Lower Serum Hepatitis B Virus DNA Levels Research Articles

Does hepatic steatosis impact chronic hepatitis B?

Does hepatic steatosis impact chronic hepatitis B?

Telbivudine treatment of hepatitis B virus-infected pregnant women at different gestational stages for the prevention of mother-to-child transmission: Outcomes of telbivudine treatment during pregnancy.

This prospective study evaluated the viability of telbivudine for blocking mother-to-child transmission (MTCT) of hepatitis B virus (HBV) infection.Pregnant women positive for the hepatitis B surface antigen began telbivudine treatment before 14 weeks of gestation (i.e., early), between 14 and 28 weeks of gestation (late), or not at all (control). In the late-treatment group, 55 women terminated telbivudine therapy within puerperium. All neonates underwent routine hepatitis B immunoglobulin plus vaccination. Mothers and infants were followed for 7 months after birth.Pregnancy outcomes were similar among the 3 groups. HBV MTCT rates in the early and late treatment and control groups were 0, 0, and 4.69%, respectively. The rates of infant vaccination success among the 3 groups were similar, as were neonatal outcomes including birth weights, asphyxia, hyperbilirubinemia, Apgar score, birth defects, and weight and height at 7 months. Puerperal discontinuation of telbivudine did not increase the alanine transaminase value at 7 months after birth, but increased serum HBV DNA levels, and rates of positive hepatitis Be-antigen.Telbivudine treatment in HBV-infected pregnant women was associated with lower serum HBV DNA levels and reduced rates of HBV MTCT; there were no associated changes in pregnancy or neonatal outcomes at birth or 7 months after birth, or in the rate of infant vaccination success. Puerperal drug withdrawal after short-term antiviral therapy will not influence hepatic function, but may increase virus replication.

The prognosis and management of inactive HBV carriers.

Patients with chronic hepatitis B virus (HBV) infection lacking the serum hepatitis B e antigen (HBeAg) and with antibodies against HBeAg (anti-HBe), are the prevalent subgroup of HBV carriers worldwide. The prognosis of these patients is different from inactive carriers (ICs), who are characterized by persistently normal serum alanine aminotransferase (ALT) and low (<2000 IU/ml) serum HBV DNA levels, a serological profile that may also be intermittently observed in patients with HBeAg-negative chronic hepatitis. This is why a confirmed diagnosis of IC requires quarterly ALT and HBV DNA measurements for at least 1 year, while a single-point detection of combined HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml has a robust predictive value for the diagnosis of IC. Characteristically, ICs have minimal or no histological lesions of the liver corresponding to liver stiffness values on Fibroscan of <5 kPa. Antiviral treatment is not indicated in ICs since the prognosis for the progression of liver disease is favourable if there are no cofactors of liver damage such as alcohol abuse, excess weight or co-infection with the hepatitis C virus or delta virus. Moreover, spontaneous HBsAg loss frequently occurs (1-1.9% per year) in these patients while the development of hepatocellular carcinoma (HCC) is rare, at least in Caucasian patients. However, an emerging issue reinforcing the need for clinical surveillance of ICs is the risk of HBV reactivation in patients who undergo immunosuppressive therapy without receiving appropriate antiviral prophylaxis. After diagnosis, management of ICs includes monitoring of ALT and HBV DNA every 12 months with periodic measurement of serum HBsAg levels to identify viral clearance.

493 CLINICAL SIGNIFICANCE OF PRECORE AND CORE PROMOTER MUTATIONS IN KOREAN CHRONIC HEPATITIS B PATIENTS

Background and Aims: The clinical significance of precore/core promoter mutations of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients is controversial. We aimed to clarify the relationships between precore (G1896A) and core promoter (A1762T, G1764A) variants and serum HBV DNA levels, hepatic inflammation, and liver fibrosis in Korean CHB patients. Methods: A total of 226 treatment-naive CHB patients were studied. Mutations in the precore/core promoter regions were detected by RFMP. Liver biopsies were performed to assess fibrosis in 186 patients, while 40 patients had imaging findings compatible with cirrhosis. Serum alanine aminotransferase (ALT) levels were used as surrogate markers for hepatic inflammation. Results: Ninety patients (39.8%) showed eAg seroconversion. Core promoter and precore mutations were found in 87.2% and 52.2% of patients, respectively. Both types of mutations were more frequent in HBeAg negative patients than in HBeAg positive patients (P < 0.001). HBeAg negative patients were older with more advanced liver fibrosis but had lower serum ALT and HBV DNA levels compared to HBeAg positive patients (all P < 0.001). HBeAg positive patients with core promoter variants did not differ from those without such variants in serum HBV DNA levels, but were older with higher ALT levels and advanced fibrosis (all P < 0.01). HBeAg positive patients with precore variants had lower serum HBV DNA levels than those without mutations (P =0.023). Advanced fibrosis was associated with older age in both HBeAg positive and negative patients (P < 0.05), while core promoter variants were independently associated with disease progression (≥F2) in HBeAg positive patients (P =0.007). ALT levels showed independent correlations with viral load in both groups (P < 0.05). Precore variants showed inverse correlations with HBV DNA levels in HBeAg positive patients (P =0.015). Neither type of variant was correlated with fibrosis, serum ALT and HBV DNA levels in HBeAg negative patients. Conclusion: A1762T/G1764A and G1896A variants are closely associated with HBeAg seroconversion in persistently viremic Korean CHB patients. In HBeAg positive patients, precore variants are associated with enhanced host immune response and are capable of decreasing serum HBV DNA levels, while core promoter variants are associated with liver damage and progression of liver fibrosis.

Replicative Activity of Hepatitis B Virus Is Negatively Associated with Methylation of Covalently Closed Circular DNA in Advanced Hepatitis B Virus Infection

Objectives: The aim of this study was to examine the methylation status of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and to elucidate the possible relationship between the cccDNA methylation and viral replicative activity in patients with HBV-related liver cirrhosis (HBV-LC). Methods: The methylation status of HBV cccDNA was investigated by bisulfite sequencing in nonneoplastic tissues from 12 patients with HBV-LC who underwent surgical resection for combined hepatocellular carcinoma. Clinical, biochemical and virologic factors were evaluated with respect to the degrees of cccDNA methylation. We also examined the effect of methylation of cccDNA on viral transcription by an in vitro transcription assay. Results: Variable degrees of CpG methylation were present in the HBV cccDNA from patients with HBV-LC. Old age, low serum HBV DNA levels and low virion productivity were significantly associated with elevated cccDNA methylation. Virion productivity of cccDNA was also lower in HepAD38 cells with a higher degree of cccDNA methylation. In vitro transcription assays showed that the transcriptional activity of HBV cccDNA was suppressed by increased methylation of cccDNA. Conclusions: Increased CpG methylation of cccDNA is associated with old age, low serum HBV DNA levels and suppressed replicative activity in HBV-LC.

Validity of the rapid strip assay test for detecting HBsAg in patients admitted to hospital in Uganda

Commercially available rapid strip assays (RSAs) for hepatitis B surface antigen (HBsAg) are used for most routine clinical testing in sub-Saharan Africa. This study evaluated the validity of RSA and a more sophisticated enzyme immunoassay (EIA) with confirmation by nucleic acid testing (NAT) in hospitalized patients in Uganda. Sera from 380 consecutive patients collected and tested for HBsAg and anti-HIV in Kampala, Uganda by RSA were sent frozen to Dallas for EIA including HBsAg, total anti-hepatitis B core, hepatitis B e antigen, and anti-HIV. NAT was performed on all HBsAg-positives and on a random sample of 102 patients that were HBsAg-negative by both assays. Overall, 31 (8%) were HBsAg positive by RSA while 50 (13%) were HBsAg-positive by EIA; 26 were concordant between the two assays. Of 55 HBsAg-positive patients, nearly all showed detectable serum hepatitis B virus (HBV) DNA by bDNA (46) or PCR (4) assay. The 26 patients who were HBsAg positive by both EIA and RSA had significantly higher median serum HBV DNA levels than the 24 patients who were HBsAg positive by EIA alone. An additional 12/102 (12%) HBsAg negative patients had very low serum HBV DNA levels by NAT. Several differences in expected results of serologic testing were observed in this large series of African patients. RSA HBsAg testing is less sensitive than EIA; even EIA failed to detect all HBV DNA positive sera. A more complex testing protocol than RSA alone will be needed in Africa to improve patient care.

Predictive Factors for Early HBeAg Seroconversion in Acute Exacerbation of Patients With HBeAg-Positive Chronic Hepatitis B

This study aimed to identify the predictors for early hepatitis B e antigen (HBeAg) seroconversion following acute exacerbation (AE) in patients with HBeAg-positive chronic hepatitis B (CHB). A total of 151 patients with HBeAg-positive CHB and AE were consecutively enrolled. AE was defined as an elevation of alanine aminotransferase level to more than 5 times the upper limit of normal and more than twice the patients' baseline value. Early HBeAg seroconversion was defined as HBeAg loss and the appearance of hepatitis B e antibody within 6 months of AE. Clinical and laboratory data were compared between an early HBeAg seroconversion group and a nonearly HBeAg seroconversion group. All patients had genotype C hepatitis B virus (HBV). Early HBeAg seroconversion occurred in 35.5% (39/110). Under univariate analysis, age, transmission mode, disease status, and serum HBV DNA level were associated with early HBeAg seroconversion. Multivariate analysis showed that nonvertical transmission mode (RR, 3.681; 95% CI, 1.279-10.592; P = .016) and low serum HBV DNA levels (< or = log [copies/mL]; RR, 6.891; 95% CI, 2.165-21.935; P = .001) were independent predictors. Patients with CHB with genotype C may have a higher chance of early HBeAg seroconversion after AE in the context of nonvertical transmission and/or had low serum HBV DNA levels (< or = 7 log [copies/mL]) at AE. Therefore, we should take into account transmission modes and serum HBV DNA levels when choosing appropriate management strategies for patients who exhibit AE of HBeAg-positive CHB with genotype C.

Decline of Serum HBV DNA and No Change Apportioned by the Same Hepatic Parenchyma Cell Volume from Hepatic Fibrosis Stage 1 to Stage 4 during the Natural History of Chronic Hepatitis B

During the initial phase of chronic hepatitis B virus (HBV) infection, serum HBV DNA levels are high. Contrarily, fibrosis, cirrhosis and hepatocellular carcinoma have been found in patients with lower serum HBV DNA levels. The aim of this study is to clarify HBV DNA level dynamics of serum apportioned by the same hepatic parenchyma cell volume (HPCV) in hepatic fibrosis stages 1–4 during the natural history of chronic hepatitis B. Serum HBV DNA levels were evaluated by real-time polymerase chain reaction. Further, serum HBV DNA levels were apportioned by and compared with the same HPCV in hepatic fibrosis stages 1–4, respectively. Serum HBV DNA levels were 8.91 × 10⁶ ± 4.37 × 10¹, 8.13 × 10⁶ ± 7.41 × 10¹, 9.55 × 10⁵ ± 1.02 × 10², and 4.07 × 10⁵ ± 7.24 × 10¹ copies/ml, respectively; there were differences among hepatic fibrosis stages 1–4 (p < 0.021–0.000). However, serum HBV DNA levels apportioned by the same volume of hepatic parenchyma cells in hepatic fibrosis stages 1–4 were 3.47 × 10¹⁰ ± 8.71 × 10², 1.02 × 10¹¹ ± 9.55 × 10², 1.41 × 10¹⁰ ± 2.57 × 10³, and 3.72 × 10¹⁰ ± 3.02 × 10³ with HPCV proportions 65.9, 62.7, 58.9, and 53.3%, respectively; there were no differences among hepatic fibrosis stages 1–4 (p > 0.203–0.967).Following the progression of hepatic fibrosis from stage 1 to 4, ongoing decline of HPCV is responsible for a declining trend of serum HBV DNA levels.

Low serum HBV DNA levels and development of hepatocellular carcinoma in patients with chronic hepatitis B: a case–control study

To investigate the level of hepatitis B virus (HBV) DNA in Chinese chronic hepatitis B (CHB) patients below which hepatocellular carcinoma (HCC) is unlikely to occur. A total of 92 CHB patients diagnosed with HCC were recruited; 184 CHB patients without HCC, matched for age, sex and HBeAg status were included as controls. HBV DNA levels were performed at the time of HCC development and at the same age time points for control group. The median HBV DNA level in HCC patients was 1.7 x 10(6) copies/mL compared with 2.2 x 10(5) copies/mL in controls (P = 0.006). In HCC patients, 21 (22.8%) were HBeAg(+), with no significant difference in HBV DNA levels compared with controls. Seventy-one (77%) HCC patients were HBeAg(-) with median HBV DNA level of 3.2 x 10(5) copies/mL, compared with 6.0 x 10(4) copies/mL in controls (P = 0.006). In HBeAg(-) patients, the control group had significantly greater proportion of patients having HBV DNA levels <10(5) and <10(4) copies/mL compared with HCC patients. Fifteen per cent of all HCC patients had HBV DNA levels <10(3) copies/mL. In HBeAg(+) patients, HBV DNA levels were high in both HCC and control patients. In HBeAg(-) patients, HCC was more likely to develop in patients with HBV DNA level >10(4) copies/mL. However, 15% of the patients with HCC had HBV DNA levels <10(3) copies/mL.

Chronic Hepatitis B: A Critical Appraisal of Current Approaches to Therapy

Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. With the exception of 2 statements, the experts' responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree.

Low HBeAg Serum Levels Correlate with the Presence of the Double A1762T/G1764A Core Promoter Mutation and a Positive Response to Interferon in Patients with Chronic Hepatitis B Virus Infection

Objective: To investigate the correlation of serum hepatitis B e antigen (HBeAg) levels with the presence of core promoter (CP) mutations, hepatitis B virus (HBV) viremia and the response to interferon (IFN) in patients with chronic hepatitis B. Methods: Fourteen HBeAg-positive patients received α-2a IFN. Diluted serum samples of responders were tested for HBeAg positivity at dilutions of 1:40, 1:160 and 1:640 at the following time points: T0 (before starting IFN), T1 [at peak alanine aminotransferase (ALT) preceding HBeAg seroconversion], T2 (at ALT normalisation) and T3 (end of treatment). Nonresponder samples were similarly tested at times T0 and T3. The HBV CP and precore regions were sequenced at the same time points as for HBeAg testing. Results: Six of 14 patients (43%) responded to IFN treatment and had lower HBeAg levels than nonresponders at T0 (p = 0.003). Five of 6 responders (83%) and none of the nonresponders had the A1762T/G1764A CP mutations (0/8, p < 0.003). At T0, HBeAg was negative at the 1:640 dilution in 5 of the 6 responders, who also had lower HBV DNA levels than nonresponders (p = 0.003). During IFN treatment, HBeAg levels decreased and HBV DNA became negative at T1 in responders. Conclusions: Low serum HBeAg and HBV DNA levels correlate with the presence of CP mutations and response to IFN treatment and can be considered as predictive markers of response to IFN.