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.
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.
Display omitted
•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.
The significance of hepatitis B e‐antigen (HBeAg) seroclearance (ESC) in the long term is not well defined. The current study aimed to determine the clinical outcomes, the factors and predictive ...scores for hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance of a large cohort of patients undergoing ESC. Patients with documented ESC were followed up 3‐ to 6‐monthly. Baseline characteristics and longitudinal laboratory results were recorded. Predictive scores for HCC (HCC‐ESC) and HBsAg seroclearance (HBsAg‐ESC) were derived from multivariate Cox regression models. A total of 723 patients underwent ESC with a median ESC age and follow‐up of 36.0 and 18.3 years, respectively. Only 3.5% and 3.0% had persistently normal alanine aminotransferase (ALT) and HBV DNA <2logs IU/mL, respectively, after ESC. For patients with 100%, 100%‐90%, 90%‐50%, 50%‐10%, 10%‐0%, and 0% normal ALT after HBeAg seroclearance, the rate of HCC was 4.3%, 2.2%, 3.6%, 3.9%, 17.3%, and 37.2% at 20 years after ESC, respectively (P < 0.001). At 20 years after ESC, the cumulative incidence of HCC and HBsAg seroclearance was 7.9% and 13.5%, respectively, with an overall survival of 91.5%. ESC age, male sex, cirrhosis, hypoalbuminemia, viral load, and ALT were significant factors for HCC, whereas ESC age, male sex, viral load, and antiviral therapy were significant factors for HBsAg seroclearance. The area under receiver operating characteristics for HCC‐ESC and HBsAg‐ESC scores to predict HCC and HBsAg seroclearance at 20 years after ESC was 0.92 and 0.74, respectively. Conclusion: Male sex, older age at ESC, ALT, and higher level of HBV DNA were associated with higher rates of HCC after ESC. HCC‐ESC and HBsAg‐ESC predictive scores can determine the likelihood of developing HCC and achieving HBsAg seroclearance. (Hepatology 2018)
BackgroundTreatment 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.MethodsNucleos(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.Results114 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.ConclusionSerum 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.Trial registration number NCT02738554
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.
ObjectiveWe 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.DesignThe 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.ResultsAll 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.ConclusionsMD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.Trial registration number NCT02065336.
Abstract Background/Aims To determine whether gender, age, hepatitis B virus genotype, core promoter and precore mutations, HBeAg/ anti-HBe status, HBV DNA, ALT levels and cirrhosis on presentation ...were independent risk factors and derive a novel risk score for the development of HCC. Methods CHB patients (820) were followed up (mean duration 76.8 months) for the occurrence of HCC. Results The 5- and 10-year prevalence of HCC were 4.4% and 6.3%, respectively. Cox regression analysis showed that male gender ( p = 0.025, RR 2.98), increasing age ( p < 0.001, RR 1.07), higher HBV DNA levels ( p = 0.02, RR 1.28), core promoter mutations ( p = 0.007, RR 3.66), and presence of cirrhosis ( p < 0.001, RR 7.31) were independent risks for the development of HCC. A risk score was derived and validated with sensitivity > 84% and specificity > 76% to predict the 5- and 10- year risks for the development of HCC. The AUC for the 5- and 10-year prediction were 0.88 and 0.89, respectively. Conclusions The risk score, based on age, gender, HBV DNA levels, core promoter mutations and cirrhosis, can estimate the chance of development of HCC in 5 and 10 years after presentation. It can be used to identify high-risk CHB patients for treatment and screening of HCC.
Summary
The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long‐term dynamic changes of liver fibrosis are limited. ...This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10‐year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow‐up LSM. Fibrosis stages were classified according to EASL‐ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)‐negative patients (224 untreated, 235 treated with nucleos(t)ide analogues NAs) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval CI: 1.032‐4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128‐16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271‐26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = −0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis‐related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB‐related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time‐dependent decline in liver stiffness.
