益气活血方治疗慢性病毒性肝炎肝纤维化的临床研究

目的明确益气活血方治疗慢性病毒性肝炎肝纤维化的临床疗效。方法采用开放、阳性药平行对照研究的方法,选取经肝穿活组织学及肝脏瞬时弹性成像技术检查确诊的慢性乙型及丙型肝炎肝纤维化患者207例,根据中医辨证施治的原则,分别采用自拟益气活血方(n=127)和扶正化瘀胶囊(n=80)治疗,疗程均为24~48周。对比分析两组患者中医症候积分、肝脏生化学、肝脏硬度值(LSM)、无创性肝纤维化指数[天冬氨酸转氨酶与血小板比值指数(APRI)、基于4因子的肝纤维化指标(FIB-4)]的变化,评估益气活血方抗肝纤维化疗效。结果益气活血方组和扶正化瘀胶囊组患者基线LSM、APRI、FIB-4比较,P值均>0.05,差异均无统计学意义。应用益气活血方和扶正化瘀胶囊患者症候积分均有一定程度改善,益气活血方在改善肝病面容、肝区不适及腰膝酸软方面优于扶正化瘀胶囊(P<0.05);肝脏生物化学指标(丙氨酸转氨酶、天冬氨酸转氨酶、γ-谷氨酰转移酶、碱性磷酸酶)随疗程延长逐渐复常,治疗24~48周复常率两组分别为100%对比100%、100%对比93.8%、96.8%对比92.3%及87.5%对比81.8%。治疗12周后两组APRI值均显著降低;治疗48周,两组LSM显著改善;而FIB-4显著改善仅见于益气活血方治疗48周,与扶正化瘀治疗组比较差异有统计学意义,P<0.05。两组治疗后LSM、APRI、FIB-4的总有效率分别为80.0%对比63.6%,P=0.046;68.4%对比52.0%,P=0.052;68.4%对比62.0%,P=0.437;益气活血方治疗患者LSM总有效率显著高于扶正化瘀胶囊治疗组。结论中药益气活血方可作为治疗慢性病毒性肝炎肝纤维化的优选方案。     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment

BackgroundAlthough concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment.MethodsIn the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72.ResultsA total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/m² (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥ 23 kg/m² (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH.ConclusionsLower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.     

Hepatocellular carcinoma risk in HBeAg‐negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first‐line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg‐negative CHB patients treated with entecavir. HBeAg‐negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0–4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion , our large nationwide study indicates that the HCC risk remains increased in entecavir‐treated HBeAg‐negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.     

Clinical efficacy of antiviral therapy in patients with hepatitis B-related cirrhosis after transjugular intrahepatic portosystemic shunt

BACKGROUNDAs a country with a high burden of hepatitis B, China has about 86 million cases of hepatitis B virus infection, ranking the first in the world. Currently, there are about 390000 deaths due to hepatitis B-related complications such as liver cirrhosis and liver cancer every year. Consequently, how to control portal hypertension, improve liver functional reserve, and reduce the incidence of hepatic failure and liver cancer in such patients is the focus of current clinical attention. Previous clinical study in our center suggested that at 24 mo after transjugular intrahepatic portosystemic shunt (TIPS), the liver functional reserve of patients with hepatitis B cirrhosis was better than that of patients with alcohol-induced and immune cirrhosis, which may be related to the effective etiological treatment.AIMTo investigate the clinical efficacy of three first-line antiviral drugs recommended by the guidelines of prevention and treatment for chronic hepatitis B in China (2019) in the treatment of patients with hepatitis B-related cirrhosis who had received a TIPS.METHODSThe clinical data of 137 patients with hepatitis B-related cirrhosis with portal hypertension after receiving TIPS at our centre between March 2016 and December 2020 were analysed retrospectively. According to different anti-viral drugs, the patients were divided into entecavir (ETV) (n = 70), tenofovir alafenamide fumarate (TAF) (n = 32), and tenofovir disoproxil fumarate (TDF) (n = 35) groups. The cumulative incidence of hepatic encephalopathy and hepatocellular carcinoma, survival, and changes in hepatic reserve function and glomerular filtration rate in patients treated with different antiviral drugs within 24 mo after surgery were investigated.RESULTSAt 24 mo after surgery, the Child–Pugh score in the TAF group (6.97 ± 0.86) was lower than that in the TDF (7.49 ± 0.82; t = -2.52, P = 0.014) and ETV groups (7.64 ± 1.17; t = -2.92, P = 0.004). The model for end-stage liver disease score in the TAF group at 24 mo after surgery was 9.72 ± 1.5, which was lower than that in the TDF (10.74 ± 2.33; t = -2.09, P = 0.040) and ETV groups (10.97 ± 2.17; t = -2.93, P = 0.004). At 24 mo after surgery, the estimated glomerular filtration rate (eGFR) in the TAF group (104.41 ± 12.54) was higher than that in the TDF (93.54 ± 8.97) and ETV groups (89.96 ± 9.86) (F = 21.57, P < 0.001).CONCLUSIONAt 24 mo after surgery, compared with TDF and ETV, TAF has significant advantages in the improvement of liver functional reserve and eGFR.     

恩替卡韦治疗失代偿期乙型肝炎肝硬化患者48周临床观察

目的观察恩替卡韦治疗乙型肝炎肝硬化患者48周疗效。方法采用随机、对照队列研究方法,将98例乙型肝炎肝硬化患者分成三组,恩替卡韦（ETV）组32例,拉米夫定（LAM）组42例,对照组24例,采用常规保肝对症治疗,疗程均为48周。观察治疗不同时间点患者的病毒学、生化学、凝血酶原时间（PT）、肝纤维化指标及Child-Pugh计分等变化情况。结果 ETV组患者HBV DNA水平显著下降,由治疗前的（6.6±1.0）log10拷贝/ml分别降低为治疗后12周、24周和48周的（3.1±1.2）、（2.8±1.1）和（2.8±1.0）log10拷贝/ml,HBV DNA转阴率优于LAM组和对照组,12周、24周、48周时依次为（59.4%、31.0%、0.0%;84.4%、66.7%、0.0%;87.5%、69.0%、0.0%）,差异均有统计学意义（P〈0.05）。在24和48周ETV组患者血清HBeAg阴转率及HBeAg/抗-HBe血清学转换率（47.6%,23.8%;52.4%,38.1%）与对照组（0.0%、0.0%;0.0%,0.0%）比较,差异有统计学意义（P〈0.05）。ALT、AST、TBil明显下降,肝纤维化指标改善,Child-Pugh计分下降,在24和48周,ETV组和LAM组较治疗前比较差异有统计学意义（P〈0.05）。结论 ETV治疗乙型肝炎肝硬化患者能有效、快速抑制病毒复制,改善肝功能、肝纤维化指标及Child-Pugh计分等。     

Early steep decline of liver stiffness predicts histological reversal of fibrosis in chronic hepatitis B patients treated with entecavir

It is unknown whether dynamic changes of liver stiffness measurement (LSM) can predict the reversibility of fibrosis. Therefore, we evaluated the utility of LSM changes in predicting histological changes of fibrosis in patients with chronic hepatitis B (CHB) on antiviral therapy. In a prospective cohort of CHB patients treated with entecavir, virological measurement and biochemical measurement along with LSM were measured at baseline and every 6 months. Liver biopsies were conducted at baseline and month 18 of treatment. Fibrosis regression was defined by the following two criteria: (a) Ishak score decrease ≥1 stage, (b) Ishak score decrease ≥1 stage or predominantly regressive by post‐treatment PIR classification. The dynamic changes of LSM and its predictive value for histological reversibility were evaluated with piecewise linear mixed‐effects model and ROC analysis. We found that at month 18 of antiviral therapy, liver fibrosis was reserved in 86 of 212 (40.6%) CHB patients by Ishak reversal criterion. Overall, a decline in LSM was associated with attenuation of Ishak score. The rate of LSM decline in the first 6 months was significantly faster in patients with fibrosis reversal (ΔLSM%_Ishak = ?2.19%/month, P = 0.0025; ΔLSM%_Ishak/PIR = ?2.56%/month, P = 0.0004). The predictive model based on baseline FIB‐4 and Ishak score as well as baseline LSM, PLT, albumin and their changes during the first 6 months could predict histological reversal (AUROC_Ishak = 0.74, 95% CI: 0.67‐0.80; AUROC_Ishak/PIR = 0.81, 95% CI: 0.74‐0.87). We conclude that in CHB patients, changes in LSM during the first 6 months of entecavir therapy can predict histological reversibility of liver fibrosis at month 18 of antiviral therapy.     

Quantitative HBcrAg and HBcAb versus HBsAg and HBV DNA in predicting liver fibrosis levels of chronic hepatitis B patients

ObjectiveTo evaluate the performance of the quantitative markers of hepatitis B core-related antigen (HBcrAg) and anti-hepatitis B core antigen antibodies HbcAb versus hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV DNA) in predicting liver fibrosis levels in chronic hepatitis B patients.MethodsTwo hundred and fifty hepatitis B e antigen (HBeAg)-positive and 245 HBeAg-negative patients were enrolled. With reference to the Scheuer standard, stage 2 or higher and stage 4 liver disease were defined as significant fibrosis and cirrhosis, respectively. A receiver operating characteristic (ROC) curve was used to evaluate the performance of the HBV markers investigated.ResultsThe areas under the ROC curves (AUCs) of HBcrAg in predicting significant fibrosis and cirrhosis in HBeAg-positive patients (0.577 and 0.700) were both close to those of HBsAg (0.617 and 0.762) (both P > 0.05). In HBeAg-negative patients (0.797 and 0.837), they were both significantly greater than those of HBV DNA (0.723 and 0.738) (P = 0.0090 and P = 0.0079). The AUCs of HBcAb in predicting significant fibrosis and cirrhosis in HBeAg-positive patients (0.640 and 0.665) were both close to those of HBsAg. In HBeAg-negative patients (0.570 and 0.621), they were both significantly less than those of HBcrAg (P < 0.0001 and P = 0.0001). Specificity in predicting significant fibrosis and sensitivity in predicting cirrhosis in HBeAg-positive patients, using a single cut-off of HBsAg ≤5,000 IU/ml, were 76.5% and 72.7%, respectively. In HBeAg-negative patients, using a single cut-off of HBcrAg >80kU/ml, they were 85.9% and 81.3%, respectively.ConclusionsHBsAg has good performance in predicting liver fibrosis levels in HBeAg-positive and HBeAg-negative patients, and HBcrAg has very good performance in predicting liver fibrosis levels in HBeAg-negative patients.     

Efficacy and safety of glecaprevir/pibrentasvir treatment in Koreans with chronic hepatitis C: A retrospective study

Background and study aimsThe introduction of direct-acting antiviral (DAA) drugs has dramatically improved chronic hepatitis C (CHC) treatment. The pangenotype DAA therapy glecaprevir/pibrentasvir (G/P) was recently recommended for treating CHC in Korea. Unfortunately, given its recent introduction, little real-world data from a Korean population exists. We examined the effectiveness and safety of G/P treatment in Koreans with CHC.Patients and methodsWe analyzed CHC patients at Samsung Changwon Hospital from June 2018 to December 2020. Sustained virologic response at 12 weeks posttreatment (SVR 12) was evaluated after treatment, and the associated factors were analyzed. Furthermore, the degree of liver fibrosis before and after treatment was compared to determine whether liver fibrosis improved.ResultsIn total, 102 patients were enrolled; 35.3 % had compensated liver cirrhosis (LC), and 11.8 % had received previous treatment. Of the 102 patients, 99 (97.1 %) reached SVR 12. Of the 81 patients who completed 8 weeks of G/P treatment, 80 (98.8 %) reached SVR 12, while 19 of the 21 (90.5 %) patients in the 12- or 16-week group reached SVR 12, with no significant difference between the two groups (P = 0.107). As a secondary endpoint, liver fibrosis before and after treatment was also compared. The Fibrosis-4 index (FIB-4) (3.3 vs 2.8, P = 0.010), aspartate transaminase (AST)-platelet ratio index (APRI) (1.3 vs 1.0, P < 0.001), and liver stiffness measurements (LSM) (9.5 vs 4.6, P < 0.001) were significantly different after G/P treatment.ConclusionsRegardless of genotype, G/P treatment for Koreans with CHC is safe, highly effective, and can improve liver fibrosis.     

直接抗病毒药物治疗慢性丙型肝炎48周临床观察

背景慢性丙型肝炎(chronic hepatitis C,CHC)是全球公共卫生问题,随着直接抗病毒药(direct antiviral therapy,DAA)在中国的应用,DAA药物成为目前国内慢性丙型肝炎抗病毒一线方案,但目前真实世界DAA治疗后长期疗效数据尚少.目的观察慢性丙型肝炎患者接受直接抗病毒药物抗病毒治疗后48 wk病毒学应答及临床疗效.方法连续收集2018-04-01/2020-04-30在天津市第三中心医院接受DAA治疗的初治CHC患者,评估治疗基线、治疗结束、治疗后12 wk及48 wk的病毒学应答及肝肾功能、肝硬度、APRI及临床结局.结果共收集291例应用DAA治疗的CHC患者,纳入145例完成抗病毒治疗及随访的CHC患者进入本研究.其中肝硬化患者占28.3%,基因型1b、2a、3a、6a分别占78.0%、17.2%、2.8%、2.0%.DAA治疗结束、治疗后12 wk及48 wk获得持续病毒学应答(sustained virological response,SVR)比例分别为100%、97.9%和97.2%,其中基因型1b、2a、3a、6a的SVR48分别为97.3%、96%、100%、100%.治疗结束后48 wk与基线相比较,丙氨酸氨基转移酶、天冬氨酸氨基转移酶、总胆红素及白蛋白的复常率分别为93.2%、91.7%、73.3%及97.7%.治疗结束后48 wk肝硬度(liver stiffness measurement,LSM)及APRI与基线水平相比均明显下降(LSM 12.5 vs 10.2kpa P<0.01;APRI 0.34 vs 0.13 P<0.01),肝硬化组及非肝硬化组患者均有明显下降(P<0.05).48 wk随访期间,其中4例(2.8%)CHC患者进展为肝硬化,8例(5.6%)肝硬化患者进展为肝硬化失代偿,3例(2.1%)肝硬化患者发生新发肝细胞癌(hepatocellular carcinoma,HCC).结论本研究真实世界中慢性丙型肝炎患者应用DAA治疗后48 wk,总体病毒持续应答率较高,肝功能、肝硬度及APRI值均明显改善.2.1%患者出现新发HCC.     

Long‐term entecavir or tenofovir disoproxil fumarate therapy in treatment‐naïve chronic hepatitis B patients in the real‐world setting

The aim of this study was to determine the long‐term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment‐naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End‐Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long‐term follow‐up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.     

Delayed viral suppression during antiviral therapy is associated with increased hepatocellular carcinoma rates in HBeAg‐positive high viral load chronic hepatitis B

The treatment option in chronic hepatitis B (CHB) patients with persistent low‐level viremia despite entecavir or tenofovir monotherapy is unclear. This study investigated the development of hepatocellular carcinoma (HCC) or cirrhosis in hepatitis B e antigen (HBeAg)‐positive high viral load CHB patients, according to the time needed to achieve complete viral suppression. A total of 325 HBeAg‐positive CHB patients with high viral load who were recently started on antiviral therapy with entecavir or tenofovir were included. The enrolled patients were divided into 2 groups with 4 separate criteria based on the time needed to achieve complete viral suppression: within 1, 2, 3 or 4 years of therapy initiation. The outcomes were development of HCC and cirrhosis. The cumulative incidence of HCC was significantly higher in patients failing complete viral suppression within 1 year (hazard ratio (HR), 4.54; 95% confidence interval (CI), 1.03‐19.93; P = .045) or 2 years (HR, 3.38; 95% CI, 1.24‐9.23; P = .018), than patients who achieved complete viral suppression within 1 or 2 years, respectively. Cumulative incidence of cirrhosis was also significantly higher in patients failing suppression within 1 year (HR, 1.95; 95% CI, 1.04‐3.66; P = .037) or 2 years (HR, 2.44; 95% CI, 1.41‐4.22; P = .001). When the time for achieving viral suppression exceeded 2 years, the cumulative incidence of HCC or cirrhosis was not different regardless of viral suppression. Complete hepatitis B virus suppression within 2 years of antiviral therapy initiation is associated with risk reduction in HCC or cirrhosis development.     

Comparison of the Efficacy of Entecavir and Tenofovir in Reducing Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients: A Real-Life Study in Turkey

BackgroundIt is controversial whether entecavir or tenofovir differs in reducing hepatocellular carcinoma (HCC) risk. We aimed to compare the efficacy of entecavir and tenofovir in reducing HCC risk in chronic hepatitis B (CHB) patients. MethodsThis retrospective study included 607 nucleos(t)ide naive CHB patients who had received entecavir or tenofovir. Patients who developed HCC during the first 12 months of therapy were excluded. Cumulative HCC incidences at years 2, 3, 4, 5 and 10 were compared between entecavir and tenofovir groups. Factors associated with HCC were determined by univariate and multivariate analyses.ResultsNineteen (3.1%) patients developed HCC, 12 (4.8%) in entecavir group and 7 (1.9%) in tenofovir group (P = .045). In the entire cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 1.8%, 2.9%, 4.4%, 5.2% and 9.9% in entecavir group, and 0.6%, 2.4%, 2.4%, 2.4% and 3.7% in tenofovir group, respectively (log-rank P = .130). In multivariate analysis, age ≥50 years, cirrhosis, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the entire cohort. In advanced fibrosis/cirrhosis cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 4.6%, 7.1%, 8.6%, 12.1% and 15.5% in entecavir group, and 1.8%, 5.6%, 5.6%, 5.6% and 8.5% in tenofovir group, respectively (log-rank P = .267). In multivariate analysis, age ≥50 years, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the advanced fibrosis/cirrhosis cohort.ConclusionEntecavir and tenofovir are similarly effective in reducing HCC risk in CHB patients.     

Hepatic steatosis leads to overestimation of liver stiffness measurement in both chronic hepatitis B and metabolic-associated fatty liver disease patients

BackgroundThe impact of hepatic steatosis on liver stiffness measurement (LSM) in both chronic hepatitis B(CHB) and metabolic-associated fatty liver disease (MAFLD) remains controversial.AimsTo determine whether LSM is affected by hepatic steatosis in CHB-MAFLD.MethodsHepatic steatosis and liver fibrosis were assessed by histological and noninvasively methods. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance of LSM.ResultsThe prevalence of MAFLD in CHB patients (n = 436)was 47.5% (n = 207). For patients with low amounts of fibrosis (F0–1 and F0–2), the median LSM was 8.8 kPa and 9.2 kPa in patients with moderate- severe steatosis,which was significantly higher than that in patients with none-mild steatosis (P < 0.05) . The positive predictive value(PPV) was lower for LSM identifying significant fibrosis (F ≥ 2) as well as severe fibrosis (F ≥ 3) in group which controlled attenuation parameter(CAP) ≥ 268 dB/m than its counterpart(68.2% vs 84.6% and 24.3% vs 45.0%). The AUROC of LSM detected F ≥ 2 was 0.833 at a cutoff of 8.8 kPa and 0.873 at a cutoff of 7.0 kPa in patients with CAP ≥ 268 and CAP < 268, respectively.ConclusionsThe presence of moderate-severe steatosis, detected by histology or CAP, should be taken into account to avoid overestimation of LSM.     

Long‐term hepatitis B surface antigen (HBsAg) kinetics during entecavir treatment in Korean patients—Functional cure unlikely

The aim of this study was to investigate the on‐treatment kinetics of quantitative HBsAg during entecavir therapy to predict the treatment period needed to achieve functional cure. From a cohort of 1009 CHB treatment‐naïve patients who were started on entecavir, the kinetics of quantitative HBsAg decline was assessed in 410 patients by a linear mixed model. The difference in the kinetics of quantitative HBsAg was determined based on the HBeAg positivity, HBeAg seroclearance and presence of baseline liver cirrhosis. Among the 410 patients, 213 patients (52.0%) were HBeAg‐positive and 217 patients (66.1%) were male with a median age of 48 years. During a median follow‐up of 53.5 months, the quantitative HBsAg level showed a slow but consistent decrease. The expected log qHBsAg levels as a function of time during entecavir treatment in HBeAg(+) and HBeAg(?) patients were 3.4773‐0.0039 × Months and 3.1853‐0.0036 × Months, respectively. The estimated time to clearance of quantitative HBsAg in our study was greater than 74.1 years in HBeAg‐positive patients and 73.5 years in HBeAg‐negative patients. The calculated time to achieve functional cure is lifelong without regard to HBeAg seroclearance or presence of liver cirrhosis. The mathematical modelling from a long‐term follow‐up of chronic hepatitis B patients on entecavir shows that HBsAg clearance requires decades of treatment. Thus, lifelong therapy is inevitable in entecavir‐treated patients to achieve functional cure.     

长期恩替卡韦经治慢性乙型肝炎患者低病毒血症的相关影响因素

目的探讨长期接受恩替卡韦治疗的慢性乙型肝炎(CHB)患者仍维持低水平病毒复制的相关影响因素。方法选取2018年11月—2020年6月于徐州医科大学附属医院门诊接受恩替卡韦抗病毒治疗至少1年的CHB患者,根据至观察期结束患者HBV DNA载量分为低病毒血症(LLV)组和持续病毒学应答(SVR)组。观察患者人口学特征参数和实验室检测指标。计量资料两组间比较采用独立样本t检验或Mann-Whitney U检验;计数资料两组间比较采用χ2检验。采用多因素logistic回归分析长期恩替卡韦经治患者出现LLV的影响因素。结果共纳入560例CHB患者,其中LLV组204例,SVR组356例。两组患者比较,年龄(Z=-3.530,P<0.001)、性别(χ2=4.270,P=0.039)、是否存在肝硬化(χ2=53.879,P<0.001)、服药依从性(χ2=5.326,P=0.021)、HBeAg阳性率(χ2=90.681,P<0.001)、治疗前基线HBV DNA载量(Z=-8.337,P<0.001)、基线HBsAg定量(Z=-10.472,P<0.001)以及用药类型(χ2=7.558,P=0.006)差异均有统计学意义。多因素logistic回归分析显示,治疗前基线HBeAg状态(OR=3.381,95%CI:1.985~5.756,P<0.001)、HBV DNA载量(OR=1.223,95%CI:1.050~1.424,P=0.010)和HBsAg定量(OR=2.448,95%CI:1.743~3.438,P<0.001)是长期恩替卡韦抗病毒治疗出现LLV的危险因素。结论在临床实践中,基线高载量HBV DNA水平、高HBsAg定量和HBeAg阳性的CHB患者即使长期坚持服用恩替卡韦抗病毒治疗,也存在较高的LLV风险。因此,对于此类人群应予以重视,需动态监测HBsAg定量、HBV DNA载量、HBeAg状态。     

扶正祛邪饮与替比夫定联合治疗对慢性乙型肝炎HBeAg血清转换作用的非随机对照研究临床观察

目的:探讨扶正祛邪饮与替比夫定联合治疗慢性乙型肝炎的疗效,重点观察HBeAg血清转换指标。方法:96例患者按意愿分为联合组50例和对照组46例,联合组患者口服替比夫定片,1次/d,600mg/次,疗程12个月。另加服扶正祛邪饮,2次/d,150ml/次,疗程6个月;对照组患者单用替比夫定,用法和疗程与联合组相同。观察两组患者治疗前后的临床症状改善、肝功能好转、HBV DNA下降、HBeAg转阴及HBeAg/抗-HBe血清转换的效果。结果:两组患者治疗后的ALT、AST、TBil、HBeAg转阴率、HBeAg/抗-HBe血清转换率、HBV DNA转阴率,与治疗前比较差异有显著性意义(P<0.01或P<0.05);两组患者治疗后的比较,联合组在ALT水平、HBeAg转阴率、HBeAg/抗-HBe血清转换率等早期应答方面优于对照组(P<0.05),联合组HBeAg转阴率、HBeAg/抗-HBe血清转换率在治疗12月时高于对照组,但差异无统计学意义(P>0.05)。结论:扶正祛邪饮联合替比夫定片治疗慢性乙型肝炎早期疗效明显,肝功能恢复较快,且能促进HBeAg转阴和HBeAg/抗-HBe血清转换提前应答,可作为慢性乙型肝炎治疗的辅助药物。     

Entecavir 1 mg versus combined lamivudine/adefovir dipivoxil in chronic HBV Egyptian patients resistant to LAM monotherapy,non-randomised controlled study

Background and study aimsThe development of antiviral-resistant mutations with long-term treatment remains a major concern in the treatment of chronic hepatitis B virus (HBV) infection. The study aimed to compare the therapeutic efficacy of entecavir 1 mg versus combined lamivudine/adefovir dipivoxil (Lam/Adv) in chronic HBV patients resistant to lamivudine monotherapy.Patients and methodsThis study included two groups of lamivudine-resistant patients who received lamivudine 100 mg for 1–3 years. Group 1 was composed of 25 cases (52% HBeAg+ve) who received combined Lam/Adv, and group 2 was composed of 13 patients (30.8% HBeAg+ve) who received entecavir 1 mg. Pre-enrolment assessment included biochemical, serological and quantitative HBV-DNA testing as well as HBeAg and hepatitis B envelope antibody (HBeAb) assessment. Evaluation was done at 3, 6, 12, 24 and 36 months of treatment by the same parameters. Hepatitis B surface antigen and antibody (HbsAg and HBsAb) were assessed after each year of treatment.ResultsAt the end of 36 months of treatment, 16 cases (69%) in group 1 completed the study period, versus 13 (100%) in group 2. Two cases in group 1 underwent HBeAg seroconversion, accompanied by HBV-DNA undetectability, at 6 and 12 months, respectively; no cases were seroconverted in group 2. Both treatments achieved improvement in alanine aminotransferase (ALT), bilirubin and alpha-foetoprotein equally at the end of the study. HBV-DNA undetectability was better achieved in group 2 when compared to group 1. HBeAg seroconversion was only achieved in two cases in group 1, whereas no cases lost HBeAg in group 2. None of our cases achieved HbsAg seroconversion or loss at the end of the study period.ConclusionThe entecavir 1-mg monotherapy group achieved better HBV-DNA undetectability starting at 3 months of treatment when compared to the Lam/Adv group; however, both lines of treatment showed almost similar results over the rest of the study period. HBeAg seroconversion was only achieved in two cases in the combined Lam/Adv group, whereas no cases lost HBeAg in the other group.     

The role of entecavir in preventing hepatitis B recurrence after liver transplantation

OBJECTIVE: Although hepatitis B recurrence after liver transplantation has been reduced to 0%–10% since the application of the combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine, the viral mutation resistance of lamivudine is still an obstacle to the outcome of liver transplantation. Here we evaluate the role of entecavir in preventing hepatitis B recurrence after liver transplantation.

METHODS:

Patients who received a liver transplantation for hepatitis B virus (HBV)‐related end‐stage liver disease in our center from March 2006 to December 2008 were enrolled in this study. All patients received entecavir (0.5 mg orally, daily) or lamivudine (100 mg orally, daily) together with a long‐term low dosage of HBIG to prevent hepatitis B recurrence after transplantation. Serum viral markers (HBsAg, anti‐HBs, HBeAg, anti‐HBc and anti‐HBe) and HBV‐DNA level were determined. RESULTS: Thirty patients receiving entecavir and 90 patients receiving lamivudine were matched with the same age and sex in both groups. No reinfection of hepatitis B was detected in the entecavir group. The hepatitis B surface antigen of patients in the entecavir group became negative within one week and no patient had any adverse effect relating to entecavir. There was no difference in the cumulative survival rate between the entecavir group and the lamivudine group (P > 0.05). CONCLUSION: This study shows that entecavir combined with low dosages of HBIG is effective and safe in preventing hepatitis B recurrence after liver transplantation, but its long‐term effect is still under investigation and a large‐sample study will be carried out in the future.     

Effects of antiviral therapy in patients with chronic hepatitis B and cirrhosis

Introduction: Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases.

Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017.

Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.