HBeAg-negative Chronic Hepatitis B Patients Research Articles

The gamma-glutamyl transpeptidase to platelet ratio predicts liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase

The gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) was proposed as a novel index for predicting liver inflammation in chronic hepatitis B (CHB) patients. We aimed to investigate GPR for predicting significant liver inflammation in CHB patients with normal (≤1×upper limit of normal, ULN) or mildly elevated (≤2×ULN) alanine transaminase (ALT). 431 treatment-naïve CHB patients with normal or mildly elevated ALT who underwent liver biopsy were enrolled. Comparision of GPR and other parameters for significant liver inflammation (G≥3). For patients with ALT≤2×ULN, the receiver-operating characteristic curves (AUROCs) of GPR in predicting significant liver inflammation were 0.837 (95%CI 0.796 to 0.878), 0.860 (95%CI 0.809 to 0.910) and 0.809 (95%CI 0.739 to 0.878) in the entire patients, HBeAg positive and HBeAg negative CHB patients, respectively. The diagnostic performance of GPR was higher than ALT (P<0.001, P<0.001, respectively), aspartate transaminase (AST) (P=0.001, P=0.003, respectively) and GGT (P=0.002, P=0.002, respectively) in the entire and HBeAg positive patients, but was comparable with AST (P=0.096) and GGT (P=0.273) in the HBeAg negative CHB patients. For patients with ALT≤1×ULN, the diagnostic accuracy of GPR was significantly higher than ALT, AST and GGT in the entire (P<0.001, P=0.008 and P=0.043, respectively) and HBeAg positive CHB patients (P<0.001, P=0.009 and P=0.024, respectively), while was comparable to AST (P=0.209) and GGT(P=0.555) in the HBeAg negative CHB patients. GPR has a better diagnostic value than conventional parameters to predict significant liver inflammation in CHB patients with normal or mildly elevated ALT levels, especially for HBeAg positive CHB.

Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B.

Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA <2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by -1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (-2.0 [1.2] vs -1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<100 IU/mL) or HBsAg loss at week 144. During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. NCT00114361.

HBV DNA and HBsAg: Early Prediction of Response to Peginterferon α-2a in HBeAg-Negative Chronic Hepatitis B.

Objective: The proportion of hepatitis e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients in China has increased rapidly. However, the response of these patients to peginterferon (peg-IFN) treatment is poor, and the antiviral treatment strategies are inconsistent. This study aimed to investigate the role of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) in early prediction of response in HBeAg-negative CHB patients receiving peg-IFN α-2a.Patients and Methods: Treatment-naïve HBeAg-negative patients were involved in this prospective study during 2014-2018. The HBV DNA and HBsAg were quantified at baseline and during treatment (weeks 12, 24 and 48) in sera. The factors associated with HBV DNA undetectable and HBsAg <100 IU/ml at treatment 48 weeks were assessed.Results: This study involved 45 patients. There was HBV DNA undetectable in 36 cases (80%), including 19 (52.8%) with HBsAg <100 IU/ml at week 48. The HBV DNA <2.0 log10IU/ml at week 24 (PPV = 96.9%, NPV = 66.7%, P = 0.018) was an independent predictor of HBV DNA undetectable at week 48. The HBsAg <800 IU/ml at baseline (PPV = 92.1%, NPV = 69.7%, P = 0.054) and HBsAg decline >5.00-fold at week 24 (PPV = 83.3%, NPV = 77.8%, P = 0.038) were independent predictors of HBsAg <100 IU/ml and HBV DNA undetectable at week 48.Conclusion: Early on-treatment quantification of HBV DNA and HBsAg in patients with HBeAg-negative CHB treated with peg-IFN α-2a may help identify those likely to be cured by this method and optimize therapy strategies.

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.

The rates of hepatitis B surface antigen (HBsAg) seroclearance after stopping nucleos(t)ide analogues (NA) in European (19% in 2years) and Asian (13% in 6years) patients with chronic hepatitis B (CHB) vary dramatically. We evaluated the incidence of hepatitis flare and HBsAg seroclearance in hepatitis B e antigen (HBeAg)-negative Chinese CHB patients who had stopped NA. This was a territory-wide retrospective study in Hong Kong. We identified HBeAg-negative CHB patients from January 2000 to December 2017 who had stopped NA treatment for more than 3months. Hepatitis flare was defined as ALT >2×ULN. The 1076 patients were predominantly middle-aged men (mean age 52years, male 74.8%) when starting NA; they stopped NA after 82±35months of treatment. At 44.3±24.6months after stopping NA, 147 (13.6%) patients had hepatitis flare, which led to resumption of NA; whereas 77 (7.2%) patients had flare but did not resume NA. Decompensation occurred in 7/914 (0.8%) patients. A total of 695 (64.6%) patients remained on NA treatment at the last visit. Eleven patients had achieved HBsAg seroclearance (6 of them had hepatitis flare and 1 of these 6 patients achieved HBsAg seroclearance after NA was restarted). Hepatic events developed in 75/695 (10.8%) patients who had NA resumed vs 43/381 (11.3%) patients who did not resume NA (P=.677). Hepatitis flare and retreatment were common in HBeAg-negative CHB patients who stopped NA treatment; whereas HBsAg seroclearance rarely occurred. Stopping NA to achieve functional cure should not be recommended at this moment.

Albumin-bilirubin score is associated with response to pegylated interferon and nucleos(t)ide analogues in chronic hepatitis B patients

Background and aimRecently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. MethodsThe ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naïve to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. ResultsALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. ConclusionsALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.

48 weeks outcome after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B patients

Introduction and objectiveThe aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection. MethodsIn 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation. ResultsThe sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50IU/mL and 1000IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses. ConclusionMonitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.

HBeAg Negativity Is Associated With More Advanced Liver Fibrosis in Patients With Chronic Hepatitis B: A Propensity Score-Matching Analysis.

Serum hepatitis B e antigen (HBeAg) status is associated with the progression of chronic hepatitis B (CHB). The authors aimed to investigate the relationship between HBeAg status and liver pathology in CHB patients. A total of 683 treatment-naive CHB patients who had undergone liver biopsy were retrospectively enrolled from 2 medical centers. Propensity score-matching (PSM) method was performed to adjust the imbalance of baseline confounders between HBeAg-positive and HBeAg-negative CHB patients. HBeAg-negative CHB patients (n=338) exhibited more advanced liver fibrosis than HBeAg-positive CHB patients (n=345) before PSM (P<0.001). However, there were no significant differences in the distribution of inflammation grades between HBeAg-positive and HBeAg-negative CHB patients (P=0.051). Of these 683 CHB patients, 123 patients were included in each group after PSM. HBeAg-negative CHB patients still showed significantly advanced liver fibrosis as compared with HBeAg-positive CHB patients (P=0.03) after PSM. Furthermore, the distribution of liver inflammation grades in the HBeAg-negative CHB patients was also more severe than patients with HBeAg-positive (P=0.037). HBeAg-negative status was identified as an independent risk factor of significant liver fibrosis (P=0.011) by multivariate analysis. HBeAg negativity is associated with more advanced liver fibrosis in CHB patients.

Cost-Effectiveness of Tenofovir Alafenamide for Treatment of Chronic Hepatitis B in Canada.

Tenofovir alafenamide (TAF) has been approved for treating chronic hepatitis B (CHB) due to a proposed better safety profile in comparison with current therapies. We evaluated the cost effectiveness of TAF and other available treatment options for hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative CHB patients from a Canadian provincial Ministry of Health perspective. A state-transition model based on the published literature was developed to compare treatment strategies involving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF. It adopted a lifetime time horizon. Outcomes measured were predicted number of liver-related deaths, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). For HBeAg-positive patients, TAF followed by ETV generated an additional 0.16 QALYs/person at an additional cost of Can$14,836.18 with an ICER of Can$94,142.71/QALY compared with TDF followed by ETV. Of the iterations, 28.7% showed that it is the optimal strategy with a Can$50,000 willingness-to-pay threshold. For HBeAg-negative patients, ETV followed by TAF would prevent an additional 13 liver-related deaths per 1000 CHB patients compared with TDF, followed by ETV. It generated an additional 0.13 QALYs/person at an additional cost of Can$59,776.53 with an ICER of Can$461,162.21/QALY compared with TDF, followed by ETV. TAF-containing strategies are unlikely to be a rational choice in either case. The results were sensitive to the HBeAg seroconversion rates and viral suppression rates of the treatments. Our analysis suggests that TAF is not cost effective at its current cost. A 33.4% reduction in price would be required to make it cost effective for HBeAg-positive patients with a Can$50,000 willingness-to-pay threshold.

Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg-negative chronic hepatitis B.

Reliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n=57) patients of the prospective DARING-B study were included and followed monthly for 3months, every 2/3months until month-12 and every 3/6months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB.

Predictors of relapse after cessation of nucleos(t)ide analog treatment in HBeAg-negative chronic hepatitis B patients: A meta-analysis

ObjectivesThe aim of this study was to identify the predictors of relapse after the withdrawal of nucleos(t)ide analog (NA) therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). MethodsThe PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched through January 2019. A random-effects model meta-analysis was performed, with hazard ratios (HR) and 95% confidence intervals (CI) used as summary statistics. ResultsSeventeen studies were included in the meta-analysis. Age (HR=1.022 per year), baseline hepatitis B surface antigen (HBsAg) (HR=1.509 per log IU/l), end of treatment (EOT) HBsAg level (HR=1.896 per log IU/l), EOT HBsAg level ≥1000 IU/ml (HR=1.749), and HBsAg decline from baseline to EOT (HR=0.748 per log IU/l) were associated with virological relapse. The predictors of clinical relapse were baseline HBsAg level (HR=1.312 per log IU/l), EOT HBsAg level (HR=1.458 per log IU/l), EOT HBsAg level ≥100IU/ml (HR=3.199) or ≥1000 IU/ml (HR=1.810), and duration of consolidation therapy (HR=0.991 per month). ConclusionsThis meta-analysis indicates that age, the duration of consolidation therapy, and levels of baseline and EOT HBsAg were factors predictive of relapse in HBeAg-negative CHB patients who discontinued NA treatment.

Predictors of sustained functional cure in hepatitis B envelope antigen‐negative patients achieving hepatitis B surface antigen seroclearance with interferon‐alpha–based therapy

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)-negative CHB patients. In this prospective study, 176HBeAg-negative CHB patients with functional cure were enrolled for 12weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3months; liver imaging examinations were performed every 3-6months during the 48-week follow-up. The sustained functional cure was evaluated. After the 48-week follow-up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment≥12weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment<12weeks (76.19% vs 90.00%, P=0.022 and 23.81% vs 9.23%, P=0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P=0.012). Consolidation treatment≥12weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135-127.151; P=0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824-37.881; P=0.006) were independent predictors of sustained functional cure. Results suggested that 12weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.

High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation.

It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT≥2 upper limit of normal (ULN). This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA<2000IU/mL and persistently normal ALT (n=3572). High viral load (HBV DNA≥2000IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n=900); Mildly active (ALT 1-2ULN, n=396); and Active (ALT≥2ULN, n=546) phases. All Active phase patients were treated with nucleos(t)ide analogues. The mean age of the patients was 47years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 - 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 - 4.21, P = 0.03) by propensity score-matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS-matched, competing risks, and multivariable-adjusted analyses. Untreated high viral load HBeAg-negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.

Efficacy and Safety of Tenofovir Disoproxil Fumarate in Treatment-Naïve Patients with Chronic Hepatitis B in Korea.

To evaluate the efficacy and safety of 144-week tenofovir disoproxil fumarate (TDF) therapy in treatment-naïve chronic hepatitis B (CHB) patients in Korean. In total, 579 treatment-naïve CHB patients at 11 medical centers were enrolled retrospective and prospective from September 2015 to January 2016 by design (NCT02533544). We evaluated the complete virologic response (CVR) rate and the renal safety of TDF. The overall CVR rate was 69.4%, 87.0%, and 89.7% at weeks 48, 96, and 144, respectively. In the HBeAg-positive CHB patients, the CVR rate at weeks 48, 96, and 144 was 61.4%, 83.1%, and 89.6%, respectively. The rates of HBeAg loss and seroconversion at weeks 48, 96, and 144 were 16.6%, 23.5%, 34.1%, and 7.6%, 8.9%, 13.3%, respectively. In HBeAg-negative CHB patients, the CVR rate at weeks 48, 96, and 144 was 82.5%, 93.2%, and 90.0%, respectively. The rate of alanine aminotransferase normalization was 36.9%, 45.4%, and 46.8% at weeks 48, 96, and 144, respectively. Of the CHB patients, 0.9% showed an elevated creatinine (> 0.5mg/dL from baseline). Age (≥ 60years) was significantly associated with a decline in renal function at week 144 (P < 0.0001). Comorbidities (diabetes or hypertension) showed the tendency to reduce renal function (P = 0.0624). Hepatocellular carcinoma developed in 10 (1.7%) patients and was related to cirrhosis. TDF therapy induced sustained viral suppression and had a favorable safety profile over a 3-year period. However, close monitoring of renal function should be mandatory in treating CHB patients receiving TDF, particularly older patients.

Importance of Prolidase Enzyme Activity and Serum Cytokeratin 18 Levels for Differential Diagnosis between Asymptomatic Hepatitis B Carriers and HBeAg Negative Chronic Hepatitis B Patients

Background: In this study, it was aimed to evaluate the relationship between the severity of necroinflammation in the liver and the stage of fibrosis and the serum levels of Serum Prolidase Activity (SPA) and Cytokeratin (CK)-18 in patients with active Chronic Hepatitis B (CHB) and asymptomatic Hepatitis B Virus (HBV) carriers. Methods: Biochemical analyses, serological parameters associated with HBV and serum prolidase activity and CK-18 levels were measured in asymptomatic HBV carriers (n=65), active CHB patients (n=60) and healthy controls (n=27). Liver biopsies were performed on asymptomatic HBV carriers and active CHB patients. Findings: SPA level was significantly higher in active CHB patients (819.92 ± 123.74 IU/L) compared to asymptomatic HBV carriers (732.99 ± 124.70 IU/L) and was higher in asymptomatic HBV carriers compared to healthy controls (529.4 ± 74.73 IU/L) (p=0.001). The diagnostic cut-off value of SPA level was found 751.15 U/L. When this cut-off value was taken to differentiate HBe-Ag negative CHB in asymptomatic HBV carriers, sensitivity and specificity of efficacy were 72% and 63% respectively (c-statistics: 0.707). A strong positive correlation was observed between serum prolidase level and the severity of fibrosis in asymptomatic HBV carriers (r=0.603, p=0.000). A positive correlation was determined between SPA level and Histological Activity Index (HAI) scores in patients with active CHB and asymptomatic HBV carriers. The serum CK-18 levels were significantly lower in the healthy control group when compared to the asymptomatic HBV carriers and active CHB patients (p=0.001). Conclusion: Prolidase enzyme may be beneficial in differentiating asymptomatic HBV carriers from HBeAg-negative CHB patients when used in combination with ALT and HBV-DNA levels.

Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status

To evaluate the long-term durability and efficacy of nucleos(t)ide analogues (NAs) and to determine the related factors for virological relapse in chronic hepatitis B (CHB) patients. CHB patients who fulfilled the criteria for discontinuing NAs therapy in accordance with the published guidelines were included in the study from December 2001. Virological relapse was defined as serum hepatitis virus B (HBV) DNA >104 copies/mL twice at least 2 weeks apart. A total of 223 CHB patients were enrolled at the time their NAs therapy was discontinued. The 10-year cumulative relapse rate (CRR) in hepatitis B e antigen (HBeAg)-positive patients was statistically lower than that in HBeAg-negative patients (30.9% vs 62.3%, P < 0.001). In the HBeAg-positive group, Cox regression analysis showed that age at cessation (hazard ratio [HR] 1.067, P < 0.001), consolidation therapy (HR 0.958, P = 0.021), and time to HBeAg seroconversion (HR 0.943, P = 0.019) were predictors for relapse. In the HBeAg-negative group, age at cessation (HR 1.040, P = 0.004) and time to HBV DNA negativity (HR 1.246, P = 0.010) were potential predictors for virological relapse. The off-treatment responses to NAs differ in CHB patients with different pretreatment HBeAg status. NA withdrawal is generally safe and feasible in young patients with CHB. Long consolidation periods should be preferred in HBeAg-positive patients to achieve better durability. Benefits of cessation of NAs do not last long in HBeAg-negative CHB patients.

Value of gamma-glutamyl transpeptidase-to-platelet ratio in predicting liver fibrosis stage in chronic hepatitis B patients in Guangdong, China

Objective To investigate the value of gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in predicting liver fibrosis stage in chronic hepatitis B (CHB) patients in Guangdong, China. Methods A total of 501 patients who were diagnosed with CHB by liver biopsy in Guangzhou 8 th People's Hospital from January 2010 to December 2016 were enrolled, among whom 335 had HBe Ag-positive CHB and 166 had HBe Ag-negative CHB. The value of GPR, gamma-glutamyl transpeptidase (GGT) , aspartate aminotransferase-to-platelet ratio index (APRI) , and fibrosis-4 (FIB-4) in predicting liver fibrosis stage (F1-F4) was analyzed. The Spearman correlation coefficient was used to analyze the correlation between diagnostic models and liver fibrosis stage, and the area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the value of each model in predicting liver fibrosis stage. Results With liver biopsy as the gold standard, of all patients, 141 had F1 stage, 183 had F2 stage, 139 had F3 stage, and 38 had F4 stage disease. The Spearman correlation analysis showed that in HBe Ag-positive and HBe Ag-negative patients, GGT, GPR, APRI, and FIB-4 were positively correlated with liver fibrosis stage (r = 0. 459, 0. 526, 0. 320, 0. 470, 0. 272, 0. 366, 0. 288, and 0. 388, all P 0. 05) ; in HBe Ag-negative CHB patients, GPR had a significantly better value in predicting marked fibrosis (≥F2) than GGT and APRI (both P 0. 05) . Conclusion GPR can be used as a noninvasive biochemical index for liver fibrosis stage in CHB patients in Guangdong, and in HBe Ag-positive CHB patients, GPR has a comparable predictive value to FIB-4 and APRI.

A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B.

Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n=346) and validation cohorts (n=173). Based on routine clinical parameters, gamma-glutamyl transpeptidase (GGT; P=0.031) and platelets (PLT; P<0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742-0.839), 0.783 (95% CI: 0.717-0.849) and 0.791 (95% CI: 0.716-0.867) in the entire patients with CHB, HBeAg-positive CHB patients and HBeAg-negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg-positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg-negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg-positive CHB patients, but was comparable with GGT in HBeAg-negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg-positive CHB.

Incidence and Predictors of HBsAg Loss After Peginterferon Therapy in HBeAg-Negative Chronic Hepatitis B: A Multicenter, Long-term Follow-up Study.

The long-term incidence and factors associated with hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients receiving peginterferon is rarely reported. From 2004 to 2016, 233 HBeAg-negative CHB patients who completed 48 weeks of peginterferon treatment from 3 medical centers in Taiwan were retrospectively enrolled. During a median follow-up of 7.4 years, 27 cases achieved HBsAg loss. The cumulative incidences of HBsAg loss and HBsAg seroconversion at 3, 5, 10 years after peginterferon treatment were 4.7%, 9.4%, 14.2%, and 3.5%, 6.4%, 12.5%, respectively, in overall patients, and 15.9%, 29.1%, 37.3%, and 13.1%, 19%, 30.6%, respectively, in patients achieving sustained off-treatment virological response (SVR). By multivariate analysis, age (<35 years; hazard ratio [HR] = 3.742, P = .007), baseline HBsAg levels (<1250 IU/mL; HR = 4.849, P = .002), HBsAg decline at week 24 (≥1 log; HR = 5.660, P = .002), and achieving SVR (HR = 8.546, P = .006) were predictors of HBsAg loss. After achieving SVR, HBsAg loss rates were higher than 30% in 5 years among patients with either younger age or lower HBsAg at baseline. HBsAg loss rate continues to increase after peginterferon treatment in HBeAg-negative CHB patients with SVR. Age, baseline HBsAg levels, on-treatment HBsAg decline, and achieving SVR are factors associated with long-term HBsAg loss.

The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients.

This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post-treatment follow-up for at least 6months (median: 55, IQR 36-85weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg-negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg-negative patients, respectively. The virological relapse rate at 78weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg ≤200IU/mL and HBsAg ≤80IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104weeks were 45.5% and 59.3% in patients with end-of-treatment HBsAg ≤80IU/mL and ≤50IU/mL, respectively. In conclusions, the end-of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients.

Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss.

Treatment with nucleos(t)ide analogues (NA) suppresses hepatitis B virus (HBV) DNA but rarely leads to functional cure of chronic hepatitis B (CHB). Following NA cessation, some hepatitis B e antigen (HBeAg)-negative CHB patients experience hepatitis B s antigen (HBsAg) loss. Cellular immune responses, including natural killer (NK) cell responses, explaining virological events following NA treatment cessation remain elusive. In a single-center prospective trial, 15 HBeAg-negative CHB patients on long-term NA treatment underwent structured NA cessation and were studied longitudinally. The NK cell compartment was assessed using high-dimensional flow cytometry and correlated with the clinical course. Unsupervised stochastic neighbor embedding analysis revealed NA-treated CHB patients to have a significantly affected NK cell compartment compared to controls. Cessation of NA treatment resulted in minor phenotypic alterations, but it significantly augmented NK cell natural cytotoxicity responses in the CHB patients. This increased NK cell functionality correlated with alanine aminotransferase flares in the patients and was particularly enhanced in patients experiencing HBsAg seroclearance at long-term follow-up. Increased NK cell function is associated with active hepatitis and HBsAg seroclearance following structured NA cessation. This adds to our knowledge of the immunological events that develop following cessation of NA treatment in CHB.