OBJECTIVE: We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation.
METHODS: From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors.
RESULTS: We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy.
CONCLUSIONS: The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.

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.
临床治愈（又称功能性治愈）是目前国内外慢性乙型肝炎（CHB）防治指南公认的理想治疗目标。我国在CHB临床治愈研究探索及临床实践中已取得较丰富的成果，基于聚乙二醇干扰素α的治疗策略可有效提升临床治愈率。不同临床分型人群临床治愈策略的总结与优化、临床治愈持久性及远期结局的探索，对于CHB临床治愈的发展具有重要意义。解决目前存在的瓶颈问题将是我们未来努力的方向。.

Chronic viral hepatitis causes an increased risk of progressive liver disease and hepatocellular carcinoma. On the wave of the World Health Organization\'s goal to reduce new cases and deaths from hepatitis B and C by 2030, there is an increasing call to expand the indications for treatment of chronic hepatitis B. Currently, the main goal of treatment is to achieve a functional cure due to the inability of current drugs to completely eradicate the virus. There are still many discrepancies between available guidelines in terms of eligibility for treatment as well as an uncertainty about the appropriate treatment duration. This editorial addresses key questions about the topic and whether indications for treatment should be expanded.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Objective: To study the curative effect of rehmannia glutinosa leaves total glycoside capsules and the role of mitochondrial autophagy on nucleos(t)ide drug-induced renal injury. Methods: Adefovir dipivoxil (ADV) was used to construct a hepatitis B virus (HBV) transgenic mouse model for renal injury. Renal function was measured in each group at one and two weeks of modeling. Mitochondrial autophagy indicators were measured at two weeks of modeling in renal tissue. Transmission electron microscopy was used to detect mitochondrial autophagy phenomena in renal tissue. The model was established for two weeks. Mouse with renal injury were treated with rehmannia glutinosa leaves total glycoside capsules or isotonic saline for eight weeks by intragastric administration. Renal function was measured. Renal tissue morphology was observed. Mitochondrial autophagy indicators were detected in renal tissue. The protective effect of different concentrations of verbascoside (the main active ingredient of rehmannia glutinosa capsule) was observed on HK-2 cell damage induced by ADV. HK-2 cells were divided into control, ADV, and ADV plus verbascoside groups. The effects of verbascoside at different times and concentrations were observed on the HK-2 mitochondrial autophagy indicators. Fifty patients with chronic hepatitis B were collected who presented with renal injury after treatment with nucleos(t)ide analogs. The random number method was used to divide 29 cases into a control group that received conventional treatment. The treatment group of 21 cases was treated with rehmannia glutinosa leaves total glycoside capsules on the basis of the control group. Serum creatinine (Scr) and urinary protein were detected at eight weeks.The χ(2) test or t-test was used for statistical analysis. Results: Compared with the control group, two weeks of modeling in the ADV group induced renal function injury in HBV mice. The expression of autophagy indicators was higher in the renal tissue of the ADV group than that of the control group. Transmission electron microscopy had revealed mitochondrial autophagy in the renal tissue of the ADV group. Compared with the control group, the renal function of HBV mice treated with rehmannia glutinosa leaves total glycoside capsules improved for two months, and the expressions of autophagy indicators were down-regulated.Verbascoside promoted proliferation in ADV-damaged HK-2 cells, and the expression of autophagy indicators was down-regulated compared with the ADV alone group. In 50 patients with renal function injury, the urinary protein improvement was significantly superior in the treatment group than that in the control group, with eighteen and three cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with a statistically significant difference (χ(2) = 9.975 0, P = 0.001 6). Serum creatinine was decreased in the treatment group compared with the control group, with 11 and 10 cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with no statistically significant difference (χ(2) = 0.593 5, P = 0.441 1). Conclusion: Rehmannia glutinosa leaves total glycoside capsule can improve the nucleos(t)ide drug-induced renal function injury in chronic hepatitis B, possibly playing a role via inhibiting PINK1/Parkin-mediated mitochondrial autophagy.
目的： 研究地黄叶总苷胶囊对核苷类药物所致肾损伤的疗效及线粒体自噬的作用。 方法： 使用阿德福韦酯（ADV）建立乙型肝炎病毒（HBV）转基因乙型肝炎小鼠肾损伤模型，造模1周及2周检测各组肾功能，造模2周时检测肾脏组织线粒体自噬指标，透射电镜检测肾脏组织线粒体自噬现象。后分别予地黄叶总苷胶囊或等渗盐水对肾损伤小鼠灌胃治疗8周，检测肾功能，观察肾脏组织形态并检测肾脏组织线粒体自噬指标。观察不同浓度毛蕊花糖苷（地黄叶总苷胶囊主要有效成分）对ADV引起HK-2细胞损伤后的保护作用。将HK-2细胞分为对照组、ADV以及ADV加毛蕊花糖苷组。观察不同时间及不同浓度毛蕊花糖苷对HK-2细胞线粒体自噬指标的影响。收集50例使用核苷（酸）类似物治疗后出现肾损伤的慢性乙型肝炎患者。随机数法分为对照组29例按常规治疗，治疗组21例在对照组的基础上给予地黄叶总苷胶囊治疗，8周检测血清肌酐（Scr）、尿蛋白。统计学方法用χ(2) 或t检验。 结果： ADV组造模2周引起HBV小鼠肾功能损伤，ADV组肾组织自噬指标表达高于对照组；透射电镜观察到ADV组肾脏组织线粒体自噬现象。与对照组相比，地黄叶总苷胶囊治疗2个月HBV小鼠肾功能好转，自噬指标表达下调。毛蕊花糖苷促进ADV损害的HK-2细胞的增殖，且较单独ADV组自噬指标表达下调。50例有肾功能损伤的患者中，治疗组的尿蛋白改善显著优于对照组，治疗组有效18例、无效3例，对照组有效12例、无效17例，差异有统计学意义（χ(2) = 9.975 0，P = 0.001 6）。治疗组血肌酐减低，治疗组有效11例、无效10例，对照组有效12例、无效17例，2组差异无统计学意义（χ(2) = 0.593 5，P = 0.441 1）。 结论： 地黄叶总苷胶囊可改善核苷（酸）类似物所致慢性乙型肝炎的肾功能损伤，可能通过抑制PINK1/PARKIN介导的线粒体自噬发挥作用。.

There are estimated 300 million people afflicted with chronic hepatitis B (CHB) worldwide. The risk of liver cirrhosis and hepatocellular carcinoma (HCC) increases considerably with chronic hepatitis B infection. While current therapeutics are effective in controlling hepatitis B virus (HBV) infection and disease progression, a cure for HBV infection remains unattainable due to an intranuclear replicative intermediate known as covalently closed circular DNA (cccDNA). It has recently been shown that serum HBV RNA is a non-invasive biomarker that reflects cccDNA transcriptional activity. This review provides a comprehensive overview and the latest updates on the molecular characteristics and clinical significance of serum HBV RNA, such as species of serum HBV RNA, forms of serum HBV RNA carriers and predictive value for relapses in CHB patients after nucleos(t)ide analogues (NAs) discontinuation and development of liver fibrosis and HCC. Furthermore, we summarize standardized assays for testing serum HBV RNA, the dynamic changes of serum HBV RNA levels in treatment-naïve CHB patients and those under NAs therapy, as well as the host and viral influencing factors of serum HBV RNA levels. Finally, we discuss the future perspectives in studies of serum HBV RNA.

Objective: To investigate the hepatitis B surface antigen (HBsAg) clearance condition and its predictive factors after treatment with nucleos(t)ide analogues to pegylated interferon-α add-on therapy in patients with chronic hepatitis B. Methods: Patients with chronic hepatitis B who visited the First Affiliated Hospital of Zhengzhou University from 2018~2019 were prospectively enrolled. HBsAg≤ 1500 IU/mL, hepatitis B e antigen-negative, HBV DNA undetectable, received antiviral treatment with nucleos(t)ide analogues for at least one year, and pegylated interferon-α add-on therapy for 48 weeks were included. The primary endpoint of study was to determine the proportion of HBsAg clearance at 72 weeks. Concurrently, the predictive factors for HBsAg clearance were analyzed. Quantitative and qualitative data were analyzed using a t-test or non-parametric test and a Fisher\'s exact test. Results: A total of 38 cases were included in this study, of which 13 cases obtained HBsAg clearance at 48 weeks of therapy and another six cases obtained HBsAg clearance throughout the extended treatment period of 72 weeks, accounting for 50.00% of all enrolled patients. There was a significant difference in HBsAg dynamics between the HBsAg clearance group and the non-clearance group (P < 0.05). Univariate logistic regression analysis showed that patients\' age, baseline, 12-and 24-week HBsAg levels, and early HBsAg reduction were predictive factors for HBsAg clearance at 72 weeks of treatment. Multivariate logistic regression analysis showed that age (OR = 1.311; P = 0.016; 95% confidence interval: 1.051~1.635) and HBsAg levels at 24 weeks of treatment (OR = 4.481; P = 0.004; 95% confidence interval: 1.634~12.290) were independent predictors for HBsAg clearance. Conclusion: Hepatitis B e antigen-negative, nucleos(t)ide analogue treated, HBsAg ≤ 1500 IU/mL, and HBV DNA undetectable, peg-IFNα add-on treatment for 48 weeks could promote HBsAg clearance in patients with chronic hepatitis B. Six of the sixteen cases (37.50%) who did not obtain HBsAg clearance at week 48 did so with the course of therapy extended to week 72. Hence, the optimal individualized treatment strategy should be customized according to the predictors rather than the fixed 48-week course. Age (≤ 38), baseline HBsAg level (≤2.86 log(10)IU/ml), HBsAg level at 24 weeks (≤ 0.92 log(10)IU/ml), and 12-week HBsAg decrease from baseline (≥ 0.67 log(10)IU/ml) indicate that patients are highly likely to obtain HBsAg clearance at the 72 weeks of combination therapy, in which the combined indicator based on HBsAg level ≤0.92 log(10)IU/ml at 24 weeks will identify 85.0% to 100.0% of patients with HBsAg clearance.
目的： 探讨核苷（酸）类似物经治慢性乙型肝炎患者加用聚乙二醇干扰素α治疗后乙型肝炎表面抗原(hepatitis B surface antigen，HBsAg)清除情况及其预测因素。 方法： 前瞻性纳入2018至2019年在郑州大学第一附属医院就诊、HBsAg ≤ 1 500 IU/ml、乙型肝炎e抗原阴性、HBV DNA不可测且接受核苷（酸）类似物抗病毒治疗至少1年的慢性乙型肝炎患者，给予加用聚乙二醇干扰素α治疗48周，主要研究终点是72周时HBsAg清除的比例，同时分析HBsAg清除的预测因素。用t检验或非参数检验分析定量数据，Fisher精确检验分析定性数据。 结果： 研究共纳入38例患者，其中13例患者在治疗48周时获得了HBsAg清除，另有6例患者在疗程延长至72周治疗期间获得了HBsAg清除，占全部入组患者的50.00%。比较HBsAg清除组和未清除组间的HBsAg动力学整体上差异有统计学意义(P<0.05)。单因素logistic回归分析结果显示，患者年龄及基线、12周、24周时HBsAg水平和治疗早期HBsAg下降幅度是治疗72周时HBsAg清除的预测因素；多因素logistic回归分析结果显示：年龄(OR值= 1.311；P = 0.016；95%置信区间：1.051～1.635)和治疗24周时HBsAg水平(OR值=4.481，P = 0.004；95%置信区间：1.634～12.290)是HBsAg清除的独立预测因素。 结论： 对核苷（酸）类似物经治、HBsAg ≤ 1 500 IU/ml、HBV DNA不可测的乙型肝炎e抗原阴性慢性乙型肝炎患者，加用Peg-IFNα治疗48周可促进HBsAg清除；在48周时未获得HBsAg清除的16例患者，将疗程延至72周后，其中6例患者(37.50%)也获得了HBsAg清除，因此需要根据预测指标定制最佳个体化治疗策略，而并非48周固定疗程；年龄(≤ 38岁)、基线HBsAg水平(≤ 2.86 log(10)IU/ml)、24周时HBsAg水平(≤ 0.92 log(10)IU/ml)和12周HBsAg自基线下降幅度(≥ 0.67 log(10)IU/ml)提示患者很大可能在联合治疗72周时获得HBsAg清除，其中基于24周时HBsAg水平≤0.92 log(10) IU/ml的联合指标将识别出85%～100%可能获得HBsAg清除的患者。.

Chronic hepatitis B (CHB) remains a major world\'s most serious public health issues. Despite the remarkable effect of nucleos(t)ide analogues (NAs) in inhibiting hepatitis B virus (HBV) deoxyribonucleic acid (DNA) as the first-line drug, there are several limitations still, such as poor antigen inhibition, drug resistance, low-level viremia, restricting patients\' functional cure. Due to the constraints of NAs, traditional medicines, such as traditional Chinese medicine (TCM), have become more prevalently used and researched in the clinical treatment of CHB as complementary alternative therapies. As a consequence, the review focuses on the background based on HBV\'s life cycle as well as the NAs\' limitations, progress based on direct and indirect pathway of targeting HBV of TCM, and challenges of TCM. We found TCMs play an increasingly important role in anti-HBV. In a direct antiviral way, they regulate HBV infection, replication, assembly, and other aspects of the HBV life cycle. As for indirect way, TCMs can exert anti-HBV effects through targeting the host, including immune regulation, apoptosis, autophagy, oxidative stress, etc. Especially, TCMs have the advantages of strong antigenic inhibition compared to NAs. Specifically, we can combine the benefits of TCMs in strong HBV antigen inhibition with the benefits of NAs in targeted antiviral effects, in order to find a suitable combination of \"TCM + NAs\" to contribute to Chinese knowledge of the realisation of the \"global elimination of HBV by 2030\" goal of the World Health Organization.

Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by 65% in a short period. Nevertheless, globally, only 2.2% of CHB patients undergo antiviral therapy. The HBV markers related to HCC occurrence and prevention are as follows: the HCC risk is the highest at a baseline of HBV DNA of 6-7 log copies/mL, and it is the lowest at a baseline of an HBV DNA level of >8 log copies/mL and ≤4 log copies/mL (parabolic, and not linear pattern). The titer of an HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. The seroclearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of the secondary prevention of hepatitis B-related HCC involving antiviral therapies with nucleos(t)ide analogues (NAs), unsolved issues include the definition of the immune-tolerant phase; the optimal time for starting antiviral therapies with NAs; the limits of increased aminotransferase (ALT) levels as criteria for therapy in CHB patients; the normalization of ALT levels with NAs and the relation to the risk of HCC; and the relation between serum HBV levels and the risk of HCC. Moreover, the first-line therapy with NAs including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) remains to be clarified. Discussed here, therefore, are the recent findings of HBV markers related to HCC occurrence and prevention, unsolved issues, and the current secondary antiviral therapy for the prevention of HBV-related HCC.

Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection.
B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA). Eligibility criteria included HBsAg > 100 IU/mL, HBV DNA < 90 IU/mL (On-NA) or > 2000 IU/mL (Not-on-NA), and alanine aminotransferase ≤ 2 × upper limit of normal (ULN; On-NA) or < 3 × ULN (Not-on-NA). Participants were randomized 3:3:3:1 to one of four treatment arms, with treatment administered weekly as subcutaneous injections with or without loading doses (LD) on days 4 and 11: bepirovirsen 300 mg (with 300 mg LD) for 24 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then bepirovirsen 150 mg for 12 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then placebo for 12 weeks; placebo for 12 weeks (with placebo LD) then bepirovirsen 300 mg without LD for 12 weeks.
The primary endpoint of the study was HBsAg < lower limit of detection and HBV DNA < lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication. The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022. The novel design of the B-Clear study will allow assessment of HBsAg and HBV DNA seroclearance post bepirovirsen treatment discontinuation in the presence and absence of background NA therapy.
ClinicalTrials.gov (NCT04449029; GSK study 209668).