HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant

ObjectiveThe involvement of HBV DNA integration in promoting hepatocarcinogenesis and the extent to which the intrahepatic HBV reservoir modulates liver disease progression remains poorly understood. We examined the intrahepatic HBV reservoir, the occurrence of HBV DNA integration and its impact on the hepatocyte transcriptome in hepatitis B ‘e’ antigen (HBeAg)-negative chronic hepatitis B (CHB).DesignLiver tissue from 84 HBeAg-negative patients with CHB with low (n=12), moderate (n=25) and high (n=47) serum HBV DNA was analysed. Covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) were evaluated by quantitative PCR, whole exome and transcriptome sequencing was performed by Illumina, and the burden of HBV DNA integrations was evaluated by digital droplet PCR.ResultsPatients with low and moderate serum HBV DNA displayed comparable intrahepatic cccDNA and pgRNA, significantly lower than in patients with high HBV DNA, while hepatitis B core-related antigen correlated strongly with the intrahepatic HBV reservoir, reflecting cccDNA quantity. Whole exome integration was detected in a significant number of patients (55.6%, 14.3% and 25% in high, moderate and low viraemic patients, respectively), at a frequency ranging from 0.5 to 157 integrations/1000 hepatocytes. Hepatitis B surface antigen >5000 IU/mL predicted integration within the exome and these integrations localised in genes involved in hepatocarcinogenesis, regulation of lipid/drug metabolism and antiviral/inflammatory responses. Transcript levels of specific genes, including the proto-oncogene hRAS, were higher in patients with HBV DNA integration, supporting an underlying oncogenic risk in patients with low-level to moderate-level viraemia.ConclusionsHBV DNA integration occurs across all HBeAg-negative patients with CHB, including those with a limited HBV reservoir; localising in genes involved in carcinogenesis and altering the hepatocyte transcriptome.

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Cost-effectiveness of antiviral treatment in adult patients with immune-tolerant phase chronic hepatitis B

Gut ◽

10.1136/gutjnl-2020-321309 ◽

2020 ◽

pp. gutjnl-2020-321309 ◽

Cited By ~ 1

Author(s):

Hye-Lin Kim ◽

Gi-Ae Kim ◽

Jae-A Park ◽

Hye-Rim Kang ◽

Eui-Kyung Lee ◽

...

Keyword(s):

Chronic Hepatitis ◽

Cost Effectiveness ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Antiviral Treatment ◽

Productivity Loss ◽

Cost Effective ◽

Hbv Dna ◽

It Strategy ◽

Immune Tolerant

ObjectiveThe cost-effectiveness of antiviral treatment in adult immune-tolerant (IT) phase chronic hepatitis B (CHB) patients is uncertain.DesignWe designed a Markov model to compare expected costs and quality-adjusted life-years (QALYs) of starting antiviral treatment at IT-phase (‘treat-IT’) vs delaying the therapy until active hepatitis phase (‘untreat-IT’) in CHB patients over a 20-year horizon. A cohort of 10 000 non-cirrhotic 35-year-old patients in IT-phase CHB (hepatitis B e antigen-positive, mean serum hepatitis B virus (HBV) DNA levels 7.6 log10 IU/mL, and normal alanine aminotransferase levels) was simulated. Input parameters were obtained from previous studies at Asan Medical Center, Korea. The incremental cost-effectiveness ratio (ICER) between the treat-IT and untreat-IT strategies was calculated.ResultsFrom a healthcare system perspective, the treat-IT strategy with entecavir or tenofovir had an ICER of US$16 516/QALY, with an annual hepatocellular carcinoma (HCC) incidence of 0.73% in the untreat-IT group. With the annual HCC risk ≥0.54%, the treat-IT strategy was cost-effective at a willingness-to-pay threshold of US$20 000/QALY. From a societal perspective considering productivity loss by premature death, the treat-IT strategy was extremely cost-effective, and was dominant (ICER <0) if the HCC risk was ≥0.43%, suggesting that the treat-IT strategy incurs less costs than the untreat-IT strategy. The most influential parameters on cost-effectiveness of the treat-IT strategy were those related with HCC risk (HBV DNA levels, platelet counts and age) and drug cost.ConclusionStarting antiviral therapy in IT phase is cost-effective compared with delaying the treatment until the active hepatitis phase in CHB patients, especially with increasing HCC risk, decreasing drug costs and consideration of productivity loss.

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High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B

Gut ◽

10.1136/gutjnl-2017-314904 ◽

2017 ◽

Vol 67 (5) ◽

pp. 945-952 ◽

Cited By ~ 57

Author(s):

Gi-Ae Kim ◽

Young-Suk Lim ◽

Seungbong Han ◽

Jonggi Choi ◽

Ju Hyun Shim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Antiviral Treatment ◽

High Serum ◽

Hbv Dna ◽

Tertiary Referral Hospital ◽

Historical Cohort ◽

Immune Tolerant

ObjectiveHigh serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality.DesignThis historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, <19 IU/mL; males, <30 IU/mL) were compared with those of 1497 immune-active (IA)-phase patients (ALT ≥80 IU/mL) treated with nucleos(t)ide analogues.ResultsThe IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; p<0.001) were significantly higher in the IT group than the IA group. In multivariable analyses, the IT group showed a significantly higher risk of HCC (HR 2.54; 95% CI 1.54 to 4.18) and death/transplantation (HR 3.38; 95% CI 1.85 to 6.16) than the IA group, which was consistently identified through inverse probability treatment weighting, propensity score-matched and competing risks analyses.ConclusionsUntreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.

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A STUDY OF HEPATITIS B VIRUS GENOTYPES IN CHRONIC HEPATITIS B PATIENTS

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2011.3.4 ◽

2011 ◽

pp. 25-29

Author(s):

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Clinical Laboratory ◽

Laboratory Data ◽

Hbv Dna ◽

Hbv Genotypes ◽

B Virus ◽

Virus Genotypes ◽

Genotype C

Aims: To measure the prevalence of HBV genotypes in chronic hepatitis B patients and their relation to HBeAg and HBV DNA level. Methods: 81 patients were enrolled in this study from January 2009 to December 2010. Clinical, laboratory data were collected during the patient’s hospitalization. Sera were quantitatively tested for HBeAg and HBV DNA. HBV genotyping was made by real-time PCR. Results: Among the 81 patients, 60.5% had genotype B, 26.7% had genotype C and 8.6% had mixed genotype B-C. Prevalence of symptoms (fatigue, anorexia, insomnia...) was higher in genotype C than in genotype B. Genotype C patients had positivity higher HBeAg than genotype B patients (56% vs. 38,8%, p <0.05). The rate of HBV DNA > 107 copies/mL was higher in genotype C group than in genotype B group (36% vs. 28,6%, p > 0.05). Conclusions: Most of the patients had genotypes B or C. Patients with genotype C had positive HBeAg and may be related to higher serological HBV DNA level than in genotype B.

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Faculty Opinions recommendation of Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718284182.793535776 ◽

2017 ◽

Author(s):

Cihan Yurdaydin

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Randomised Trial ◽

Dna Vaccination ◽

Hbv Dna

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Predictive Value of Hepatitis B Surface Antigen and Gamma-Glutamyl Transpeptidase for Significant Liver Fibrosis Among Patients with Immune-Tolerant Phase Chronic Hepatitis B

SSRN Electronic Journal ◽

10.2139/ssrn.3351986 ◽

2019 ◽

Author(s):

Yu-Rui Liu ◽

Jie-Min Zhang ◽

Zu-Xiong Huang ◽

Meng-Xin Lin ◽

Na-Ling Kang ◽

...

Keyword(s):

Chronic Hepatitis ◽

Liver Fibrosis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Predictive Value ◽

Hepatitis B Surface Antigen ◽

Gamma Glutamyl Transpeptidase ◽

Immune Tolerant ◽

Glutamyl Transpeptidase ◽

Significant Liver Fibrosis

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Total Antioxidant Capacity in HBV Carriers, a Promising Biomarker for Evaluating Hepatic Fibrosis: A Pilot Study

Antioxidants ◽

10.3390/antiox10010077 ◽

2021 ◽

Vol 10 (1) ◽

pp. 77

Author(s):

Jing-Hua Wang ◽

Sung-Bae Lee ◽

Dong-Soo Lee ◽

Chang-Gue Son

Keyword(s):

Oxidative Stress ◽

Chronic Hepatitis ◽

Liver Fibrosis ◽

Hepatitis B ◽

Antioxidant Capacity ◽

Chronic Hepatitis B ◽

Hepatic Fibrosis ◽

Total Antioxidant Capacity ◽

Hbv Dna ◽

Total Antioxidant

Oxidative stress plays a pivotal role in the progression of chronic hepatitis B; however, it is unclear whether the status of blood oxidative stress and antioxidant components differs depending on the degree of hepatic fibrosis. To explore the relationship between oxidative stress/antioxidant capacity and the extent of hepatic fibrosis, fifty-four subjects with liver fibrosis (5.5 ≤ liver stiffness measurement (LSM) score ≤ 16.0 kPa) by chronic hepatitis B virus (HBV) were analyzed. From the analysis of eight kinds of serum oxidative stress/antioxidant profiles and liver fibrosis degrees, the level of total antioxidant capacity (TAC) reflected a negative correlation with the severity of hepatic fibrosis (Pearson correlation, r = −0.35, p = 0.01). Moreover, TAC showed higher sensitivity (73.91%) than the aspartate transaminase (AST) to platelet ratio index (APRI, 56.52%) in the receiver operating characteristic (ROC) curves. Interestingly, the TAC level finely reflected the fibrosis degree in inactive carriers (HBV DNA < 2000 IU/mL), while the APRI did in active carriers (HBV DNA > 2000 IU/mL). In conclusion, TAC is a promising biomarker for evaluating the progression of liver fibrosis in patients with HBV, and this finding may indicate the involvement of TAC-composing factors in the pathogenesis of hepatic fibrosis in chronic HBV carriers.

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