantly across European countries.

Detection of hepatitis B activity in HBeAg-negative carriers with normal aminotransferase levels in central Brazil

Background and rationale for the study. Hepatitis B virus (HBV) chronic infection may follow a benign course with low risk of cirrhosis or liver cancer. As differentiation of inactive status from HBeAg-negative chronic hepatitis B is often challenging, monitoring of inactive HBV carriers is important to detect viral relapse or formerly undetected activity. The incidence of hepatitis activity in HBeAg-negative carriers with normal aminotransferases was examined by retrospective analysis of a cohort of carriers who had been followed-up at a hospital in Central Brazil. All patients had remained free of evidence of liver disease and maintained normal aminotransferase levels throughout the first year of follow-up. The incidence density of chronic HBV activity was determined and an incidence curve was constructed using the Kaplan-Meier method. Cox regression models were developed to identify for surrogate markers of activity.Results. Among the 224 patients who comprised the cohort, chronic HBV activity was detected in 30 during follow-up. The incidence density of activity was 11.8 per 100 person-years (95% confidence interval: 8.3-16.9). The results of Cox regression analysis indicated that chronic HBV activity was associated with entrance in the latter years of the period examined (p = 0.001) and initial normal aspartate aminotransferase (AST) levels close to the upper-normal value (p = 0.022).Conclusion. Normal AST levels near the upper-normal value may be an indicator of relapse or previously undetected activity, and should thus be monitored closely in HBeAg-negative HBV carriers, in whom risk of relapse should remain an important managing consideration.

Low Prevalence of Liver Disease but Regional Differences in HBV Treatment Characteristics Mark HIV/HBV Co-Infection in a South African HIV Clinical Trial

BackgroundHepatitis B virus (HBV) infection is endemic in South Africa however, there is limited data on the degree of liver disease and geographic variation in HIV/HBV coinfected individuals. In this study, we analysed data from the CIPRA-SA ‘Safeguard the household study’ in order to assess baseline HBV characteristics in HIV/HBV co-infection participants prior to antiretroviral therapy (ART) initiation.Methods812 participants from two South African townships Soweto and Masiphumelele were enrolled in a randomized trial of ART (CIPRA-SA). Participants were tested for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA. FIB-4 scores were calculated at baseline.ResultsForty-eight (5.9%) were HBsAg positive, of whom 28 (58.3%) were HBeAg positive. Of those with HBV, 29.8% had an HBV DNA<2000 IU/ml and ALT<40 IU/ml ; 83.0% had a FIB-4 score <1.45, consistent with absent or minimal liver disease. HBV prevalence was 8.5% in Masiphumelele compared to 3.8% in Soweto (relative risk 2.3; 95% CI: 1.3–4.0). More participants in Masiphumelele had HBeAg-negative disease (58% vs. 12%, p = 0.002) and HBV DNA levels ≤2000 IU/ml, (43% vs. 6% p<0.007).ConclusionOne third of HIV/HBV co-infected subjects had low HBV DNA levels and ALT while the majority had indicators of only mild liver disease. There were substantial regional differences in HBsAg and HbeAg prevalence in HIV/HBV co-infection between two regions in South Africa. This study highlights the absence of severe liver disease and the marked regional differences in HIV/HBV co-infection in South Africa and will inform treatment decisions in these populations.

Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogs: Is the glass half full or half empty?

Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogs: Is the glass half full or half empty?

Predictive value of HBsAg quantification for determining the clinical course of genotype C HBeAg‐negative carriers

Hepatitis B virus surface antigen (HBsAg) quantification has been suggested to discriminate inactive carriers from hepatitis e antigen (HBeAg) negative chronic hepatitis, but it could be genotype-dependent. We studied the predictive value of HBsAg quantification in genotype C HBeAg-negative hepatitis B virus (HBV) carriers. We recruited 104 HBeAg-negative HBV carriers with HBV DNA levels<2,000IU/ml and normal alanine aminotransferase (ALT) levels for at least 12months and prospectively followed them for>36months. Patients were classified into two groups: inactive carriers (IC) who showed HBV DNA levels<2,000IU/ml and persistently ALT≤40IU/ml throughout the follow-up period and patients with HBeAg-negative chronic hepatitis (ENH). After follow-up, 73 patients were categorized into the IC group and 31 patients into the ENH group. HBsAg levels were significantly lower in the IC group than in the ENH group. The diagnostic accuracy of single-point HBsAg levels for predicting viral activation was favourable (AUROC=0.710, P<0.001). Diagnostic accuracy improved when HBsAg was combined with baseline HBV DNA levels (AUROC=0.750, P<0.001). The combination of HBsAg levels>850IU/ml and HBV DNA>850IU/ml predicted the reactivation of HBV replication with 84.6% diagnostic accuracy. Although it is inferior to other genotypes and to serum HBV DNA alone, single-point HBsAg level has a favourable diagnostic accuracy in genotype C HBeAg-negative HBV carriers and is expected to provide additional information for managing chronic hepatitis B.

Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers

Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.

New approaches in the management of chronic hepatitis B: role of tenofovir.

In the field of HIV management, tenofovir disoproxil fumarate (TDF) plays a pivotal role and has been demonstrated to be a safe and well-tolerated antiviral agent. Recent data showed the efficacy of TDF in the treatment of chronically hepatitis B virus (HBV)-infected patients. TDF was superior to adefovir dipivoxil (ADV) in both nucleos(t)ide-naïve HBeAg-positive and HBeAg-negative HBV patients, and appeared to be one of the most potent antiviral agents so far. In addition, several reports showed that TDF was also effective in the nucleos(t)ide-experienced population, although conflicting results have been presented concerning patients with genotypic resistance to ADV. TDF seems to have a good resistance profile as well. The rtA194T mutation in association with lamivudine resistance may confer resistance to TDF, although both in vivo and in vitro studies regarding this mutation demonstrate conflicting results. As treatment with TDF may be associated with nephrotoxicity, all TDF-treated patients should be monitored for renal function at baseline and periodically thereafter. While the relative roles of interferon vs nucleos(t)ide analogues (NA) as initial anti-HBV therapy remains unclear, TDF will probably become one of the key factors in HBV management both as first-choice NA for nucleos(t)ide-naïve patients and as rescue therapy for nucleos(t)ide-experienced patients.

Clinical features and survival in Chinese patients with hepatitis B e antigen‐negative hepatitis B virus‐related cirrhosis

To compare the clinical features of hepatitis B e antigen (HBeAg)-negative and HBeAg-positive cirrhosis, and to define the survival and prognostic indicators of Chinese HBeAg-negative hepatitis B virus (HBV)-related cirrhosis. Two hundred and seventeen patients with chronic hepatitis B cirrhosis were studied. Survival was calculated using the Kaplan-Meier method. Proportional hazards Cox regression procedure was used to identify independent predictors of survival. The relationship between HBV-DNA viral load and prognosis was also investigated. The mean follow-up time was 35 months (3-47 months). HBeAg-negative liver cirrhosis patients comprised the greatest number of cirrhosis patients. Median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, median total leukocytes (WBC), hemoglobin (Hb), platelet (Plt) and HBV-DNA levels and the proportion of HBV-DNA > 10(5) copies/mL were lower in HBeAg-negative patients. There were fewer complications in patients treated with lamivudine than in other patients. Survival rates were significantly reduced in patients with HBeAg-negative cirrhosis (P = 0.0024). The baseline Child-Pugh scores and more than one decompensation during follow up were independent variables correlated with survival of HBeAg-negative liver cirrhosis patients (P = 0.006 and P = 0.001, respectively). The HBV-DNA viral load did not correlate with any complications or mortality rates of HBeAg-negative patients. The clinical features of HBeAg-negative and -positive liver cirrhosis differ. Survival was significantly reduced for Chinese patients with HBeAg-negative than -positive cirrhosis. Factors contributing to the prognosis were baseline Child-Pugh scores and the presence of more than one decompensation during follow up.