Background and Aims
Large‐scale comprehensive studies on HBV RNA in chronic hepatitis B are lacking. We aimed to study the HBV RNA profile and its correlation with other viral markers in patients ...with chronic hepatitis B who are treatment‐naïve and patients receiving nucleos(t)ide analogues (NA).
Approach and Results
Biomarkers, including HBV RNA and hepatitis B core‐related antigen (HBcrAg), were measured in 388 patients. Of these, 246 were treatment‐naïve and were categorized into HBeAg‐positive chronic infection (n = 41), HBeAg‐positive chronic hepatitis (n = 81), HBeAg‐negative chronic infection (n = 39), HBeAg‐negative chronic hepatitis (n = 66), and HBsAg seroclearance (n = 19). These biomarkers were also measured in 142 patients who were NA‐treated receiving tenofovir or entecavir at baseline, week 48, and week 96. The pattern of serum HBV RNA levels mirrored HBV DNA (1‐2 logs higher than HBV RNA) and HBcrAg in patients who were treatment‐naïve. HBV RNA correlated best with HBcrAg (r = 0.84) and to a lesser extent with HBV DNA (r = 0.737) (both P < 0.001). In patients with HBsAg seroclearance, 15.8% and 15.8% had detectable serum HBV RNA and HBcrAg, respectively. NA treatment reduced serum HBV RNA by 1.46 logs and 1.77 logs at weeks 48 and 96, respectively. At week 96 of NA therapy, only 19.1% patients who were tenofovir‐treated and 25.7% patients who were entecavir‐treated had unquantifiable HBV RNA (P > 0.05). In patients who were treated and had undetectable HBV DNA, 77.5% and 30% had quantifiable HBV RNA and HBcrAg, respectively.
Conclusions
HBV RNA showed distinct and corresponding profiles in patients with HBV in different disease phases. HBV RNA and HBcrAg could be used to monitor residual transcriptional activities in patients with HBsAg seroclearance. NA led to reduction of serum HBV RNA. Monitoring of viral activities can still be achieved in patients with undetectable HBV DNA by serum HBV RNA.
Background & Aims
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core‐related antigen (HBcrAg) is a ...novel marker for HBV disease. We aimed to determine whether HBcrAg could be a surrogate marker for intrahepatic cccDNA.
Methods
Three hundred and five liver biopsies and the corresponding sera collected from 138 nucleos(t)ide analogues‐treated patients were analysed. 124 patients had paired liver biopsies at baseline and 1‐year post‐treatment, and 43 patients had a third biopsy after 6‐12 years of treatment. Serum HBcrAg, HBV DNA and hepatitis B surface antigen (HBsAg), and intrahepatic HBV DNA and cccDNA were measured.
Results
HBcrAg strongly correlated with cccDNA (r=.70), intrahepatic total HBV DNA (r=.67) and serum HBV DNA (r=.69; all P<.0001). In the 130 samples with undetectable serum HBV DNA, HBcrAg was detectable in 101 (78%) samples, and HBcrAg levels still correlated positively with cccDNA (r=.42, P<.0001). At ≥6 years of therapy, the median logarithmic reduction in HBcrAg was 2.7 log kU/mL, which was comparable to the magnitude of reduction in cccDNA. Twenty‐one patients had undetectable cccDNA after ≥6 years of treatment, in whom 15 (71%) had detectable HBcrAg (range: 1.2‐537 kU/mL).
Conclusions
Serum HBcrAg is a reliable surrogate marker for intrahepatic cccDNA. HBcrAg could be a very sensitive marker to reflect the cccDNA content and persistence of disease even with the cccDNA levels below the detection limit of assays.
For patients with chronic liver disease, different optimal liver stiffness cut-off values correspond to different stages of fibrosis, which are specific for the underlying liver disease and ...population.
To establish the normal ranges of liver stiffness in the healthy Chinese population without underlying liver disease.
This is a prospective cross sectional study of 2,528 healthy volunteers recruited from the general population and the Red Cross Transfusion Center in Hong Kong. All participants underwent a comprehensive questionnaire survey, measurement of weight, height, and blood pressure. Fasting liver function tests, glucose and cholesterol was performed. Abdominal ultrasound and transient elastography were performed on all participants.
Of the 2,528 subjects, 1,998 were excluded with either abnormal liver parenchyma on ultrasound, chronic medical condition, abnormal blood tests including liver enzymes, fasting glucose, fasting cholesterol, high body mass index, high blood pressure, or invalid liver stiffness scan. The reference range for the 530 subjects without known liver disease was 2.3 to 5.9 kPa (mean 4.1, SD 0.89). The median liver stiffness was higher in males compared with females (4.3 vs 4.0 kPa respectively, p<0.001). There was also a decline in median Lliver stiffness in the older age group, from 4.2 kPa in those <25 years to 3.4 kPa for those >55 years (p=0.001).
The healthy reference range for liver stiffness in the Chinese population is 2.3 to 5.9 kPa. Female gender and older age group was associated with a lower median liver stiffness.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Concomitant non-alcoholic fatty liver disease is common in patients with chronic hepatitis B (CHB) infection, although its impact on liver-related outcomes remains controversial. We aimed to study ...the effect of hepatic steatosis on the risk of fibrosis progression and the likelihood of HBsAg seroclearance.
Treatment-naïve patients with CHB, normal alanine aminotransferase and low viraemia (serum HBV DNA <2,000 IU/ml) were prospectively recruited for baseline and 3-year transient elastography assessment. Fibrosis staging was defined according to the EASL-ALEH guidelines, with fibrosis progression defined as ≥1 stage increment of fibrosis. Hepatic steatosis and severe hepatic steatosis were defined as controlled attenuation parameter (CAP) ≥248 dB/m and ≥280 dB/m, respectively.
A total of 330 patients (median age 50.5 years, 41.2% male, median HBV DNA 189 IU/ml) were recruited. Twenty-two patients (6.7%) achieved HBsAg seroclearance during follow-up, and the presence of hepatic steatosis was associated with a significantly higher chance of HBsAg seroclearance (hazard ratio 3.246; 95% CI 1.278–8.243; p = 0.013). At baseline, 48.8% and 28.8% of patients had steatosis and severe steatosis, respectively, while 4.2% had F3/F4 fibrosis at baseline, increasing to 8.7% at 3 years. The rate of liver fibrosis progression in patients with persistent severe steatosis was higher than in those without steatosis (41.3% vs. 23%; p = 0.05). Persistent severe hepatic steatosis was independently associated with fibrosis progression (odds ratio 2.379; 95% CI 1.231–4.597; p = 0.01).
CAP measurements have predictive value in patients with virologically quiescent CHB. The presence of hepatic steatosis was associated with a higher risk of fibrosis progression but, paradoxically, a 3-fold increase in HBsAg seroclearance rate.
Co-existing fatty liver disease in patients with chronic viral hepatitis B infection leads to worsening liver fibrosis, but also increases the chance of cure from hepatitis B virus. Routine bedside assessment of liver fat content is important for risk assessment in treatment-naïve patients with chronic hepatitis B.
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•Hepatic steatosis was associated with a 3-fold increase in likelihood of HBsAg seroclearance in quiescent CHB infection.•Cumulative probability of HBsAg seroclearance at 3 years was 18.4% in those with steatosis and low serum HBV DNA (<200 IU/ml).•Fibrosis progression was still observed in 25.2% patients despite virological quiescence.•Persistent severe hepatic steatosis was associated with a 2-fold increased risk of fibrosis progression at 36 months.•Routine CAP measurement in patients with apparently low-risk CHB has prognostic value.
Treatment cessation in chronic HBV infection may be durable in certain patient subgroups before hepatitis B surface antigen (HBsAg) seroclearance. The role of serum HBV RNA in determining treatment ...cessation suitability has not been well-investigated.
Nucleos(t)ide analogue (NUC) treatment was discontinued in non-cirrhotic patients with chronic HBV with serum HBsAg <200 IU/mL and fulfilling internationally recommended criteria for treatment cessation. Patients were monitored till 48 weeks with baseline and serial measurements of serum HBsAg, HBV RNA and hepatitis B core-related antigen. NUCs were resumed when HBV DNA reaches >2000 IU/mL regardless of alanine aminotransferase (ALT) levels.
114 entecavir-treated patients (median age 58.4 years, median serum HBsAg 54.4 IU/mL) with median treatment duration of 6.7 years were recruited. The 48-week cumulative rate of HBV DNA >2000 IU/mL was 58.1%. End-of-treatment serum HBV RNA and off-treatment serial HBV RNA were both independently associated with HBV DNA >2000 IU/mL (HR 2.959, 95% CI 1.776 to 4.926, p<0.001; HR 2.278, 95% CI 1.151 to 4.525, p=0.018, respectively). Patients with HBV RNA ≥44.6 U/mL had a cumulative 48-week rate of 93.2%, while combining HBV RNA undetectability and HBsAg <10 IU/mL had a cumulative 48-week rate of 9.1%. 24 patients (38.7%) developed off-treatment ALT elevation, highest peak ALT was 1515 U/L. 8 patients (median serum HBsAg 2.6 IU/mL) developed HBsAg seroclearance.
Serum HBV RNA measurement is essential for deciding on entecavir cessation in patients with chronic HBV, especially with low HBsAg levels. Patients can be stratified on their risk of off-treatment relapse based on both viral determinants.
NCT02738554.
Occult hepatitis B infection (OBI) refers to a condition where replication-competent HBV DNA is present in the liver, with or without HBV DNA in the blood, in individuals with serum HBsAg negativity ...assessed by currently available assays. The episomal covalently closed circular DNA (cccDNA) in OBI is in a low replicative state. Viral gene expression is mediated by epigenetic control of HBV transcription, including the HBV CpG island methylation pathway and post-translational modification of cccDNA-bound histone, with a different pattern from patients with chronic HBV infection. The prevalence of OBI varies tremendously across patient populations owing to numerous factors, such as geographic location, assay characteristics, host immune response, coinfection with other viruses, and vaccination status. Apart from the risk of viral reactivation upon immunosuppression and the risk of transmission of HBV, OBI has been implicated in hepatocellular carcinoma (HCC) development in patients with chronic HCV infection, those with cryptogenic or known liver disease, and in patients with HBsAg seroclearance after chronic HBV infection. An increasing number of prospective studies and meta-analyses have reported a higher incidence of HCC in patients with HCV and OBI, as well as more advanced tumour histological grades and earlier age of HCC diagnosis, compared with patients without OBI. The proposed pathogenetic mechanisms of OBI-related HCC include the influence of HBV DNA integration on the hepatocyte cell cycle, the production of pro-oncogenic proteins (HBx protein and mutated surface proteins), and persistent low-grade necroinflammation (contributing to the development of fibrosis and cirrhosis). There remain uncertainties about exactly how, and in what order, these mechanisms drive the development of tumours in patients with OBI.
Type 2 diabetes (T2D) is common among patients with chronic hepatitis B infection (CHB) and has been associated with increased risk of carcinogenesis, including HCC. We investigated factors ...associated with HCC and fibrosis progression among patients with CHB with T2D (CHB+T2D).
Chinese patients with CHB were prospectively recruited for the incidence of HCC and fibrosis progression defined by transient elastography. Among patients with CHB+T2D, glycemic control was assessed by mean glycated hemoglobin (HbA1c) and HbA1c variability determined using HbA1c measurements in the 5 years preceding recruitment. A total of 2330 patients with CHB were recruited (mean age 54.6 ±11.8 years old, 55.5% male, 57.9% antiviral-treated), with 671 (28.8%) having CHB+T2D (mean T2D duration 7.2 ± 4.6 years, mean HbA1c 7.2 ± 0.9%). T2D was independently associated with HCC (HR 2.080, 95% CI 1.343-3.222) and fibrosis progression (OR 4.305, 95% CI 3.416-5.424) in the overall cohort. In patients with CHB+T2D, factors reflecting glycemic burden (T2D duration HR 1.107, 95% CI 1.023-1.198), mean HbA1c (HR 1.851, 95% CI 1.026-3.339), time reaching target HbA1c (HbA1c-TRT; HR 0.978, 95% CI 0.957-0.999), liver stiffness (HR 1.041-1.043), and smoking (HR 2.726-3.344) were independently associated with HCC (all p < 0.05), but not HbA1c variability or controlled attenuation parameter. The same glycemic burden-related factors (T2D duration, mean HbA1c, and HbA1c-TRT), in addition to baseline fasting glucose, baseline HbA1c, AST and antiviral therapy, were independently associated with fibrosis progression at 3 years.
High glycemic burden was associated with HCC development and fibrosis progression among patients with CHB+T2D, highlighting the importance of glycemic control in reducing liver-related complications.
Background & Aims: Our aims were to study the virologic, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance. Methods: We ...determined the age of HBsAg seroclearance that is associated with a lower risk for hepatocellular carcinoma (HCC) in 298 CHB patients (median follow-up, 108 months). The following virologic and histologic features were also determined: liver stiffness (n = 229), liver histology, serum HBV DNA levels over time (n = 265), intrahepatic HBV DNA with covalently closed circular DNA (cccDNA) levels, and messenger RNA (mRNA) expression. Results: The median age of HBsAg seroclearance was 49.6 years. Seven (2.4%) patients developed HCC. Cumulative risk for HCC was higher in patients with HBsAg seroclearance at ages ≥50 years compared with those with HBsAg seroclearance at ages <50 ( P = .004) years. Of these 2 groups of patients, 29.5% and 7.9%, respectively, had significant fibrosis by liver stiffness measurement ( P = .001), and 15.4% of patients had mild histologic fibrosis. Intrahepatic total HBV DNA and cccDNA were detected in 100% and 79.3% of patients, respectively. All patients had undetectable surface and precore/pregenomic RNA transcripts. One (9.1%) patient had X mRNA expression. Serum HBV DNA were detectable in 13.4%, 6.1%, and 3.7% of patients within 1 year and 5–10 and >10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels. Conclusions: HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age <50 years was associated with a lower risk for the development of HCC.
Background and Aim
Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs in patients that are chronically infected with the hepatitis B virus. As the functional ...cure and ultimate treatment endpoint of chronic hepatitis B (CHB), HBsAg seroclearance is an important milestone in the natural history of CHB and serves great clinical value. This study aims to identify host and viral factors associated with HBsAg seroclearance.
Methods
This is a retrospective study carried out in the Queen Mary Hospital, Hong Kong. By analyzing the plasma retrieved from the serum archive (collected during 2011–2021) of 100 CHB patients attending the hospital's liver clinic, the longitudinal cytokine profiles between the HBsAg‐losers and the control groups were compared.
Results
Data revealed that plasma levels of IP‐10 were significantly lower at 3–5 years prior to HBsAg seroclearance compared with patients who remained HBsAg positive (P < 0.05). Receiver operating characteristic curve analysis reveals that plasma IP‐10 levels at multiple time points before HBsAg seroclearance return area under receivor‐operating characteristic curve (AUC) greater than 0.7. Plasma IP‐10 levels at 42.39 pg/mL produced an AUC = 0.723 with 74.0% sensitivity and 75.5% specificity to predict subsequent HBsAg seroclearance in the next 3–5 years. Low plasma IP‐10 identified 91.4% patients with quantitative HBsAg < 100 IU/mL who would subsequently develop HBsAg seroclearance, compared with 37% with higher plasma IP‐10 levels (P < 0.001).
Conclusions
Low plasma levels of IP‐10 are associated with subsequent HBsAg seroclearance, suggesting potential clinical utilities of measurement of IP‐10 in predicting HBsAg seroclearance, especially among patients with low HBsAg.
We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.
The ...present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4-9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.
All patients had 28.9-30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of -1.7 and -3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with
10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.
MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.
NCT02065336.
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