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Background: Direct high-quality evidence remains absent on the benefits of HBeAg-negative chronic hepatitis B patients (CHB) with normal alanine transaminase (ALT) and positive HBV DNA after nucleos(t)ide analogs (NAs) treatment., Methods: This is a single-center, open-label, randomized parallel controlled trial with a follow-up duration of 96 weeks. An estimated 300 patients will be recruited at West China Hospital of Sichuan University, China. After stratified by serum HBV DNA (< 2000 vs. ≥ 2000 IU/ml), eligible patients will be randomized (allocation ratio 1:1) to receive either antiviral therapy (the treatment group) or regular examination alone (the control group). The primary outcomes are rates of virological response and changes in the levels of serum HBV pregenomic RNA (pgRNA) and scores of health-related qualities of life., Discussion: This randomized controlled trial focuses on HBeAg-negative patients with normal ALT, including those of the inactive carrier phase and the grey zone, whose antiviral treatment remains controversial. Additionally, a health-related quality of life scale is introduced to comprehensively estimate the benefit of antiviral treatment apart from virological response and adverse liver events. Meaningfully, the study findings will provide high-quality and direct evidence for optimal clinical management in such populations., Trial Registration: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300069391) on 15 March 2023., (© 2024. The Author(s).)

Background & Aims: Factors predicting HBsAg seroclearance after treatment cessation, irrespective of nucleos(t)ide analogue (NA) resumption, have important clinical implications. We evaluated predictors of long-term HBsAg seroclearance after entecavir cessation., Methods: This study followed-up Chinese patients with chronic hepatitis B from two previous studies of entecavir cessation. All patients were non-cirrhotic, HBeAg-negative, with undetectable HBV DNA (<20 IU/ml) at end-of-treatment (EOT). They were monitored closely for 48 weeks with regular HBV DNA, quantitative HBsAg (qHBsAg) and alanine aminotransferase (ALT) measurements. Entecavir was resumed at HBV DNA >2,000 IU/ml, irrespective of ALT levels. After the initial 48 weeks, patients were assessed every 6 months, regardless of entecavir resumption, to monitor for HBsAg seroclearance., Results: A total of 194 patients (63.4% male, mean age 49.9 years, on entecavir for a median of 47.2 months) were recruited; 94 (48.5%) and 158 (81.4%) patients had EOT qHBsAg <100 IU/ml and <1,000 IU/ml, respectively; 151 (77.8%) patients were eventually resumed on entecavir. After follow-up for a median of 70.7 (51.0-118.2) months, 28 (14.4%) patients had HBsAg seroclearance. qHBsAg levels at weeks 36 and 48 after EOT independently predicted HBsAg seroclearance (both p <0.01), whereas qHBsAg from EOT to week 24 only trended towards statistical significance. The ratio of ALT/qHBsAg at all time points from EOT to week 48 independently predicted HBsAg seroclearance (hazard ratios ranging from 1.003-1.028, all p <0.01) with excellent diagnostic performance (area under the receiver-operating characteristic curve 0.799-0.933, negative predictive value >90% at different time points), regardless of whether entecavir was resumed., Conclusions: The ALT/qHBsAg ratio after entecavir cessation predicts HBsAg seroclearance, even in patients who were resumed on treatment. Its use may mitigate the risk of severe hepatitis flares in patients managed by observation without treatment resumption., Impact and Implications: Current predictors of HBsAg seroclearance after finite nucleos(t)ide analogue (NA) therapy have suboptimal predictive value. We demonstrated that the ALT/qHBsAg ratio may be able to reflect the balance between host control and virological activity. The ALT/qHBsAg ratio at different time points from end-of-treatment till week 48 independently and accurately predicted HBsAg seroclearance in patients who have stopped entecavir. The ALT/qHBsAg ratio may be utilized by clinicians for patient selection and retreatment decisions in finite NA therapy., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis B Virus (HBV) infection is a global public health challenge that seriously endangers human health. Soft coral, as a major source of terpenoids, contains many structurally novel and highly bioactive compounds. Sixteen cembranoids (1-16), including a new one named sinupedunol B (16), were isolated from the South China Sea Soft coral Sinularia pedunculata. The structure of the sinupedunol B (16) was determined through a combination of spectroscopic analysis and X-ray single-crystal diffraction. In this study, cembranoids isolated from Sinularia pedunculata were found of anti-HBV activity for the first time. Among them, flexilarin D (6) showed significant anti-HBV activity with an IC 50 value of 5.57 μM without cytotoxicity. We then analyzed the structure-activity relationship (SAR). Furthermore, it is demonstrated that flexilarin D (6) can accelerate the formation of capsid, inhibit HBeAg, HBV core particle DNA, HBV total RNA and pregenomic RNA in a dose dependent manner. We also confirmed the anti-HBV activity of 6 in HepG2-NTCP infection system. Finally, we demonstrated the anti-HBV mechanism of these compounds by inhibiting the ENI/Xp enhancer/promoter., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: Pay-it-forward incentives effectively promote hepatitis B virus (HBV) and hepatitis C virus (HCV) testing among men who have sex with men (MSM) by offering free testing and donation opportunities. This study aims to explore the interaction between pay-it-forward incentives and recreational drug use on HBV and HCV testing uptake among Chinese MSM., Methods: We pooled data from two pay-it-forward studies that aimed to promote dual HBV and HCV testing among MSM in Jiangsu, China. We explored factors associated with hepatitis testing uptake in the two study groups and examined the interaction between pay-it-forward incentives and recreational drug use on hepatitis testing uptake., Results: Overall, 511 MSM participated in these two studies, with 265 participants in the pay-it-forward incentives group and 246 participants in the standard-of-care group. Among these participants, 59.3% in the pay-it-forward incentive group and 24.8% in the standard-of-care group received dual HBV and HCV testing, respectively. In the pay-it-forward incentives group, participants who used recreational drugs in the past 12 months (adjusted OR (AOR)=1.83, 95% CI 1.09 to 3.06) were more likely to receive dual HBV and HCV testing, compared with those who never used recreational drugs, whereas in the standard-of-care group, those who used recreational drugs were less likely to receive dual HBC and HCV testing (AOR=0.38, 95% CI 0.18 to 0.78). MSM with higher community connectedness (AOR=1.10, 95% CI 1.00 to 1.21) were also more likely to receive hepatitis testing with pay-it-forward incentives. There was a synergistic interaction on both the multiplicative (ratio of ORs=4.83, 95% CI 1.98 to 11.7) and additive scales (the relative excess risk of interaction=2.97, 95% CI 0.56 to 5.38) of pay-it-forward incentives and recreational drug use behaviours on dual HBV and HCV testing uptake among MSM., Conclusion: Pay-it-forward incentives may be particularly useful in promoting hepatitis testing among MSM who use recreational drugs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The global prevalence of hepatitis B virus (HBV) has presented a persistent challenge for public health prevention and treatment. However, studies that assess the public's access to anti-HBV drugs are absent., Aim: To examine the availability, pricing, and affordability of anti-HBV drugs in Jiangsu province, China and provide recommendations for improvement., Method: An enhanced methodology developed by the World Health Organization (WHO) and Health Action International was applied in a cross-sectional study that included 1026 healthcare facilities distributed in 13 prefectural-level cities in Jiangsu province., Results: Since almost all drugs had an availability of less than 30%, the accessibility of anti-HBV drugs was notably low. Primary healthcare facilities had the lowest availability, reporting 1.4% for Original Brands (OBs) and 1.7% for lowest-priced generics (LPGs). Furthermore, the northern Jiangsu region recorded the lowest availability at 0.7%. LPGs demonstrated higher availability than OBs, with median availability probabilities of 2.6% and 1.4%, respectively. The drugs listed on the WHO Essential Medicines List exhibited higher availability than those on other lists. The median price ratios for OBs, LPGs, and volume-based purchasing drugs were 0.83, 0.50, and 0.27, respectively, less than 1.5 times the international reference price. Despite favorable pricing, affordability rate was 23% for urban residents and 0% for rural residents, which was discouraging., Conclusion: Low availability and affordability of anti-HBV drugs were observed. Policy recommendations should emphasize the improvement of LPG availability by incentivizing priority prescribing. Healthcare subsidies should be provided more effectively and equitably., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Clinical cure (herein referred to as functional cure) is currently recognized as the ideal therapeutic goal by the guidelines for the prevention and treatment of chronic hepatitis B (CHB) at home and abroad. China has achieved significant results in research and exploration based on pegylated interferon alpha therapeutic strategies to promote the effectiveness of CHB clinical cure rates in clinical practice. The summary and optimization of clinical cure strategies in different clinical type classifications, as well as the exploration of clinical cure continuity and long-term outcomes, are of great significance for solving the current bottleneck problem and our future efforts in the developmental directions of clinical cure in CHB populations.

Background & Aims: Regulatory T cell (Treg) depletion increases antitumor immunity. However, severe autoimmunity can occur following systemic loss of Tregs, which could be avoided by selectively depleting intratumoral Tregs. Herein, we aimed to investigate the role of tumor-infiltrating CCR4 + Tregs in hepatocellular carcinoma (HCC) and to provide a potential target strategy for immunotherapy., Methods: CCR4 + Tregs were analyzed by flow cytometry in murine models and clinical samples. The function of tumor-infiltrating and induced CCR4 + Tregs was interrogated by genetic and epigenetic approaches. To block CCR4 + Treg chemotaxis, we developed an N-terminus recombinant protein of CCR4 (N-CCR4-Fc) as a neutralizing pseudo-receptor that effectively bound to its ligand CCL22. The efficacy of CCR4 antagonism as an immunotherapeutic agent was evaluated by tumor weights, growth kinetics and survival curves., Results: CCR4 + Tregs were the predominant type of Tregs recruited to hepatitis B-associated HCC (HBV + HCC), correlating with sorafenib resistance and HBV load titers. Compared with CCR4 - Tregs, CCR4 + Tregs exhibited increased IL-10 and IL-35 expression, and enhanced functionality in suppressing CD8 + T cells. CCR4 + Tregs also displayed PD-1 + TCF1 + stem-like properties. ATAC-seq data revealed substantial chromatin remodeling between tumor-infiltrating Tregs (TIL-Tregs) and induced Tregs, suggesting that long-term chromatin reprogramming accounted for the acquisition of enhanced immunosuppressive stem-like specificity by CCR4 + TIL-Tregs. Treatment with a CCR4 antagonist or N-CCR4-Fc blocked intratumoral Treg accumulation, overcame sorafenib resistance, and sensitized tumors to PD-1 checkpoint blockade., Conclusions: Intratumoral stem-like CCR4 + Tregs orchestrated immunosuppressive resource cells in the tumor microenvironment. CCR4 could be targeted to enhance antitumor immunity by specifically blocking infiltration of Tregs into the tumor microenvironment and inhibiting maintenance of the TIL-Treg pool., Lay Summary: Targeting regulatory T cells is a promising approach in cancer immunotherapy; however, severe autoimmunity can occur following systemic regulatory T cell loss. This could be avoided by selectively depleting intratumoral regulatory T cells. Herein, targeting intratumoral stem-like CCR4 + regulatory T cells helped to overcome sorafenib resistance and sensitize tumors to immune checkpoint blockade in mouse models of liver cancer. This approach could have wide clinical applicability., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Rational administration of peginterferon can remarkably reduce serum HBsAg level and improve the rate of HBsAg loss. Considering the high cost and adverse drug reaction of peginterferon, we aimed to develop a simple-to-use scoring system at early stage of treatment to predict low HBsAg level or HBsAg clearance at the end of treatment in virological suppression chronic hepatitis B (CHB) patients., Methods: Non-cirrhotic CHB patients with NA (nucleoside/nucleotide analogues)-induced virological suppression initiated either by add-on or switch-to peginterferon for ≥ 48 weeks were enrolled from January 2012 to June 2017 in these two tertiary centers. The retrospective experiment identified 320 suitable patients, including 192 in training and 128 in validation cohorts., Results: Using logistic regression, a simple-to-use scoring system integrating baseline HBsAg level <1000 IU/mL, HBsAg decline >0.5 log at week 12 and ALT flare at week 12 was developed in the training cohort and good for predicting HBsAg <100 IU/mL, HBsAg <10 IU/mL and HBsAg loss at the end of 48-week treatment. The area under receiver operating characteristics curve was 0.84, 0.86 or 0.78 in the training cohort and 0.88, 0.79 or 0.81 in the validation cohort, respectively., Conclusions: Our simple-to-use scoring system may guide for clinicians to decide whether to continue peginterferon in CHB patients to achieve low HBsAg levels or HBsAg clearance at the end of treatment, which might lead more cost-effective decision and get more patients to reach functional cures in Chinese population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the efficacy and potential side-effects of nucleotide/nucleoside analogues and hepatitis B immunoglobulin injection of newborns in blocking mother-to-child transmission of hepatitis B virus in the middle and late pregnancy period. 238 cases of enrolled pregnant women were divided into the Telbivudine group, the Tenofovir group, the Lamivudine group, and the hepatitis B immunoglobulin (HBIG) group. Enrolled patients received corresponding therapies. Clinical and laboratory data were collected. Results showed that the levels of HBV DNA of the enrolled pregnant women in the Telbivudine, Tenofovir, and Lamivudine groups decreased rapidly after 12 weeks of drug intervention compared with those in the control. HBsAg positive rate in newborns and in children 24 weeks after birth was 0/60, 0/60, 0/60, 3/30, and 11/28 in the Telbivudine, Tenofovir, Lamivudine, HBIG, and control groups, respectively. No significant side-effects were identified after following up to 12 months after birth. Our results show that routine HBV vaccine plus HBIG injections is insufficient in blocking mother-to-child HBV transmission. Administration of nucleotide/nucleoside analogues or HBIG at pregnancy is suggested to maximize the blocking of vertical HBV transmission., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Xiaojun Sun et al.)

Objective: To conduct a multicenter randomized controlled trial of the efficacy of standardized Chinese herbal medicines (CHMs) against acute- on-chronic liver failure (ACLF) and provide reproducible and high-level evidence for clinical practice., Methods: This is a prospective, multicenter, centrally randomized controlled trial. Patients diagnosed with hepatitis B virus-related ACLF (n = 510) will be allocated to the standard medical therapy or CHM group at a 1∶1 ratio. Two CHMs will be used on the basis of the traditional Chinese medicine syndrome: Liangxue Jiedu granules for excess syndromes and Yiqi Jiedu granules for deficiency syndromes. The primary outcome is transplant-free survival at week 12. The secondary outcomes are (a) transplant-free survival at week 24, (b) liver function as assessed using the model for end-stage liver disease score at week 12, (c) liver function as assessed using the Child-Pugh score at week 12, and (d) the incidence of complications at week 12., Discussion: The effectiveness and safety of CHM formulations will be assessed following treatment for ACLF.

Aims: Hepatitis B surface antigen (HBsAg) loss is associated with disease control and improvement of prognosis. Therefore, it is regarded as the optimal treatment endpoint for chronic hepatitis B (CHB) patients. Pegylated interferon (PegIFN)-based extended therapy regimens was assessed in several studies. In order to summarize a conclusion on the HBsAg loss rate and safety in this regimen, a systematic review and meta-analysis was performed., Methods: Studies on Hepatitis B and PegIFN were searched thoroughly in Pubmed, EMBASE, and the Cochrane Library from inception to November 18, 2019. The primary endpoint of this study was the HBsAg loss rate at the end of the extended duration therapy. The secondary endpoint was safety. All analyses were performed by using the R3.6.1 version Software. Quality assessment of RCTs was carried out by using Review manager 5.3., Results: A total of nine studies, including 545 CHB patients met the inclusion criteria. The pooled HBsAg loss rate after PegIFN-based extended duration therapy was 11% (95% CI: 0.05-0.19), I 2  = 82%, P < 0.01(Q test). The extended duration therapy regimen was safe and tolerable. Subgroup analysis showed HBsAg loss rates were 14% (95% CI: 0.04-0.29) and 10% (95% CI: 0.02-0.20) respectively for HBeAg positive and HBeAg negative patients (P = 0.52). HBsAg loss rates were 11%(95%CI:0.03-0.22)and 12%(95%CI:0.04-0.24)respectively for PegIFN monotherapy and PegIFN with Nucleos(t)ide analogs (NAs) therapy (P = 0.84). HBsAg loss rates were 25% (95% CI: 0.19-0.31) and 8% (95% CI: 0.03-0.15) respectively for the advantageous group and non-advantageous group (P = 0.001)., Conclusions: For CHB patients, extended duration of PegIFNα-based treatment for more than 48 weeks is likely to improve HBsAg clearance rate. Specially, the advantageous group will benefit a lot. In addition, the extended duration therapy regimen is safe and tolerable., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Data on tenofovir alafenamide fumarate (TAF) for preventing mother-to-child transmission of hepatitis B virus (HBV) are lacking., Aims: To investigate the efficacy and safety of TAF therapy for preventing hepatitis B mother-to-child transmission., Methods: Mothers with chronic HBV infection, positive for hepatitis B e-antigen and with HBV DNA >200 000 IU/mL received TAF for preventing mother-to-child transmission were enrolled retrospectively from multiple centres with data collection on mother-infant dyads up to postpartum week 24-28. Primary measurements were the mother-to-child transmission rate and infants' malformation rate. Secondary assessments included maternal HBV DNA reduction at delivery, and maternal or infant adverse events during follow up., Results: Among 71 mothers enrolled, the mean (±SD) age was 30.3 (±2.2) years. TAF was initiated during the second or third trimester and continued to delivery with a mean (±SD) duration of 12.8 (±4.0) weeks. At delivery, 85.9% (61/71) of the mothers achieved HBV DNA <200 000 IU/L. Seventy-three infants (two sets of twins) were born from mothers treated with TAF and none had congenital defects or malformations. All infants received HBV immunoglobulin and vaccine at birth with additional HBV vaccinations at one and six months. At age 24-28 weeks, all infants had negative hepatitis B surface antigen and undetectable levels of HBV DNA (<100 IU/mL). Body weight, height, and head circumferences were comparable to national standards for physical development. No severe adverse effects were reported in either mothers or infants., Conclusions: TAF for highly viraemic mothers effectively prevented mother-to-child transmission of hepatitis B. There were no safety concerns for either mothers or infants with 24-28 weeks of follow up., (© 2020 John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: Hepatitis B, an infectious disease caused by hepatitis B virus (HBV), is still a serious problem affecting global public health. Abrus cantoniensis Hance (AC), a traditional Chinese medicinal herb, has been used as a folk medicine for treating hepatitis in China from ancient times. However, its active ingredients are still unclear., Aim of Study: Our previous study indicated that saponins extracted from AC (ACS) were the active anti-HBV ingredients in AC. This study aimed to further investigate the anti-HBV effect of ACS in vitro and in vivo., Materials and Methods: HepG2.2.15 cells which consecutively produce HBV DNA and HBV antigens were used for in vitro test, and C57BL/6 mice infected by a recombinant adeno-associated virus 8 vector carrying 1.3 copies of HBV genome (rAAV8-HBV1.3) were used for in vivo test. The histopathological changes and the immune indices were evaluated in mice model. Genechip was conducted to identify genes and pathways regulated by ACS in HepG2.2.15 cells., Results: In this study, we confirmed that ACS treatment prominently inhibited production of HBV DNA, Hepatitis Be Antigen (HBeAg), and Hepatitis B surface antigen (HBsAg) in HepG2.2.15 cells. ACS treatment also decreased serum HBsAg, HBeAg, and HBV DNA level in rAAV8-1.3HBV transfected mice, which is in accordance with the in vitro results. Moreover, HBV infection-induced liver inflammation was significantly relieved by ACS, which could be observed in H&E staining and immunohistochemistry of HBcAg. ACS treatment elevated IFN-γ level in mice serum and increased CD4 + T cell percentage in splenocytes. KEGG pathway analysis showed that phenylalanine metabolism pathway and tyrosine metabolism pathway were greatly regulated by ACS treatment., Conclusion: ACS exerted potent inhibitory effects on HBV replication both in vivo and in vitro, which may provide basis for its potential clinical usage., (Copyright © 2019 Elsevier B.V. All rights reserved.)

GLS4 is a novel inhibitor of the hepatitis B virus (HBV) capsid assembly with inhibitory activities against nucleot(s)ide-resistant HBV strains. This study investigated the pharmacokinetics, safety, and tolerability of GLS4 and the effects of food and ritonavir in healthy adults. GLS4 was administered in a single-ascending-dose study over 1 to 240 mg and multiple-ascending-dose study that ranged from 30 mg once daily to 180 mg three times daily. The drug interaction study included sequential design (day 1 for 120 mg GLS4 alone, day 5 for 100 mg ritonavir alone, followed by 9 days of both drugs) and a placebo control (9 days of both 240 mg GLS4 and 100 mg ritonavir). The results showed that the steady-state trough concentration of multiple dosing of GLS4 alone was significantly lower than the 90% effective concentration of 55.7 ng/ml, even with increasing dosing frequency and dosage. An initial dose of 100 mg ritonavir significantly boosted plasma concentration at 24 h of 120 mg GLS4 from 2.40 to 49.8 ng/ml (geometric mean ratio, 20.7; 90% confidence interval, 17.0 to 25.3), while a milder effect was observed on the area under the curve from 0 to 24 h, with a 7.42-fold increase, and on the maximum concentration, with a 4.82-fold increase. The pharmacokinetics change in GLS4 persisted after 9 days of chronic dosing, with a trough concentration of 182 ng/ml. Both single and multiple doses of GLS4 up to 240 mg with or without ritonavir were well tolerated. These results support the investigation of a novel HBV treatment regimen containing GLS4 with 100 mg ritonavir added solely to enhance GLS4 concentrations in plasma. (This study was registered at the China Platform for Registry and Publicity of Drug Clinical Trials [http://www.chinadrugtrials.org.cn] under numbers CTR20132137 and CTR20150230.)., (Copyright © 2019 American Society for Microbiology.)

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC) in China. The occurrence of HCC can significantly be reduced with effective long-term antiviral treatment. Since the widespread clinical use of nucleos(t)ide analogues, such as entecavir and tenofovir that has a strong potency and high genetic barrier to resistance; the detection rate of HBV DNA in serum of patients with chronic hepatitis B is no more than 85% ~ 95%, but HCC can still occur in a small number of patients. This article will review whether the timing and selection of NAs treatment differ to prevent and reduce the incidence of HCC.

The norbisabolane-type sesquiterpenoids bearing a spiroketal functionality have been found in Phyllanthus spp. and showed anti-HBV activities. As part of an ongoing effort to search for promising anti-HBV sesquiterpenes from Phyllanthus plants, we report four new norbisabolane-type sesquiterpenoids, phyacidusin A (1), phyacidusin B (2), phllanthacidoid A1 (3) and phllanthacidoid N1 (4), from stem of P. acidus collected in Xishuangbanna, Yunnan province, China. The absolute configuration of new compounds was established by coupling constants and ROESY correlations, as well as comparation of NMR data with those of known compounds. The absolute configuration of new compounds 1 and 2 was further confirmed by X-ray diffraction. Compound 2 showed effect to HBsAg with an IC 50 value of 11.2 ± 0.01 μM, while compound 3 inhibited HBeAg secretion with an IC 50 value of 57.1 ± 0.02 μM. The results enriched the diversity of anti-HBV norbisabolane sesquiterpenes., (Copyright © 2019. Published by Elsevier B.V.)

In 2016, the WHO proposed the goal for elimination of hepatitis B as public health threat, by 2030. China has the heaviest burden caused by hepatitis B virus (HBV) infection in the world, and serves as the major contributor to the goal of eliminating hepatitis B by 2030, globally. During the past 30 years, great progress has been made towards the implementation on prevention and control programs of HBV infection, in China, that enabling the WHO 2030 target to be fulfilled. However, due to the size of population, the large number of HBV infections and the low coverage of diagnosis and treatment programs, China is still facing the challenge in reaching the 2030 target, on time. This paper elaborates the achievements and gaps regarding the on-going prevention and control programs, including vaccination, prevention of maternal-to-child transmission, blood and injection safety, diagnosis and treatment on HBV infection and putting forward several suggestions on relevant policies for achieving the goal of hepatitis B elimination by 2030, in China.

Objective: To compare the reduction of hepatocellular carcinoma (HCC) risk between long-term treatment of entecavir and low genetic barrier antiviral agents in hepatitis B virus (HBV)-related cirrhotic patients., Study Design: An observational study., Place and Duration of Study: Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China, from October 2008 to October 2016., Methodology: HBV-related cirrhotic patients with antiviral treatment for at least 12 months were consecutively included. Propensity score matching analysis was performed to improve comparability of the data from both entecavir group and the control group. Log-rank test was used to compare influence of various nucleos(t)ide analogs (NAs) for incidence of HCC. Independent risk factors were estimated by multivariable Cox proportional hazards models., Results: The total cohort included 207 HBV-related cirrhotic patients, of which 83 patients were treated with entecavir initially. The present study found no statistical difference for the incidence of HCC between entecavir group and the control group in the total cohort (p=0.525). However, the difference became statistically significant (p=0.014) after propensity score matching. Number needed to treat (NNT) were 8 patients, 6 patients and 3 patients at years 2, 3 and 4, respectively. Multivariable Cox regression in propensity score matching cohort revealed older age (HR: 1.066, p=0.041), NAs of low generic barrier (HR: 6.944, p=0.016), NAs resistance (HR: 3.648, p=0.041), and lower platelet counts (<80x10 ⁹/L) (HR: 6.718, p=0.009) as independent risk factors for HCC incidence., Conclusion: Entecavir is more efficient in reducing the incident HCC risk for HBV-related cirrhotic patients in comparison to low genetic barrier NAs.

Purpose. ERF3 , having been found expressing differently in liver tissues in our previous work, including eRF3a and eRF3b , which are structural homologs named GSPT1 and GSPT2 Recent studies have indicated that eRF3b involved in the development and proliferation of HepG2 cell, and eRF3a may be associated with tumor susceptibility. Based on this, we tested the effects of GSPT1 and GSPT2 single-nucleotide polymorphisms for all major Hepatitis B virus (HBV) outcomes and lamivudine (LAM) treatment in Han Chinese. Method. A total of 1649 samples were enrolled, and peripheral blood samples were collected in the present study. The single-nucleotide polymorphisms in the GSPT1 and GSPT2 region were genotyped using MALDI-TOF MS. Results. Our study demonstrated there was no obvious relevance of either GSPT1 -rs33635 or GSPT2 -rs974285 polymorphisms with HBV susceptibility, spontaneous recovery, and development of HBV-related diseases. However, we showed for the first time to our knowledge that GSPT1 -rs33635C was a predictor for LAM therapy (viral response: odds ratio (OR) = 2.436, P =0.022; biochemical response: OR = 3.328, P =1.73 × 10 -4 ). Conclusions. These findings might provide potential implications for therapeutic guidance., (© 2019 The Author(s).)

Hepatitis B virus (HBV) carrier woman of childbearing age with high viral load is an important source of vertical transmission of hepatitis b virus from mother-to-child in China. Routine blockade with immunoglobulin combined with hepatitis B vaccine is used for neonates born to pregnant women with high viral load of hepatitis B virus, but in some cases, immunoprophylaxis fails. The main application of antiviral drugs in pregnancy is to reduce the serum viral load, thereby significantly improve the blocking rate of vertical transmission between mother and infant. Current evidence suggested that if the maternal age is less than 30 years old, with no obvious liver fibrosis or cirrhosis and there is no increase in ALT level >2ULN( upper limit of normal) during the treatment, the treatment with antiviral drugs can be stopped after delivery immediately. Additionally, ALT level should be examined at 4, 12 and 24 weeks after stopping the drug. Antiviral therapy for the occurrence of hepatitis attack should be given if criteria for HBV treatment are met.

Since the 40th anniversary of China's reform and opening-up, earth-shattering development has taken place in all walks of life across the country. Research field on the prevention and treatment of chronic hepatitis B has been rewarding after 40 years of trials and tribulations. Additionally, hepatitis B vaccination program and effective antiviral therapy has amazingly reduced the prevalence of hepatitis B virus infection. Coupled with the literary evidence, a consensus has gradually emerged in the field of anti-HBV treatment that "high potency, low incidence of drug resistance and immunomodulation coexists". We believe that in the near future, according to the principle of "prevention first, prevention with treatment", universal vaccination program for infants, vaccination of high-risk groups, active treatment of HBV carriers and chronic hepatitis B patients, and the realization of "early screening, diagnosis and treatment" of hepatocellular carcinoma will eradicate HBV infection.

Background: The aims of this study were to describe antiviral drug (AD) utilization and costs in patients with chronic HBV infection., Methods: We conducted a retrospective study of patients in the hospital and calculated annual proportions of AD utilization and costs among patients. A two-part model was used to estimate adjusted odds ratio (OR) for antiviral therapy and cost ratios for antiviral costs associated with demographics., Results: Of a total of 14,920 records, 143,658 records were involved in the analysis. The annual proportions of AD utilization were 56.99% (45.65%) for inpatients (outpatients) during 2008-2015 and increased annually. Entecavir (ETV), in particular, increased from 11.08% to 70.26% (11.05% to 49.35%) for inpatients (outpatients). The patients with medical insurance were more likely to use AD than patients without insurance, and the adjusted OR was 1.11 (95% CI: 1.03, 1.19) for inpatients and 1.66 (1.59, 1.73) for outpatients. With the disease progressing, the proportion of antiviral costs in total direct medical costs decreased from 13.91% to 4.07% (71.29% to 49.29%) for inpatients (outpatients)., Conclusions: The use of AD for chronic HBV infection was less than expected based on established guidelines, and only half of patients received antiviral treatment. However, the AD utilization, especially ETV, increased annually. Reimbursement policy was the most important factor affecting antiviral treatment. Antiviral therapy was an important part of the direct medical costs, especially in the early stage of disease.

Introduction: Most chronic hepatitis B (CHB) patients in China are primitively treated with a combination of lamivudine (LAM) and adefovir dipivoxil (ADV). Although antiviral resistance can be avoided with this combination therapy, using it can have harmful side effects related to ADV, specifically kidney and bone injury. This study was designed to compare viral suppression and kidney safety when switching LAM and ADV combination therapy de novo to entecavir (ETV) monotherapy in patients with CHB and compensated hepatic cirrhosis. Materials and methods: In total, 360 CHB and compensated liver cirrhosis patients who received treatment of LAM and ADV combination therapy for more than 1 year were included in this study. One hundred and eighty patients continued combination therapy to serve as a control group and the other 180 patients were switched to ETV monotherapy to serve as the experimental group. The total course of therapy was 3 years. Laboratory studies were done every 3 months to measure liver and kidney function. Studies included glomerular filtration rate (eGFR), HBV-DNA, urine β2-microglobulin (β2-M) and retinol binding protein (RBP). Results: In the experimental group, an HBV-DNA level below 20 IU/ml was found in 77.65%, 85.88%, and 94.77% in years 1, 2, and 3, respectively. In the control group, HBV-DNA levels were below 20 IU/ml in 69.66%, 75.42%, and 85.80% in years 1, 2, and 3, respectively. Low HBV-DNA levels in the experimental group were significantly less common than in the control group on the second and third year; P values were 0.009 and 0.006 for years 2 and 3, respectively. The cumulative genetic mutation rate was 3.49% in the experimental group and 8.88% in the control group ( P =0.044). Decreases in eGFR more than 30% from baseline were found in 0%, 0.56%, and 1.74% of patients in the experimental group and 4.49%, 9.14% and 14.79% in patients in the control group in the first, second, and third year, respectively. Serum creatinine more than 50 μmol/L above baseline was found in 0%, 0% and 1.74% of patients in the experimental group and 1.12%, 4.00% and 5.32% of patients in the control group in years 1, 2, and 3, respectively. The urine β2-M and RBP levels were abnormal more often in the experimental group than in the control group. Conclusion: Switching to ETV monotherapy can decrease HBV-DNA levels, reduce the genetic mutation rate, and prevent renal damage caused by LAM and ADV combination therapy in patients with CHB and compensated liver cirrhosis. Patients receiving LAM and ADV combination therapy de novo should be switched to ETV monotherapy immediately., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Five caffeoyl phenylethanoid glycosides, including two new ones linderruelliosides A (1) and B (2), were isolated from the leaves and stems of Lindernia ruellioides. Their structures were elucidated on the basis of spectroscopic methods, including extensive NMR and MS spectra. In addition, all these compounds were tested for their anti-HBV activity. Compounds 1, 3, and 4 showed anti-HBV activities, with IC 50 values of 54.87, 30.74, and 69.02 μM for HBsAg and 26.70, 5.17, and 7.08 μM for HBeAg, respectively.

Introduction and Aim: Accurately predicting the prognosis of individual patient is crucial in the management of ACLF. We aimed to establish a specific prognostic model for HBV-related ACLF patients treated with nucleoside analog (NA)., Material and Methods: We prospectively collected 205 ACLF cases diagnosed according to the APASL criteria. A dynamic prognostic model based on APASL criteria was established and validated. To demonstrate that the model is also applicable to those within EASL criteria, we divided the patients into two groups: met APASL criteria only (group A, n = 123); met both APASL and EASL criteria (group B, n = 82). Its prognostic accuracy was also compared with chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score in group B., Results: The model is: R = 0.94 x Bilirubin + 0.53 x evolution of Bilirubin - 0.45 x PT-A - 0.22 x evolution in PT-A -0.1 x PLT + 10 x anti-HBe. The area under receiver operating characteristic curve (AUC) of the model for predicting 90-day mortality was 0.86, which was significantly higher than that of model for end stage liver disease(MELD), MELD-Na, CLIF-SOFA, ΔMELD (7d) and ΔMELD-Na (7d), ΔCLIF- SOFA(7d) (all p &lt; 0.01). The AUC of our model in the validation group was 0.79 which was superior to MELD (0.45) CLIF-SOFA (0.53) score in group B patients (p &lt; 0.01)., Conclusion: In conclusion, the model was superior to the conventional methods in predicting the outcomes of patients with HBV related ACLF treated with NA. It is the first description of a novel prognostic model using consecutive data in patients with HBV-induced acute-on-chronic liver failure (ACLF) treated by nucleoside analogs.

Limited studies have investigated the antiviral efficacy of entecavir (ETV)-based rescue therapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients. We retrospectively analyzed the efficacy of entecavir (ETV) monotherapy versus ETV-tenofovir disoproxil fumarate (TDF) combination therapy in 220 LAM-resistant CHB patients. Among 220 patients, 114 patients were treated with ETV monotherapy and 106 were treated with ETV-TDF combination therapy for at least 24 months. There were no significant differences between the two groups in baseline characteristics. During the follow-up of 24 months, virologic response (VR) occurred in 146 (66.4%) patients (58 patients belonged to the ETV monotherapy group and 88 patients belonged to the ETV-TDF combination group). The VR rates were different between the ETV and ETV-TDF groups (32.5% vs. 57.5% at 6 months, 50.0% vs. 77.4% at 12 months; and 50.9% vs. 83.0% at 24 months, P<0.001). In addition, both groups showed no difference in terms of the biochemical and HBeAg response. The rates of viral breakthrough at 6, 12 and 24 months were significantly different between ETV and ETV-TDF groups (2.63%, 4.39% and 9.65% vs. 0.00%, 0.94% and 1.89% at 6, 12 and 24 months, respectively). The ETV-TDF group was superior to the ETV group in achieving a virologic response. Moreover, the ETV-TDF was lower than the ETV group in achieving the initial viral breakthrough and genotypic mutations. Therefore, ETV-TDF combination therapy might be a better regimen than ETV monotherapy in the subgroup of LAM-resistant Chinese patients with CHB.

Objectives: We aimed to determine the prevalence of hepatitis B virus (HBV) drug-resistant mutations in patients co- infected with HBV/human immunodeficiency virus (HIV), including both drug-naïve subjects and those who received antiretroviral therapy (ART) in Guangxi, where the prevalence of HIV/HBV co-infection is highest in China., Methods: Two hundred and three subjects co-infected with HBV/HIV were recruited, including 123 drug-naïve patients (group 1) and 80 who received ART (group 2). The polymerase gene of HBV in the serum of all study subjects was analysed., Results: The results showed that the prevalence of HBV drug-resistant mutations in group 2 (76.5%, 95% CI 56.3-96.7) was significantly higher than that in group 1 (1.4%, 95% CI -1.4 to 4.2; χ2 = 50.955, p < 0.05). The major pattern of lamivudine (3TC)-resistant mutations is L180M+M204I+L80I (35.7%). In total, 95% of subjects with resistant mutations had cross-resistance to telbivudine and entecavir. No putative tenofovir disoproxil fumarate (TDF) resistance change was found. Five subjects (6.5%) in group 2 had HBV viral loads over 10 × 106 copies/mL. Four of them had 3TC-resistant mutations. Multivariate analysis showed that ART was the only factor associated with the development of drug-resistant mutations., Conclusion: Treating HIV in HIV/HBV co-infection with antiretroviral agents may result in a very high prevalence of HBV 3TC-resistant mutations. TDF could not completely suppress HBV replication., (© 2018 S. Karger AG, Basel.)

Background: In China, the clinical management of chronic hepatitis B (CHB) is complicated by the use of variousnucleoside/nucleotide analogue (NUC) regimens in treatment-naive patients, including NUCs with low genetic barriers to resistance, with/without add-on therapy and de novo NUC combinations. This longitudinal observational study therefore investigated the real-world clinical management and efficacy of NUC therapy in treatment-naive CHB patients in China., Methods: Treatment-naive CHB patients initiated on NUC therapy were enrolled from 63 hospitals in tier-2 Chinese cities. Demographic and treatment-specific data were collected, with the objective of reporting real-world treatment patterns and comparing the effectiveness of entecavir (ETV) treatment and lamivudine (LAM)-based treatment. We herein report the first-year data., Results: 3,408 NUC-naive patients were enrolled and treated with NUCs (53% ETV, 18% LAM-based, 29% other). Overall, 6.6% of patients modified their initial treatment, with ETV having lower rates of treatment modification than other major NUCs (P<0.05). At week 52, the virological response rate was higher with ETV than with LAM-based treatment (77.0% versus 61.4%; P<0.0001). LAM-based treatment was associated with a higher probability of virological breakthrough and genotypic resistance (21.4% and 19.6%, respectively) than ETV (1.6% and 0.1%, respectively; P<0.0001). Treatment-related adverse events or serious adverse events were uncommon., Conclusions: In this nationwide observational study, more than 50% of patients with CHB in tier-2 city hospitals in China initially received ETV therapy. Consistent with clinical trial results, ETV was more effective than LAM-based treatments in a real-world setting, with the rate of treatment modification being relatively low in ETV-treated patients. ClinicalTrials.gov Identifier: NCT01726439.

Globally, one third of prevalent chronic hepatitis B (CHB) virus infection (HBV) occurred in China. Assessing the prevalence of CHB infesction and status of HBV-related services among pre-conception women will provide insight into risks of mother to child transmission (MTCT). A cross-sectional analysis of data from the National Free Pre-pregnancy Checkups (NFPC) program in 2010-2014 was conducted. A standardized questionnaire which collected demographic information and enzyme-linked immunosorbent assays (ELISA) which tested serological HBV markers were applied. A total of 16,051,850 rural women aged 15-49 years were included. 5.2% of women were infected with CHB, among whom, 28.6% were also hepatitis B e antigen (HBeAg) positive. The most CHB concentrated places were distributed in southeastern coastal provinces. Women born after 1992 did not experience a higher level of vaccine-induced immunity compared to those born before 1992. Nine in ten rural women with CHB were not aware of their HBV status and a very small proportion of women (0.22%) had received antiviral treatment. Our data demonstrated an overall high-intermediate burden of CHB. Heterogeneity of geographic distribution, high proportion of HBeAg, insufficient awareness of HBV status, and low access to HBV treatment are challenges for preventing the MTCT.

Objectives: To study the prevalence of drug-resistant HBV in patients with therapy failure in a Chinese tertiary referral liver centre., Methods: 1223 HBV-infected patients who underwent genotypic resistance testing between 2010-2014 were studied., Results: 3TC genotypic resistance was the most common (46.5%), followed by LdT resistant (46.2%), ETV intermediate (37.9%), ADV resistant (11.4%), TDF intermediate (11.4%) and ETV resistant (1.7%). The 3TC resistance rate increased from 39.8% in 2010 to 56.6% in 2013, before decreasing to 49.5% in 2014, evidence of a lagging effect of l-nucleoside consumption. M204I, N236T and L180M+M204V+V173L/S202G were the most common substitutions for l-nucleoside (3TC and LdT), ADV and ETV genotypic resistant phenotypes, respectively. 3TC-exposed patients showed a high multiple genetic resistance rate (3TC-resistant+LdT-resistant+ETV intermediate; 58.8%). Resistance rates to 3TC, LdT and ETV in HCC patients were significantly higher than in cirrhosis and CHB patients. Resistance rates to different drugs showed no statistical difference between genotype B and C patients, whilst some amino acid substitution showed genotype bias, e.g. N236T incidence in genotype B was significantly higher than in genotype C (43.2% vs. 5.9%; P<0.0001), and genotype C isolates had a significantly higher A181V/T incidence than genotype B (54.9% vs. 19.3%; P<0.0001)., Conclusions: 3TC genotypic resistance was most common in this centre, whilst ETV had the lowest resistance rate. HBV genotypes had no impact on antiviral drug resistance, except for some drug resistance substitutions bias. Optional initial therapy and subsequent rescue treatment should be based on knowledge of nucleos(t)ide analogue resistance., (Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Background: Hepatitis delta virus (HDV) in conjunction with hepatitis B virus (HBV) increases adult morbidity and mortality. A number of studies have performed cost-benefit analyses for HBV interventions, but they have ignored the impact of HDV on these outcomes., Methods: Using a mathematical model of HBV-HDV epidemiology, we compare health benefits and cost outcomes of four interventions: testing with HBV adult vaccination (diagnosis), diagnosis with antiviral treatment for HBV infections (mono-infections), diagnosis with antiviral treatment for HBV-HDV infections (dual-infections), and awareness programs. The relationship between optimal levels and outcomes of each of these interventions and HDV prevalence in HBV infected individuals ranging from 0 to 50% is determined., Results: Over a 50 year period under no intervention, HBV prevalence, per capita total cost and death toll increase by 2.25%, -$11 and 2.6-fold respectively in moderate HDV endemic regions compared to mono-infected regions; the corresponding values for high HDV endemic regions are 4.2%, -$21 and 3.9-fold. Optimal interventions can be strategized similarly in mono and dually endemic regions. Only implementation of all four interventions achieves a very low HBV prevalence of around 1.5% in a moderate HDV endemic region such as China, with 2.8 million fewer deaths compared to no intervention. Although the policy of implementation of all four interventions costs additional $382 billion compared to no intervention, it still remains cost-effective with an incremental cost-effectiveness ratio of $1400/QALY. Very high efficacy awareness programs achieve less prevalence with fewer deaths at a lower cost compared to treatment and/or vaccination programs., Conclusion: HDV substantially affects the performance of any HBV-related intervention. Its exclusion results in over-estimation of the effectiveness of HBV interventions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: To investigate the association between interferon-induced protein with tetratricopeptide repeats 1 ( IFIT1 ) polymorphisms and interferon-α (IFNα) treatment efficiency among Chinese hepatitis B virus (HBV) infection patients., Methods: Two hundred and twenty five newly diagnosed chronic hepatitis B (CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen (HBeAg) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms (SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes., Results: At the end of the treatment, HBeAg seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218 (A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64 (95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response (response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype (response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBeAg seroconversion, combined response or sustained response was observed., Conclusion: IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation., Competing Interests: Conflict-of-interest statement: All authors declare no conflict of interest.

Entecavir (ETV) is a potent viral replication inhibitor for chronic hepatitis B (CHB) patients. To investigate the efficacy of ETV in Chinese nucleos(t)ide(NA)-experienced CHB patients. Among 89 CHB patients with ETV monotherapy for ≥6 months, 33/89 (37%) or 56/89 (73%) were NA-naïve or NA-experienced. During a median follow-up of 5.75 years, all NA-naïve CHB patients achieved VR without genotypic ETV-resistance. However, VR was observed in 50/56 (~90%) of NA-experienced CHB patients during a median follow-up of 4.75 years. Antiviral efficacy was not reduced in patients with previous lamivudine (LAM) with/without LAM-resistance (HR 0.465; 95% CI 0.196-1.100; p > 0.05) (HR 0.472; 95% CI 0.205-1.091; p > 0.05). Patients with a primary treatment failure to adefovir (ADV) had a reduced probability of achieving VR compared to NA-naïve (HR 0.496; 95% CI 0.287-0.857; p < 0.01). Previous ADV-experienced patients with a partial VR (HR 1.253; 95% CI 0.429-3.665; p > 0.05) did not influence antiviral response to ETV. The antiviral efficacy of ETV is not influenced by previous treatment LAM with/without LAM-resistance. ETV may still be an option in ADV-experienced patients with a partial VR, but not advised in patients with a primary treatment failure to ADV.

Background: Although combination antiretroviral therapy (cART) including tenofovir (TDF)+lamivudine (3TC) or emtricitabine (FTC) is recommended for treatment of HIV/HBV coinfected patients, TDF is unavailable in some resource-limited areas. Some data suggest that 3TC monotherapy-based cART may be effective in patients with low pretreatment HBV DNA., Methods: Prospective study of 151 Chinese HIV/HBV coinfected subjects of whom 60 received 3TC-based cART and 91 received TDF+3TC-based cART. Factors associated with HBV DNA suppression at 24 and 48 weeks, including anti-HBV drugs, baseline HBV DNA, and baseline CD4 cell count, were evaluated overall and stratified by baseline HBV DNA using Poisson regression with a robust error variance., Results: Baseline HBV DNA ≥20,000 IU/mL was present in 48.3% and 44.0% of subjects in the 3TC and TDF groups, respectively (P = 0.60). After 48 weeks of treatment, HBV DNA suppression rates were similar between these 2 groups (96.8% vs. 98.0% for 3TC and TDF+3TC, P > 0.999) in subjects with baseline HBV DNA <20,000 IU/mL; whereas in those with baseline HBV DNA ≥20,000 IU/mL, TDF+3TC was associated with higher suppression rates (34.5% vs. 72.5% in 3TC and TDF+3TC groups, respectively, P = 0.002). In stratified multivariate regression, TDF use (RR 1.98, P = 0.010) and baseline HBV DNA (per 1 log increase in International Units Per Milliliter, RR 0.74, P < 0.001) were associated with HBV DNA suppression only when baseline HBV DNA ≥20,000 IU/mL., Conclusion: This study suggests that 3TC monotherapy-based cART is efficacious for HBV treatment through 48 weeks in HIV/HBV coinfection when baseline HBV DNA <20,000 IU/mL. Studies with long-term follow-up are warranted to determine if this finding persists.

Introduction: Traditional Chinese herbs are widely used for the treatment of chronic hepatitis B (CHB) in China. The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing peginterferon therapies with peginterferon plus Chinese herbal therapies in hepatitis B e antigen (HBeAg)-positive CHB patients., Methodology: The main biomedical databases were searched to identify RCTs that compared the efficiency of peginterferon with peginterferon plus Chinese herbs in CHB patients., Results: The literature search yielded 616 studies, and 8 RCTs (624 patients) matched the selection criteria. Combined therapies of peginterferon plus Chinese herbal therapies were superior to peginterferon therapies alone in achieving the serum HBV DNA clearance rate (64.5% vs. 45.0%), serum HBeAg clearance rate (47.4% vs. 33.5%), and HBeAg seroconversion rates (39.2% vs. 23.1%) at the end of treatment. Combined therapies were more effective than peginterferon alone therapies in the improvement of liver fibrosis related biomarkers, including hyaluronic acid, procollagen type III, type IV collagen, and lamina. Combined therapies also resulted in fewer relapses, fewer adverse events, and more rapid alanine transaminase normalization., Conclusions: The current evidence suggests that peginterferon plus Chinese herbal therapies were associated with higher virological response than peginterferon alone in HBeAg-positive CHB patients.

Mutations in the major hydrophilic region (MHR) of the surface antigen of hepatitis B virus (HBV) may result in vaccine escape, failure of immunotherapy and antiviral resistance. These mutants may be transmitted and constitute a public health threat. We aimed to determine the prevalence of MHR mutations of HBV in areas of high endemicity in Guangxi, China. HBV surface gene was analysed from 278 HBsAg-positive asymptomatic individuals recruited from Guangxi using cluster sampling. Three genotypes, B, C and I, were identified. The overall prevalence of MHR mutations is 17·6%. The prevalence of MHR mutations in genotype B (15·1%) is not significantly different from that in genotype C (16·4%). However, the prevalence in subgenotype C5 (31·1%) is significantly higher than in subgenotype C2 (13·0%) (χ 2 = 6·997, P < 0·05). The prevalence of escape mutations and overlapping polymerase substitutions in subgenotype C5 is significantly higher than in subgenotypes B2 and C2. In total, 7·9% of MHR mutants are escape mutations and 72·1% of MHR mutations produced amino-acid changes in the overlapping polymerase, including resistance mutations to entecavir. Our results suggest that the prevalence of MHR mutations varies with subgenotype. The prevalence of escape mutations and polymerase mutations may be associated with subgenotype.

Hepatitis B virus (HBV) infection is a critical global health issue and moderately epidemic in Western China, but HBV molecular epidemiology characteristics are still limited. We conducted this study to investigate HBV genotypes and antiviral resistant mutations in this multi-ethnic area. A total of 1316 HBV patients were recruited from four ethnic groups from 2011 to 2013. Genotypes and resistant mutations were determined by Sanger sequencing. Four genotypes (B, C, D and C/D) were identified. Genotype B and C were common in Han population, while genotype D was predominant in Uygurs. Genotype C was the major genotype in both Tibetans and Yis, and recombinant C/D was found in Tibetans only. Lamivudine resistance was common in all populations, especially in Hans with prevalence of 42.8%. Entecavir resistance was barely observed regardless of ethnicity. Genotype C isolates had higher rates of rtA181T/V than genotype B (13.5% vs. 5.1%, P < 0.001), in accordance with higher prevalence of resistance to adefovir (20.0% vs. 9.5%, P < 0.001). While incidence of resistant mutations to other drugs and clinical factors showed no difference among different genotypes. HBV genotypes and resistance-conferring mutations had different geographic and demographic distributions in Western China, which provided molecular epidemiology data for clinical management.

In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15-20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.

Aim: To evaluate the clinical outcomes of 240-wk treatment with entecavir (0.5 mg) in Chinese nucleoside-naive patients with cirrhosis., Methods: A total of 204 nucleoside-naive patients with compensated (n = 96) or decompensated (n = 108) hepatitis B virus (HBV)-induced cirrhosis at the Department of Gastroenterology of the China-Japan Union Hospital (Jilin University, Changchun, China) who were treated with entecavir (0.5 mg) for 240 wk were enrolled in this study. Liver biopsy samples obtained from 38 patients prior to treatment (baseline) and at week 240 were evaluated by different independent histopathologists. Efficacy assessments included the proportions of patients who achieved an HBV DNA level < 500 copies/mL, the association of interleukin-28B genetic variation with antivirus therapy, clinical outcomes, and histologic improvement. Changes in liver disease severity were analyzed, and liver histologic evaluation was performed in 38 patients with paired biopsies. Student t tests were used to compare the means of continuous variables between the groups, and the proportions of patients who achieved the endpoints were compared using the χ(2) test., Results: At week 240, 87.5% of the patients with compensated cirrhosis and 92.6% of the patients with decompensated cirrhosis achieved a HBV DNA level < 500 copies/mL. Three patients had genotypic entecavir resistance within the 240-wk period. No significant association was observed between virologic response and interleukin-28 genotype (CT, 88.2% vs CC, 90.6%). The proportion of patients with Child-Pugh class A disease was significantly increased at week 240 (68%) from the baseline (47%; P < 0.01). The proportion of patients with Child-Pugh class B disease was significantly decreased at week 240 (25%) from the baseline (39%; P = 0.02). In the patients with paired liver biopsies, the mean reduction in the Knodell necroinflammatory score from the baseline was 3.58 ± 1.03 points (7.11 ± 1.80 vs 3.53 ± 1.35, P < 0.01). The mean reduction in Ishak fibrosis score from the baseline was 1.26 ± 0.64 points (5.58 ± 0.50 vs 4.32 ± 0.81, P < 0.01)., Conclusion: Entecavir is an effective treatment option for patients with HBV-related compensated or decompensated cirrhosis that can result in sustained virologic suppression and histologic improvement.

Aim: To develop models to predict hepatitis B e antigen (HBeAg) seroconversion in response to interferon (IFN)-α treatment in chronic hepatitis B patients., Methods: We enrolled 147 treatment-naïve HBeAg-positive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment. Patients were tested for serum alanine aminotransferase (ALT), hepatitis B virus-DNA, hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen, HBeAg, antibody to hepatitis B e antigen (anti-HBe), and antibody to hepatitis B core antigen (anti-HBc) at baseline and 12 wk, 24 wk, and 52 wk after initiating treatment. We performed univariate analysis to identify response predictors among the variables. Multivariate models to predict treatment response were constructed at baseline, 12 wk, and 24 wk., Results: At baseline, the 3 factors correlating most with HBeAg seroconversion were serum ALT level > 4 × the upper limit of normal (ULN), HBeAg ≤ 500 S/CO, and anti-HBc > 11.4 S/CO. At 12 wk, the 3 factors most associated with HBeAg seroconversion were HBeAg level ≤ 250 S/CO, decline in HBeAg > 1 log10 S/CO, and anti-HBc > 11.8 S/CO. At 24 wk, the 3 factors most associated with HBeAg seroconversion were HBeAg level ≤ 5 S/CO, anti-HBc > 11.4 S/CO, and decline in HBeAg > 2 log10 S/CO. Each variable was assigned a score of 1, a score of 0 was given if patients did not have any of the 3 variables. The 3 factors most strongly correlating with HBeAg seroconversion at each time point were used to build models to predict the outcome after IFN-α treatment. When the score was 3, the response rates at the 3 time points were 57.7%, 83.3%, and 84.0%, respectively. When the score was 0, the response rates were 2.9%, 0.0%, and 2.1%, respectively., Conclusion: Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-α therapy.

Aim: To investigate the prevalence of nature tyrosine-methionine-aspartic acid-aspartic acid motif mutations in chronic hepatitis B (CHB) patients and to evaluate the efficacy of lamivudine., Methods: A total of 1268 CHB patients were recruited from the outpatient and inpatient departments of six centers. Tyrosine-methionine-aspartic acid-aspartic acid (YMDD) mutations were analyzed using the hepatitis B virus (HBV) drug resistance line probe assay. Forty voluntary patients were selected from those with positive or negative natural YMDD mutations to undergo treatment with lamivudine., Results: YMDD mutations were detected in 288 (22.71%) of the 1268 CHB patients. Multivariate analysis revealed that the patients' HBV DNA level (P=0.0282) and hepatitis B e antigen status (P=0.0133) were also associated with natural YMDD mutations. The rates of normalization of alanine aminotransferase levels and HBV DNA nondetection at 6, 24, 36, and 48 wk were compared between the patients with natural YMDD mutations and those without, and the differences were not significant. However, there was a significant difference in the cumulative emergence rates of virological breakthrough at 48 wk in the patients with natural YMDD mutations and those without (32.5% vs 12.5%, P=0.032)., Conclusion: Naturally occurring YMDD mutations are detectable in a large proportion of CHB patients; breakthrough hepatitis tended to occur in patients with natural YMDD mutations.

Aim: To observe the effect of response-guided add-on therapy with adefovir (ADV) and lamivudine (LAM) in cirrhotic hepatitis B (CHB) patients., Methods: A total of 100 patients with CHB and cirrhosis were divided into three arms according to hepatitis B virus (HBV) DNA level after 24 wk LAM monotherapy: Arm A (complete response, HBV DNA ≤ 60 IU/mL, n = 49), Arm B (partial response, HBV DNA: 60-2000 IU/mL, n = 31) and Arm C (inadequate response, HBV DNA > 2000 IU/mL, n = 20). ADV was added to LAM at week 48 in Arms A and B, but at week 24 in Arm C. Virological response, YMDD mutations, biochemical response, and liver function were evaluated., Results: Comparison of the three arms demonstrated that early complete virologic response at week 24 was associated with maintained viral suppression (undetectable rate of HBV DNA at week 144 was 95.96%, 66.67% and 35.29%, respectively, P = 0.000) and reduced YMDD mutations (mutation rate at week 144 was 0%, 3.23% and 15%, respectively, P = 0.015) after 144 wk treatment. For patients who failed to achieve complete virological response at week 24, switching to combination therapy further decreased HBV DNA level by 1 log10 IU/mL. All three arms obtained biochemical benefits including decline of alanine aminotransferase and elevation of albumin. In patients who developed HBV DNA breakthrough for YMDD mutations, ADV add-on therapy did not induce further multiple drug resistance to LAM or ADV., Conclusion: Optimized response-guided add-on therapy of ADV and LAM maintains long-term suppression of HBV DNA and improves liver function in CHB patients with compensated liver cirrhosis.

In order to investigate the mutation of HBV polymerase gene reverse transcription conserved region (P region) in chronic hepatitis B (CHB) patients, 212 CHB patients who took antiretroviral treatment with nucleotide analogues were chosen. The drug resistance mutations of HBV P region and HBV genotype were detected by Pyrosequencing. Sequence analysis showed that the drug resistance sites of HBV P region located at sites 173; 180; 181; 184; 204; 236 and 250. The main site of HBV P region drug resistance was 204 and 180, accounting for 35.8% and 23.5%, respectively. There were significant differences in the mutation rate of site 180 among different age groups. There were also significant differences in the mutation rate of site 204 among younger than 30 age group, 41 to 50 age group and 51 to 60 age group. (P < 0.05, P < 0.01). The mutation rate of site 180 combined with site 204 was 66.6%. The mutation rate of site 181 combined with site 236 was 23.3%. The age of C genotype infected patients was significantly older than B genotype infected patients (P < 0.01). M204V/I mutation mostly existed in the form of joint L180M mutation, the mutation rate was age-related. The detection of HBV genotypes and drug resistance sites of HBV P region have important clinical implications for the treatment and prognosis of patients with CHB.

Background: This study aimed to clarify the clinical significance of drug-resistant HBV in nucleoside/nucleotide analogue (NA)-naive Chinese patients with chronic HBV infection in real clinical practice., Methods: A total of 845 NA-naive patients who were admitted to Beijing 302 Hospital between July 2007 and March 2012 were included in the study. HBV drug-resistant mutations were examined by direct sequencing of the viral reverse transcriptase gene and verified by clonal sequencing. Phenotypic analysis of viral replication capacity and drug susceptibility were performed by measuring viral replicative intermediate level in 1.1-mer mutant or wild-type HBV amplicon-transfected HepG2 cells in absence or presence of serially diluted drugs., Results: Drug-resistant mutations were detected in 2.01% (17/845) of the patients by direct sequencing, including 15 with lamivudine-resistant mutations (rtM204V, rtM204I), one with adefovir-resistant mutation (rtA181V), and one with both lamivudine- and adefovir-resistant mutations (rtA181V, rtM204I). Clonal sequencing identified 13 drug-resistant HBV strains: rtL80I+M204I, rtL80I+M204V, rtL180M+M204I, rtL180M+M204V, rtM204I, rtM204V, rtL80I+L180M+M204I, rtL80I+L180M+M204V, rtA181V, rtA181V+M204I, rtA181T+N236T, rtA181V+N236T and rtN236T. Phenotypic analysis showed that two pre-existing lamivudine-resistant strains (rtL80I+M204I, rtL180M+M204V) had >1,000-fold resistance to lamivudine, and one pre-existing adefovir-resistant strain (rtA181V+N236T) had 15.4-fold resistance to adefovir compared with the wild-type strain. A follow-up study showed that the presence of pre-existing rtM204I strain in one patient increased from 20% at baseline to 85% after 13 months of entecavir treatment with corresponding recession of wild-type strain in the viral pool., Conclusions: The incidence of drug-resistant HBV mutations was low in NA-naive Chinese HBV-infected patients. Pre-existing mutants had similar resistance characteristics to those from NA refractory patients.

A high prevalence of the rtI187V polymerase substitution of hepatitis B virus (HBV) was detected in nucleoside/nucleotide-analogue-naive and -treated chronic hepatitis B (CHB) patients. We aimed at assessing the replicative capacity and susceptibility to lamivudine (LAM) and adefovir (ADV) in vitro of HBV harbouring rtI187V alone or in conjunction with LAM- or ADV-resistant mutations. The reverse transcriptase region of HBV isolates was directly sequenced from a cohort of 300 CHB patients from China. Replication-competent HBV constructs containing rtI187V and combined with LAM-resistant (rtM204I, rtL180M/rtM204V) mutations were generated, and compared with WT, LAM-resistant single (rtM204I) or double (rtL180M/rtM204V) and ADV-resistant (rtN236T) clones. In a Chinese cohort of 300 CHB patients, 8.7 % (26/300) showed substitution of rtI187 with V. Of note, the rtI187V prevalence in HBV genotype B was significantly higher than that in HBV genotype C (95.2 vs 4.8 %). In vitro phenotypic assays showed that the viruses bearing the rtI187V substitution had impaired replication efficacy when compared with the WT and the virus carrying rtI187V combined with LAM-resistant single or double mutations showed even more significantly impaired replicative capacities. Furthermore, rtI187V HBV remained susceptible towards treatment with LAM or ADV in vitro whereas the combination of the rtI187V substitution with LAM-resistant mutations rendered HBV resistant to LAM but still sensitive to ADV. Our study revealed that the rtI187V substitution in the HBV polymerase frequently occurred in CHB patients, particularly those with HBV genotype B. However, the emergence of the rtI187V substitution significantly impaired viral replication but without affecting drug sensitivity in vitro., (© 2014 The Authors.)

Aim: To describe a population of outpatients in China infected by hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and assess their current management status., Methods: A multicenter, cross-sectional study of HBV- and/or HCV-infected patients was conducted from August to November, 2011 in western China. Patients ≥ 18 years of age with HBV and/or HCV infections who visited outpatient departments at 10 hospitals were evaluated, whether treated or not. Data were collected on the day of visit from medical records and patient interviews., Results: A total 4010 outpatients were analyzed, including 2562 HBV-infected and 1406 HCV-infected and 42 HBV/HCV co-infected patients. The median duration of documented infection was 7.5 years in HBV-infected and 1.8 years in HCV-infected patients. Cirrhosis was the most frequent hepatic complication (12.2%), appearing in one-third of patients within 3 years prior to or at diagnosis. The HCV genotype was determined in only 10% of HCV-infected patients. Biopsy data were only available for 54 patients (1.3%). Antiviral medications had been received by 58.2% of patients with HBV infection and 66.6% with HCV infection. Nucleos(t)ide analogs were the major antiviral medications prescribed for HBV-infected patients (most commonly adefovir dipivoxil and lamivudine). Ribavirin + pegylated interferon was prescribed for two-thirds of HCV-infected patients. In the previous 12 mo, around one-fifth patients had been hospitalized due to HBV or HCV infection., Conclusion: This observational, real-life study has identified some gaps between clinical practice and guideline recommendations in China. To achieve better health outcomes, several improvements, such as disease monitoring and optimizing antiviral regimens, should be made to improve disease management.

Aim: To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure (ACLF)., Methods: This was a single center, prospective cohort study. Eligible, consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100 mg/d. All patients were given standard comprehensive internal medicine. The primary endpoint was survival rate at day 60, and secondary endpoints were reduction in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels, and improvement in Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores at day 60 and survival rate at week 52., Results: One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B: 65 were included in the entecavir group and 54 in the lamivudine group (full analysis set). No significant differences were found in patient baseline clinical parameters. At day 60, entecavir did not improve the probability of survival (P = 0.066), despite resulting in faster virological suppression (P < 0.001), higher rates of virological response (P < 0.05) and greater reductions in the CTP and MELD scores (all P < 0.05) than lamivudine. Intriguingly, at week 52, the probability of survival was higher in the entecavir group than in the lamivudine group [42/65 (64.6%) vs 26/54 (48.1%), respectively; P = 0.038]. The pretreatment MELD score (B, 1.357; 95%Cl: 2.138-7.062; P = 0.000) and virological response at day 30 (B, 1.556; 95%Cl: 1.811-12.411; P =0.002), were found to be good predictors for 52-wk survival., Conclusion: Entecavir significantly reduced HBV DNA levels, decreased the CTP and MELD scores, and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.

Background and Aims: Lamivudine (LAM) is still widely used for anti-HBV therapy in China. The study aimed to clarify whether a newly-found rtM204Q mutation from patients was associated with the drug resistance., Methods: HBV complete reverse-transcriptase region was screened by direct sequencing and verified by clonal sequencing. Replication-competent plasmids containing patient-derived 1.1mer mutant or wild-type viral genome were constructed and transfected into HepG2 cells. After cultured with or without serially-diluted antiviral drugs, intracellular HBV replicative intermediates were quantitated for calculating the 50% effective concentration of drug (EC₅₀)., Results: A total of 12,000 serum samples of 9,830 patients with chronic HBV infection were screened. rtM204Q mutation was detected in seven LAM-refractory patients. By contrast, rtM204I/rtM204V mutations were detected in 2,502 patients' samples. The rtM204Q emerged either alone or in concomitance with rtM204I/rtM204V, and all were accompanied with virologic breakthrough in clinical course. Clonal sequencing verified that rtM204Q mutant was predominant in viral quasispecies of these samples. Phenotypic analysis showed that rtM204Q mutant had 89.9% of replication capacity and 76-fold increased LAM EC₅₀ of the concomitant wild-type strain. By contrast, rtM204I mutant in the sample had lower replication capacity and higher LAM resistance (46.3% and 1396-fold increased LAM EC₅₀ of the wild-type strain) compared to rtM204Q mutant. rtM204Q mutant was susceptible to adefovir dipivoxil (ADV) in vitro and ADV/ADV+LAM rescue therapy in clinic., Conclusion: rtM204Q is suggested to be a novel LAM-resistance-associated mutation. It conferred a moderate resistance with higher competent natural replication capacity compared to rtM204I mutation.

The emergence of mutations that confer drug resistance in patients with chronic hepatitis B (CHB) is increasing in China. We aimed to compare the cumulative efficacy and resistance of adefovir (ADV) monotherapy and ADV add-on lamivudine (LAM) (ADV+LAM) therapy in LAM-resistant patients. One-hundred adult CHB patients with LAM-resistance mutations were identified. Of these 100, 52 patients were treated with ADV monotherapy and 48 were treated with ADV+LAM combination therapy for at least 24 months. After 2-year treatment, the cumulative rates of serum alanine aminotransferase normalization were, respectively, 73.1 and 83.3 % in the ADV monotherapy and ADV+LAM therapy groups (P = 0.216). Additionally, 36 patients receiving ADV plus LAM had hepatitis B e antigen loss/seroconversion, as compared with 30 in patients (P = 0.068). More patients who received LAM plus ADV than those who received ADV alone had HBV DNA levels below 1,000 international unit/milliliters (83.3 vs. 50 %, P < 0.001). Viral breakthrough and genotypic mutations were detected in 19 (36.5 %) and 9 (18.8 %) patients in the ADV monotherapy and ADV+LAM therapy groups, respectively (P = 0.048). ADV+LAM combination therapy demonstrated faster and significantly greater suppression of HBV DNA compared with ADV therapy alone for patients with LAM-resistance mutations. ADV+LAM was superior to ADV monotherapy in achieving the initial viral breakthrough and genotypic mutations. ADV+LAM combination therapy was rational for most of LAM-resistant Chinese patients with chronic hepatitis B.