Reduction Of HBV DNA Research Articles

Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.

Isoquinolinone-based HBV capsid assembly modulators that bind at the dimer:dimer interface of HBV core protein have been shown to suppress viral replication in chronic hepatitis B patients. Analysis of their binding mode by protein X-ray crystallography has identified a region of the small molecule where the application of a constraint can lock the preferred binding conformation and has allowed for further optimization of this class of compounds. Key analogues demonstrated single digit nM EC50 values in reducing HBV DNA in a HepDE19 cellular assay in addition to favorable ADME and pharmacokinetic properties, leading to a high degree of oral efficacy in a relevant in vivo hydrodynamic injection mouse model of HBV infection, with 12e effecting a 3 log10 decline in serum HBV DNA levels at a once daily dose of 1 mg/kg. Additionally, maintenance of activity was observed in clinically relevant HBV core protein variants T33N and I105T.

The Use of Tenofovir Disoproxil Fumarate in the Management of eAg-Negative Chronic Hepatitis B Infection.

Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis.

Comparison of the efficacy and safety of TAF, TDF, and LdT to prevent the transmission of hepatitis B in pregnant women: A retrospective study.

To compare the efficacy and safety of telbivudine (LdT), tenofovir alafenamide fumarate (TAF), and tenofovir disoproxil fumarate (TDF) for preventing hepatitis B transmission in immune-tolerant pregnant women with HBV infection. We conducted a retrospective cohort study involving women who had hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 2 × 105 IU/mLand initiated LdT, TDF, or TAF to prevent mother-to-child transmission (MTCT). The primary endpoint was the safety of mothers and infants. The secondary endpoints were maternal HBV DNAreduction at delivery and MTCT rate. A total of 96 patients were enrolled in the study (LdT group, n = 36; TDF group, n = 35; TAF group, n = 25). All infants received hepatitis B virus immunoprophylaxis. The MTCT rate was 0%([0 of 25] vs. [0 of 35] vs. [0 of 36], p > .05). No severe liver function damage occurred in any of the mothers. Babies delivered in all groups had prenatal ultrasound screening abnormalities, but abnormality rates were not statistically significant between groups. The application of TDF, TAF, or LdT to immune-tolerant HBV-infected pregnant women in middle-late pregnancycan successfully interrupt MTCT of the HBV virus. However, for all three groups of pregnant women who delivered babies with abnormal prenatal ultrasound screening, an expanded sample size may be needed for further observation.

Short-Term Efficacy of Tenofovir Alafenamide in Acute-On-Chronic Liver Failure: A Single Center Experience.

Patients with acute-on-chronic liver failure (ACLF) who take entecavir (ETV) and tenofovir disoproxil fumarate (TDF) experience a reduction in hepatic events and mortality. The effectiveness of tenofovir alafenamide (TAF) was not well investigated. This study was aim to compare the antiviral efficacy and mortality between TAF and ETV in patients with ACLF caused by the hepatitis B virus (HBV). One hundred and six patients with HBV-ACLF who received TAF (25 mg/day) and ETV (0.5 mg/day) for 12 weeks were analyzed. The primary endpoints were overall mortality and liver transplantation (LT) at week 12. Biochemical responses, virologic responses, mortality, drug safety, and side effects were evaluated. At 4 and 12 weeks of TAF treatment, patients showed significantly higher HBV-DNA reduction (P < .001), higher HBV-DNA undetectability rates (P < .001), and lower HBV DNA levels (P < .001) in serum. Lower Child-Turcotte-Pugh (CTP) scores (P = .003) were observed at 4 weeks in the TAF group, although the CTP scores showed no difference between TAF group and ETV group at 12 weeks (P = 1.143). Lower alanine aminotransferase (ALT) levels of patients in the TAF group at week 4 and 12 were observed (P = .023 and P < .0001, separately). The mortality of TAF group was lower after 4 weeks of treatment (P = .038); however, the 2 groups had similar mortality rates at week 8 and 12. Among the causes of death in HBV-ACLF patients, we found the same incidence of liver-related problems in both groups (P > .05). This study showed that ACLF patients with chronic HBV infection treated with TAF had a rapid decline in HBV DNA, a higher rate of ALT reduction and improved CTP scores compared to the ETV group, thereby improving patient survival.

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients.

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (-) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.

Anti-hepatitis B virus activity of lithospermic acid, a polyphenol from Salvia miltiorrhiza, in vitro and in vivo by autophagy regulation

Ethnopharmacological relevanceSalvia miltiorrhiza (the roots of S. miltiorrhiza Bunge, Danshen in Chinese), a traditional Chinese medicine, has been clinically used to prevent and treat various diseases, such as cardiovascular and cerebrovascular diseases, diabetes, and hepatitis B, in China and some other Asian countries. Lithospermic acid (LA), a polyphenol derived from S. miltiorrhiza, has been reported to exhibit multiple pharmacological properties, such as anti-inflammatory, anti-HIV, and anti-carbon tetrachloride-induced liver injury activities. However, little is known about the anti-hepatitis B virus (HBV) activity of LA. Aim of the studyThe study was projected to investigate the anti-HBV activity of LA in vitro (HepG2.2.15 and pHBV1.3-transfected HepG2 cells) and in vivo (pAAV-HBV1.2 hydrodynamic injection [HBV-HDI] mice) and explore the potential mechanism as well. Materials and methodsHepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) contents were detected by ELISA kits. HBV DNA and hepatitis B core antigen (HBcAg) levels were evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry assay, respectively. The proteins in autophagy process, lysosomal acidic function, and autophagy-related signaling pathways were examined by Western blot. Transmission electron microscopy was used to observe the number of autophagosomes and autolysosomes. Confocal microscopy was applied to analyze the autophagic flux and lysosomal acidification, using mCherry-enhanced green fluorescent protein (EGFP)-microtubule-associated protein light chain (LC)3 and lysosomal probes, respectively. ResultsLA exhibited anti-HBV activity by inhibiting HBV DNA replication in HepG2.2.15 and pHBV-transfected HepG2 cells in dose- and time-dependent manners and hampering HBsAg and HBeAg levels in HepG2.2.15 cells to a certain extent. LA reduced HBV DNA, HBsAg/HBeAg, and HBcAg levels in the serum/liver tissues of HBV-HDI C57BL/6 mice during the 3-week treatment and suppressed the withdrawal rebound of HBV DNA and HBsAg in the mice serum. LA increased LC3-II protein expression and the number of autolysosomes/autophagosomes and promoted the degradation of sequestosome 1(p62) protein in vitro and in vivo. LA enhanced the co-localization of LC3 protein with autolysosomes, further confirming the ability of LA to induce a complete autophagy. Knockdown of autophagy-related gene (Atg) 7 or 5 in vitro and administration of 3-methyladenine (an autophagic inhibitor) in vivo disabled the inhibitory efficacy of LA on HBV DNA replication, suggesting that the anti-HBV efficacy of LA depended on its ability of inducing autophagy. LA could enhance lysosomal acidification and improve the function of lysosomes by promoting the protein expression of lysosomal-associated membrane protein (LAMP)-1, LAMP-2, and mature cathepsin D, which may contribute to the autophagic induction of LA. LA inhibited the activation of AKT and mammalian target of rapamycin (mTOR) induced by HBV, which was reversed by IGF-1 (an agonist of the PI3K/AKT/mTOR signaling pathway), indicating that LA elicited autophagy through hampering the PI3K/AKT/mTOR signaling pathway. ConclusionWe revealed the anti-HBV activity and mechanism of LA in vitro and in vivo. This study facilitates a new understanding of the anti-HBV potent components of S. miltiorrhiza and sheds light on LA for further development as an active constituent or candidate used in the therapy against HBV infection.

From the Editor’s Desk…

From the Editor’s Desk…

Risk of hepatocellular carcinoma in antiviral treatment-na\xefve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis

BackgroundLong-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction.MethodsThe PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis.ResultsA total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis.ConclusionETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

The Safety and Efficacy of a Therapeutic Vaccine for Chronic Hepatitis B: A Follow-Up Study of Phase III Clinical Trial.

The objective of the present study was to assess the safety and efficacy of a therapeutic vaccine containing both HBsAg and HBcAg (NASVAC) in patients with chronic hepatitis B (CHB) three years after the end of treatment (EOT) as a follow-up of a phase III clinical trial. NASVAC was administered ten times by the nasal route and five times by subcutaneous injection. A total of 59 patients with CHB were enrolled. Adverse events were not seen in any of the patients. Out of the 59 CHB patients, 54 patients exhibited a reduction in HBV DNA, compared with their basal levels. Although all the patients had alanine transaminase (ALT) above the upper limit of normal (>42 IU/L) before the commencement of therapy, the levels of ALT were within the ULN level in 42 patients. No patient developed cirrhosis of the liver. The present study, showing the safety and efficacy of NASVAC 3 years after the EOT, is the first to report follow-up data of an immune therapeutic agent against CHB. NASVAC represents a unique drug against CHB that is safe, of finite duration, can be administered by the nasal route, is capable of reducing HBV DNA and normalizing ALT, and contains hepatic fibrosis.

Programmed death 1 expressing CD8+ CXCR5+ follicular T cells constitute effector rather than exhaustive phenotype in patients with chronic hepatitis B.

Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B (CHB) infection. Recently, a subset of CD8 T cells expressing C-X-C chemokine receptor type 5 (CXCR5) and exhibiting features of TFH cells has been identified during chronic viral infections. However, in CHB, knowledge of their roles is limited. We characterized circulating CD8+ CXCR5+/- cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8+ CXCR5+ cells whereas CD8+ CXCR5- cells were increased. However, among CHB, CD8+ CXCR5+ cells were higher in patients with low HBsAg and HBV-DNA levels, patients who were HBeAg negative and had high fibrosis scores, and these cells exhibited a significant association with HBsAg and HBV-DNA reduction. Contrarily, CD8+ CXCR5- cells were expanded and positively correlated with patients having high HBsAg, HBV-DNA, and alanine aminotransferase levels. CD8+ CXCR5+ cells express costimulatory molecules ICOS, OX40, CD40 ligand, inhibitory molecule programmed death 1, transcription factors B-cell lymphoma (BCL)-2, BCL-6, and signal transducer and activator of transcription 3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature given that they constitute different subsets of cytotoxic follicular T cells (TCF), including TCF1, TCF2, TCF17, and TCF22. Despite expressing high PD-1, CD8+ CXCR5+ cells are activated, proliferating, secreting more IFN-γ, IL-21, and IL-22, and have better cytolytic potential than CD8+ CXCR5- cells, which were inhibited after PD-1/PD-L1 blockade. CD8+ CXCR5+ cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. In conclusion, CD8+ CXCR5+ cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1, and are associated with HBsAg and HBV-DNA reduction. These cells competently support B-cell function, required for viral clearance, which may serve as potential therapeutic targets for CHB.

Kinetics of hepatitis B surface antigen in pregnant women with and without tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother-to-infant transmission in highly viremic HBV-infected women. Data on hepatitis B surface antigen (HBsAg) levels in pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV-infected mothers with HBV DNA ≥7.5log10 IU/ml were tested for HBsAg and HBV DNA from baseline to 6months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32±0.47 vs. 4.54±0.35log10 IU/ml, p=.0004) and markedly lower HBV DNA (4.26±0.97 vs. 8.11±0.70log10 IU/ml, p<.0001) than the control group. In the TDF group, mean reduction of HBsAg and HBV DNA from baseline to delivery were 0.22±0.38 and 3.96±0.93log10 IU/ml. HBsAg reduction had a positive correlation (r=.309; p=.0017) with HBV DNA reduction, and was predictive of HBV DNA reduction ≥3log10 IU/ml (area under the receiver operating characteristic curve, 0.67; 95% confidence interval, 0.50-0.82). At 6months postpartum, TDF and control group had comparable HBsAg and HBV DNA. In conclusion, HBsAg decreased slightly at delivery in pregnant women receiving TDF. For monitoring the effect of antiviral therapy during pregnancy, HBV DNA is a better marker than HBsAg. Our data provided valuable information regarding monitoring HBV-infected pregnant women using antiviral therapy.

The NTCP p.Ser267Phe Variant Is Associated With a Faster Anti-HBV Effect on First-Line Nucleos(t)ide Analog Treatment.

Sodium taurocholate cotransporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus infection of host hepatocytes. Previously, many studies confirmed that the NTCP p.Ser267Phe variant was a protective factor against HBV-related disease progression. We therefore designed this study to investigate whether the NTCP p.Ser267Phe variant exerts an additive anti-HBV effect in chronic hepatitis B (CHB) patients on mainstream NAs treatment. After propensity score matching (PSM), a total of 136 CHB patients were included, among whom 68 were heterozygous carriers and 68 were wild-type controls. Proportions of primary nonresponse, partial virological response, virological breakthrough and hepatitis B reactivation and the HBV DNA clearance rate at each time point were compared using the chi-square test. Kaplan-Meier analysis and matched t-tests were also performed to estimate the speed of viral clearance and serum HBV DNA reduction, respectively. The proportion of primary nonresponse was significantly lower in heterozygous carriers than in wild-type controls (p < 0.001), especially in patients using entecavir (p = 0.013). Specifically, heterozygous carriers achieved HBV DNA clearance faster than wild-type controls (log-rank p = 0.0198). HBV DNA levels were reduced more in heterozygous carriers after 12 weeks (p < 0.001) and 24 weeks (p = 0.006) of treatment, especially among patients using ETV. Here, our study demonstrated that heterozygous mutations in rs2296651 enhanced the antiviral response of first-line NAs and helped to explore the possibility of combining NAs and NTCP blockers for a better anti-HBV effect.

Observational study on the response of tenofovir monotherapy versus tenofovir plus telbivudine dual therapy in patients with hepatitis B virus related acute on chronic liver failure.

Introduction:HBV is major health problem globally due to complications, including ACLF, cirrhosis and hepa¬tocellular carcinoma. ACLF due to exacerbation of CHB is associate with 30%-70% mortality. Reduction of HBV-DNA is therefore a target of therapy in ACLF-B.Methods:Patients with spontaneous reactivation of HBV [(ALT >5×ULN or >2× baseline) and HBV-DNA >20,000 IU/ml] were randomized to Tenofovir mono therapy (300 mg/day) or Tenofovir plus Telbivudine (600 mg/day) dual therapy with standard care. Clinical and biochemical parameters were evaluated at baseline, 1 week, 4 weeks and at 3 months. Virological evaluation was done at baseline and at 3 months. Primary end points were reduction of HBV-DNA and resolution of ascites, as applied. Secondary end point was reduction of liver related complications, therapy related adverse effects and survival at 3 months.Results:27 patients were enrolled. 15 received mono therapy with Tenofovir and 12 received dual therapy (Tenofovir plus Telbivudine). Baseline parameters in 2 groups had no significant difference. In both groups there was significant improvement of S. bilirubin, ALT, INR, CTP score and MELD score. Only MELD score showed significant improvement in patient with dual therapy at 3 months in comparison to mono therapy. 11 patients on Tenofovir mono therapy (n=15) showed undetected HBV-DNA (91.7%) at 3 months and one patient had detectable HBV-DNA (<2,000 IU/ml). 10 patients on dual therapy (n=12) had undetectable HBV-DNA (100%). Ascites resolved in 3 patients in both groups. Patients receiving dual therapy showed significant improvement in AKI on follow up compared to those on Tenofovir mono therapy. Among 5 deaths, 3 received mono therapy with Tenofovir and 2 dual therapy. Predictors of mortality had high S. bilirubin, HBV-DNA, MELD score and CTP score.Conclusion:In spontaneous reactivation of HBV presenting as ACLF, combination of Telbivudine plus Tenofovir is safer with less nephrotoxicity and better outcomes.

Role of tenofovir and telbivudine in treatment of hepatitis B related acute on chronic liver failure.

Introduction:ACLF is characterized by acute deterioration of liver function in patients with chronic liver disease. HBV is one of the most important causes of both acute insult and underlying chronic liver disease in ACLF. Reactivation of HBV is one of the common causes of ACLF in our region. ACLF requires multiple organ support and is associated with high short and medium term mortality. This is the reason why early, rapid reduction of HBV DNA is essential in treating ACLF-B.Methods:Consecutive patients of ACLF-B due to spontaneous reactivation of HBV (ALT> 5xULN or >2 x baseline and HBV DNA >20,000 IU/ml) were randomized into tenofovir group (300mg/day) and telbivudine group (600mg/day) along with standard medical treatment. Clinical and laboratory parameters were evaluated at baseline, day-7, day-14, day-30 and day-90. HBV DNA was evaluated at baseline and after three months of therapy. Primary end point was survival or death at three months. Secondary end point was improvement of liver function assessed by Child-Turcotte Pugh score and MELD score at three months.Results:30 patients were enrolled in the study and 15 of them received tenofovir and 15 patients received telbivudine. Most of the baseline parameters showed no difference except serum AST and serum creatinine level that showed statistically significant difference between two groups. After antiviral therapy both groups showed significant clinical improvement along with CTP and MELD scores. However statistically significant improvement between tenofovir and telbivudine groups was only seen with MELD score. Survival rate was 80% in tenofovir group and 60% in telbivudine group, but this was not statistically significant. Low serum albumin at baseline was predictor of mortality.Conclusion:In patients of ACLF-B, antiviral therapy with both tenofovir and telbivudine improve liver function, but there is no statistically significant difference in survival between tenofovir and telbivudine.

Comparison of HBV DNA Quantitative Log in Patients Hepatitis B with Telbivudine Therapy Compared with Tenofovir Therapy in Saiful Anwar General Hospital Malang: January 2016 - December 2017

Background: Hepatitis B is a health problem with high endemic in Indonesia. Hepatitis B virus infection is transmitted parenterally, has a risk of liver cirrhosis and hepatocellular carcinoma. Detection and quantification of HBV DNA are markers of active HBV replication and determine treatment options for hepatitis B. Methods: compare log reduction of HBV DNA in patients treated with Telbivudine and Tenofovir. Results: There was no significant difference in HBV DNA levels between before and after Tenofovir treatment, namely 6 months follow-up (OR 95% CI = 5.41 [0.83 - 35.16], p = 0.0770) and 12 months (OR 95% CI = 5.39 [0.83 - 34.99], p = 0.0780). Telbivudine administration showed a significant difference in HBV DNA levels between before and after treatment at 6 months follow-up (OR 95% CI = 13.69 [4.53 - 41.40], p = 0.0001) and 12 months (OR 95% CI = 13.69 [ 4.53 - 41.41], p = 0.0001). Comparison of Tenofovir and Telbivudine therapy showed no significant difference at 6 months follow-up (OR 95% CI = 0.44 [0.10 - 1.88], p = 0.2690) but significant at 12 months follow-up (OR 95% CI = 6.23). [1.39 - 27.97], p = 0.0170). Conclusion: Â There was a significant difference between the administration of Telbivudine as a treatment for hepatitis B with lower serum HBV DNA levels compared with the administration of Tenofovir at 12-month follow-up therapy.

Mechanisms of wolfberry in the treatment of liver diseases

<p indent=0mm>The fruit of <italic>Lycium barbarum</italic> (the wolfberry or goji berry) has been widely used as a drug and functional food in many traditional Chinese medicine literature. However, only in recent years has its specific health-promoting mechanism been investigated. Modern technology of pharmacology has identified a variety of bioactive ingredients from the Goji berry, such as polysaccharide, pigments, and lycibarbarspermidines, with properties of anti-inflammation, antioxidant, anti-apoptosis, anti-fibrosis, and anti-tumor. Acute and chronic liver diseases represent a major world public health problem. The clinical curative rate for some liver diseases, such as chronic hepatitis B, cirrhosis, and liver cancer remains unsatisfactorily low. In the current review, we summarized the updated mechanisms of bioactive ingredients derived from the Goji berry in liver diseases, which may pave the way for their future clinical application. The hepatoprotective properties of <italic>Lycium barbarum</italic> polysaccharide (LBP) have been characterized in several liver disease models, including acute liver injury, liver failure, non-alcoholic liver disease, alcoholic liver disease, liver fibrosis, and liver cancer. However, delineating the active ingredient(s) from LBP in different types of liver diseases is a challenge. Wolfberry also contains the highest concentration of the antioxidant xanthophyll carotenoid zeaxanthin dipalmitate (ZD). ZD is a zeaxanthin diester formed from zeaxanthin (ZE) and palmitic acid. Inducing non-alcoholic in the transgenic HBV mice model reactivated HBV replication, while ZD administration reduced HBV DNA replication and serum HBsAg levels. The immediate hepatocyte membrane receptors of ZD during alcoholic liver injury have also be identified. Treating human adipose-derived mesenchymal stem cells (hADMSC) with ZD before transplantation increased stem cell survival and improved the therapeutic outcome in acute liver disease/failure models. Betaine is a natural amino acid and one of the major constituents of <italic>Lycium barbarum</italic>. It is shown to play antioxidant and anti-inflammatory roles in toxin-induced liver injury and fatty liver disease model. Recently, we identified fifteen new dicaffeoylspermidine derivatives, lycibarbarspermidines A-O, from wolfberry. The oxygen radical absorbance capacity assay revealed that A-O all displayed antioxidant capacity and are related to the effects of wolfberry. Our pilot study results also revealed their potential hepatoprotective properties in alcoholic and non-alcoholic liver diseases. Of note, all published papers reported no side effects from LBP, ZD, betaine, or lycibarbarspermidines. Nonetheless, since the investigation of the properties of herbal active compounds is on the rise and with wolfberry’s increasing popularity and commercialization as a food supplement, those major ingredients will likely get more attention from the scientific community, and its effect on liver disease might be studied further.

Establishment of a system for finding inhibitors of ε RNA binding with the HBV polymerase.

Although several nucleo(s)tide analogs are available for treatment of HBV infection, long‐term treatment with these drugs can lead to the emergence of drug‐resistant viruses. Recent HIV‐1 studies suggest that combination therapies using nucleo(s)tide reverse transcriptase inhibitors (NRTIs) and non‐nucleo(s)tide reverse transcriptase inhibitors (NNRTIs) could drastically inhibit the viral genome replication of NRTI‐resistant viruses. In order to carry out such combinational therapy against HBV, several new NRTIs and NNRTIs should be developed. Here, we aimed to identify novel NNRTIs targeting the HBV polymerase terminal protein (TP)‐reverse transcriptase (RT) (TP‐RT) domain, which is a critical domain for HBV replication. We expressed and purified the HBV TP‐RT with high purity using an Escherichia coli expression system and established an in vitro ε RNA‐binding assay system. Then, we used TP‐RT in cell‐free assays to screen candidate inhibitors from a chemical compound library, and identified two compounds, 6‐hydroxy‐DL‐DOPA and N‐oleoyldopamine, which inhibited the binding of ε RNA with the HBV polymerase. Furthermore, these drugs reduced HBV DNA levels in cell‐based assays as well by inhibiting packaging of pregenome RNA into capsids. The novel screening system developed herein should open a new pathway the discovery of drugs targeting the HBV TP‐RT domain to treat HBV infection.

Therapeutic efficacy of hepatitis B virus vaccine in treatment of chronic HBV infections: A systematic review and meta-analysis.

There is a need for improved treatment of patients with chronic hepatitis B (CHB). We reviewed the literature to explore the efficacy of HB vaccines alone or in combination therapy (CT) with antiviral drugs in CHB patients and to meta-analyze data from randomized controlled trials. We conducted a systematic search in ten databases. All studies investigating the efficacy of HBV vaccine in HBV infected patients were included with no restrictions. Among 1359 studies initially identified, 23 studies (n = 1956 patients) were included for the final analysis. CT showed a significant reduction of HBV DNA compared with analogue monotherapy (AM) at the 12-month follow-up period (odds ratio (OR) = 2.835, 95% confidence interval (CI) [1.275, 6.306], p = .011). Additionally, CT also remarkably induce HbsAg loss in comparison with AM (OR = 11.736, 95% CI [1.841, 74.794], p = .009). Our pooled data revealed no difference between treatment and control regarding alanine aminotransferase normalization, HBeAg seroconversion, and HBeAg disappearance. In addition, CT using vaccine and NAs resulted in a statistically significant higher incidence of adverse effects than AM. The therapeutic effects of combination therapy for patients with CHB were encouraging, but future studies need to investigate all possible treatment combinations and assess their cost-effectiveness.

Kinetics of hepatitis B surface antigen quasispecies during REP 2139-Ca therapy in HBeAg-positive chronic HBV infection.

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca, whereas 3 of 12 patients did not show responses (>1log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the 'pre-S/S' open reading frame including the 'a' determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P=.28). However, these responders showed significant decline in viral complexity (P=.001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P=.99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in 'a' determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy.

Therapeutic vaccination for chronic hepatitis B: A systematic review and meta‐analysis

Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines+standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow-up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD=0.01, 95% CI -0.05 to 0.07, and when comparing therapeutic vaccines+standard of care vs standard of care, RD=0.03, 95% CI -0.03 to 0.09. For HBVDNA reduction at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD=-0.03, 95% CI -0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD=0.15, 95% CI 0.02-0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow-up for therapeutic vaccines+standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection.