Chinese Experience on theLamivudine in Treatment of Chronic Hepatitis B Infection

Lamivudine, the β-L-enatimer of 2^ , 3^ -thiacytidine, is a potent inhibitor of HBV polymerase, which block HBV DNA synthesis in hepatocytes. Thousands of chronic hepatitis B patients throughout the world have been treated with lamivudine with favorable result. This reportsummerized the efficacy of lamivudine in treatment of chronic hepatitis B virus infection in mainland China. This multicenter, double-blind, randomized,     

Improved Efficacy of a Pegylated Interferon-α-2a Stepwise Optimization Treatment Strategy in the Treatment of Hepatitis B e Antigen-positive Chronic Hepatitis B Patients

Current pegylated interferon-α (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg-positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN–based treatment to 96 weeks on the patients’ 12-week or 24-week early virological response (12W EVR, at least a 2 log₁₀ reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log₁₀ reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 ≤HBeAg ≤10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG-IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT × ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients.     

Evaluation of α-Glutathione-S-Transferase as a Biomarker of Lamivudine Therapy for Chronic Hepatitis B

Hepatic damage associated with chronic hepatitis B (CHB) relies on measurement of serum transaminases and asssessment of hepatic histology. We determined if serum hepatic function tests, including α-glutathione-S-transferase ((GST), were of value in monitoring or predicting the effect of lamivudine therapy for CHB. Thirty-nine patients received orally 100 mg of lamivudine daily for 48 weeks. Blood samples were obtained at baseline and at 24 and 48 weeks. At the end of the treatment period the patients were then divided into four groups according to the pattern of HBs and HBe antigens. At baseline and at 24 weeks ALT, AST, and (GST had lower values in the complete response compared to the complete failure groups. Using ROC analysis, only ALT at 24 weeks (area under the curve = 0.803) had significant diagnostic ability in detecting responders. These results reaffirm the value of measuring serum ALT as an indicator of treatment response and provide information on the potential use of (GST as an additional prognostic biomarker in this patient group.     

Are physicians following guidelines? A survey of Hepatitis B management strategies

Purpose

Practice guidelines for chronic hepatitis B (CHB) assist physicians in management; however, there are also areas where they provide no guidance. This paper aimed to examine treatment preferences for CHB among physicians based upon the Asia Pacific Association for the Study of the Liver (APASL) consensus guidelines 2008.

Methods

A questionnaire was prepared consisting of 18 questions grouped into 8 sections: basic information of participants, the proportion and number of CHB patients on treatment, case scenarios of treatment initiation, preferences for antiviral therapy, scenarios for stopping and continuing antiviral therapy, monitoring patients during therapy, and viral resistance management. The questionnaire was introduced to the APASL 2009 conference delegates.

Results

A total of 508 participants from 34 countries participated in the survey. Lamivudine or peg-interferon monotherapy was the preferred first-line therapy, while lamivudine/adefovir combination was the drug of choice for rescue therapy. Drug efficacy and cost were the most important factors to consider before initiating treatment, while viral resistance had a low priority. In general, the APASL guideline was strictly followed in about 50–60 % of the scenarios (initiating, stopping, or continuing antiviral therapy).

Conclusions

The survey concluded that clinical management preferences differed from APASL guidelines in many instances.     

Association of Interleukin-18 Gene Polymorphisms with Hepatitis B Virus Clearance

The outcome of hepatitis B virus (HBV) infection can be affected by host immune factors. Interleukin-18 (IL-18) was originally discovered as an interferon-γ-inducing factor and plays a critical role in immune response. We assessed the association between the clearance of HBV infection and single-nucleotide polymorphisms (SNPs) in the IL-18 gene. Between March 2002 and December 2004, a total of 1,050 Korean subjects were enrolled in the study and divided into two groups: (1) the HBV spontaneous recovery group (n = 320) and (2) the chronic HBV carrier group (n = 730). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions ?667G>T, ?148G>C, +8925C>G, and +13925A>C. We observed that the subjects bearing the IL-18 ?148C allele [odds ratio (OR), 0.25; confidence interval (CI), 0.09–0.68; P = 0.01], the +8925G allele (OR, 0.36; CI, 0.15–0.88; P = 0.02), and the +13925C allele (OR, 0.25; CI, 0.13–0.82; P = 0.01) were significantly associated with HBV clearance in a recessive model. This study indicates that the ?148C, +8925G, and +13925C alleles of the IL-18 gene are likely associated with HBV clearance in a Korean population.     

High Risk of Hepatitis B Virus Reactivation in Nucleos(t)ide Analogue-Induced Hepatitis B e Antigen Seroconverters Older Than 40 Years

Background

A recent study showed that chronic hepatitis B virus (HBV) carriers with nucleos(t)ide analogue (NA)-induced hepatitis B antigen (HBeAg) seroconversion occurring before the age of 30 years have a higher risk of HBV reactivation.

Aim

To compare the risk of HBV reactivation and HBeAg seroreversion between patients with spontaneous and NA-induced HBeAg seroconversion.

Methods

A total of 135 and 251 non-cirrhotic patients with NA-induced and spontaneous HBeAg seroconversion, respectively, were analyzed.

Results

NA-induced HBeAg seroconverters faced higher risks of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconverters (P < 0.001). In spontaneous HBeAg seroconverters, age at HBeAg seroconversion, sex, HBV DNA levels before HBeAg seroconversion, HBV genotype C, and pre-S deletions were independent predictors of HBV reactivation. In NA-induced HBeAg seroconverters, only age at baseline was an independent predictor of HBV reactivation. To determine whether the difference in the incidence of HBV reactivation or HBeAg seroreversion between two groups was age-specific, we analyzed these patients according to their age at HBeAg seroconversion (20–29, 30–39, and ≥40 years). Our data showed that NA-induced HBeAg seroconversion was an independent predictor of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconversion in patients older than 40 years at HBeAg seroconversion, but not in patients between 20–29 and 30–39 years of age.

Conclusions

NA-induced HBeAg seroconverters are associated with higher risks of HBV reactivation and HBeAg seroreversion compared to spontaneous HBeAg seroconverters, especially in patients who are older than 40 years at HBeAg seroconversion.     

Efficacies of β-L-D4A against Hepatitis B virus in 2.2.15 cells

AIM： To investigate the antiviral effect of beta-L- enantiomer of 2;3＇-didehydro-2＇,3″-dideoxyadenosine （13-L-D4A） on 2.2.15 cells transfected with the hepatitis B virus （HBV） genome.
METHODS： Lamivudine （3TC） as a positive control. Then, HBV DNA in treated 2.2.15 cells and the Hepatitis B surface antigen （HBsAg） in the culture supernatants were detected to determine the inhibitory effect of β-L- D4A. At the same time, 3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide （MTT） was used to detect the survival ratio of 2.2.15 cells.
RESULTS： β-L-D4A has a dose-dependent inhibitory effect on HBV DNA replication; this effect was apparent when the concentration was above 1 mol/L. When β-L- D4A was at the highest concentration, 100 mol/L, the HBsAg inhibition ratio was above 50%. The Therapeutic index （TI） of β-L-D4A was above 2.1.
CONCLUSION： β-L-D4A has a dose-dependent inhibitory effect on the replication of HBV DNA and the secretion of HBsAg at low toxicity,     

Hepatitis B: Who to treat? A critical review of international guidelines

Chronic hepatitis B remains a global problem, affecting more than 250 million individuals worldwide. Around one‐fifth of infected individuals develop advanced fibrosis or hepatocellular carcinoma (HCC). The World Health Organization (WHO) guidelines as well as the 2016 American Association for the Study of Liver Diseases (AASLD) guidelines are based on robust data and relied on multiple external systematic reviews to answer identified questions. In contrast, the latest guidelines from the European Association for the Study of the Liver (EASL), Asia Pacific Association for the Study of the Liver (APASL) and AASLD (2018 version) were developed by consensus of expert panels. Treatment is generally recommended for individuals at a high risk of disease progression, namely those with high alanine aminotransferase (ALT) levels, active viral replication and advanced fibrosis or cirrhosis. Although guidelines generally agree on treatment indications for special populations, current guidelines do not factor in clinically relevant factors such as age, gender and genotype into the treatment decision process. There is an unmet need for a better predictive model to select high‐risk individuals, thus, more high‐quality studies are needed.     

Clinical Analysis of Polyethylene Glycol Interferon-α Treatment in 155 Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B (CHB) Patients

PurposeThis study aims to investigate the antiviral effect of polyethylene glycol (PEG)-interferon α-2a and PEG-interferon α-2b treatment on hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) at the 48th week of treatment and the 24th and 48th week after withdrawal, in order to provide guidance on the antiviral treatment of HBeAg-positive CHB patients.Material and methodsAntiviral treatment was performed on 155 HBeAg-positive CHB patients. Among these patients, 66 patients received PEG-interferon α-2a treatment and 89 patients received PEG-interferon α-2b treatment; and these treatments were administered by subcutaneous injection, once per week, which lasted for 48 weeks. Other antiviral and hepatoprotective drugs were not used during the treatment.ResultsAt the 48th week of treatment, ALT recovery rate, HBsAg seroconversion rate, HBeAg seroconversion rate and HBV DNA titers dropped below 200 IU/mL rate were 69.7%, 6.1%, 27.3% and 50.0%, respectively, in the PEG-interferon α-2a group; and were 70.8%, 6.7%, 33.7% and 62.9%, respectively, in the PEG-interferon α-2b group. At the 24th and 48th week of follow-up after withdrawal, HBsAg seroconversion rate in these two groups did not change; and HBeAg seroconversion rate further increased. Furthermore, HBV DNA revealed a low recurrence rate. The difference between these two groups was not significantly significant.ConclusionsPEG-interferon α-2a and PEG-interferon α-2b are effective antiviral drugs for the treatment of HBeAg-positive CHB, which has a HBsAg seroconversion rate of more than 5%. Furthermore, this sustained response effect was maintained at the 24th and 48th week of follow-up after withdrawal.     

The Expression of Hypoxia-Inducible Factor-1α in Hepatitis B Virus-Related Hepatocellular Carcinoma: Correlation with Patients’ Prognosis and Hepatitis B Virus X Protein

Hypoxia inducible factor-1α (HIF-1α) was well correlated with carcinogenesis and tumor progression in many kinds of cancer. In this study, high expression of HIF-1α was found in 37 of the 72 (51.39%) tumor specimens, and significantly correlated with venous invasion and lymphonode invasion. Patients with high expression of HIF-1α had a significantly shorter overall survival rate and disease-free survival rate than those with low expression. Multivariate analysis showed high HIF-1α expression was a borderline independent factor of overall survival. HIF-1α expression was also found to be significantly correlated with the expression of hepatitis B virus X protein (HBx), and over-expressed HBx upregulated HIF-1α protein expression in vitro. These results suggested that HIF-1α, which was partially regulated by HBx, might be a prognostic marker of HBV-related HCC patients. Dr. Huahong Xie, Dr. Jiugang Song, and Dr. Kaige Liu contributed equally to this study.     

Tolerance and Antiviral Effects of High-Dose Interferon-α B/D in Patients with Chronic Hepatitis B

A novel recombinant interferon- B/Dhybrid was applied to assess tolerability, antiviraleffect, and biological activity in chronic hepatitis B.The study was designed as an open nonrandomized trial. Treatment comprised a two-week run-in phasewith 16 MU three times a week followed by 14 weeks with64 MU three times a week (or 48 MU if toxicity occurredwith 64 MU). Total follow-up was 36 weeks. Nineteen patients were included; three discontinuedtreatment during the run-in with 16 MU. Fourteen of 16patients had 14 weeks of treatment with 32 MU threetimes a week. Fourteen dose reductions were necessary in nine patients. The adverse experienceprofile was similar to other interferon-s.HBV-DNA decreased using all doses studied. HBV-DNAbecame undetectable in five patients, two of whom hadHBeAg seroconversion. No HBsAg seroconversion was observed. It isconcluded that interferon- B/D is well toleratedin high doses. The anti-viral effect starts at at least16 MU three times a week.