ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B.

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.

Limited Value of HBV-RNA for Relapse Prediction After Nucleos(t)ide Analogue Withdrawal in HBeAg-negative Hepatitis B Patients.

International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg-negative patients after 2-3 years of viral suppression. Detectable HBV-RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg-negative patients. This study proves the impact of HBV-RNA levels in the prediction of relapse in a large cohort of HBeAg-negative patients, mainly infected with genotype B or C. Serum levels of HBV-RNA, HBsAg, anti-HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg-negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV-DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients (N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV-RNA level did not differ significantly between relapsers and off-treatment responders (p = 0.92). No significant difference occurred in proportions of detectable HBV-RNA levels between off-treatment responders (N = 27/70; 38.6%) and relapsers (N = 31/84; 36.9%) (p = 0.99). Combining predefined HBsAg cut-offs (100 IU/mL, p = 0.0013), anti-HBc cut-offs (325 IU/mL, p = 0.0117) or HBcrAg cut-offs (2 log U/mL, p = 0.66) with undetectable HBV-RNA (HBsAg, p = 0.0057; anti-HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV-RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg-negative patients. Trial Registration: ABX 203-002: NCT02249988; Terminator 2: NCT03643172.

Differential Relapse Patterns After Discontinuation of Entecavir vs Tenofovir Disoproxil Fumarate in Chronic Hepatitis B.

BACKGROUND AND AIMS: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. METHODS: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. RESULTS: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. CONCLUSIONS: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.

Diabetes Mellitus Impacts on the Performance of Hepatocellular Carcinoma Risk Scores in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: We examined whether changing clinical characteristics and presence of diabetes mellitus (DM) impact the performance of hepatocellular carcinoma (HCC) risk scores. METHODS: Adult patients with chronic hepatitis B (CHB) on ≥6 months of entecavir/tenofovir treatment between January 2005 and March 2020 were identified using a territory-wide electronic database in Hong Kong. DM was defined by antidiabetic agents, hemoglobin A1c ≥6.5%, fasting glucose ≥7 mmol/L, and/or diagnosis codes. PAGE-B, modified PAGE-B (mPAGE-B), and aMAP scores were assessed by area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with CAMD and REAL-B scores with DM as a component. RESULTS: Of 48,706 patients, 2792, 11,563, 15,471, and 18,880 started entecavir/tenofovir treatment between 2005-2008, 2009-2012, 2013-2016, and 2017-2020, respectively; DM prevalence rose from 15.5% in 2005-2008 to 24.3% in 2017-2020. AUROCs were comparable across the 4 periods in the 5 HCC risk scores (AUROCs ranged between 0.75 and 0.81). At a median follow-up of 4.4 years, 1512 non-diabetic (4.0%) and 645 (6.2%) diabetic patients developed HCC. AUROCs of all 5 scores were lower in diabetic patients than in non-diabetic patients (AUROCs ranged between 0.67-0.71 vs 0.78-0.82; all P < .001). REAL-B score achieved an AUROC of 0.71 in diabetic and 0.82 in non-diabetic patients. Both diabetic and non-diabetic patients in the low-risk group by REAL-B score had a low HCC incidence below the threshold of cost-effective HCC surveillance, ie, 0.2% annually. CONCLUSIONS: REAL-B score is accurate and preferred in entecavir/tenofovir-treated CHB patients because of the increasing prevalence of DM.

The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen-Negative Patients.

BACKGROUND & AIMS: Hepatitis B flare occurs earlier and is more severe in patients stopping tenofovir (TDF) compared with entecavir (ETV). This study investigated relationship between hepatitis B virus (HBV) kinetics, onset timing, and the severity of flares. METHODS: Hepatitis B e antigen-negative chronic hepatitis B patients who developed off-ETV or off-TDF hepatitis flare were recruited. Their HBV kinetics and the severity of flares were compared between patients with early (<6 months) and late (between 6 and 24 months) flares. Propensity score matching was performed at 1:1 adjusting for age, sex, cirrhosis, and end-of-treatment (EOT) hepatitis B surface antigen between off-ETV and off-TDF flares. RESULTS: After propensity score matching, 76% and 15% of each 107 off-TDF and off-ETV patients, respectively, developed early flare. A much steeper HBV DNA upsurge (ΔHBV DNA/month) was observed in off-TDF than off-ETV flares (2.12 vs 0.73 log10 IU/mL; P < .01). Greater ΔHBV DNA/month correlated with earlier timing and higher peak alanine aminotransferase levels of flares. ΔHBV DNA/month ≥2.5 log10 IU/mL was an independent factor for severe off-TDF flare, and ≥1 log10 IU/mL was a predictor for severe off-ETV flares. CONCLUSIONS: Greater HBV DNA upsurge rate (ΔHBV DNA/month) ≥1 log10 IU/mL is a key factor for an earlier onset and more severe flare. More frequent ΔHBV DNA/month ≥1 log10 IU/mL in off-TDF than off-ETV flares may explain why off-TDF flare mostly occurred early and was more severe. More stringent monitoring in those with ΔHBV DNA/month ≥1 log10 IU/mL at flare, especially ≥2.5 log10 IU/mL in early off-TDF flares, is important for timely retreatment to prevent decompensation.

Aldo-keto reductase family 1 member B10 is regulated by nucleos(t)ide analogues for chronic hepatitis B.

The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) expression has been reported in advanced chronic liver diseases as well as cancer tissues. We observed an association between related to HCC incidence and serum AKR1B10 by analyzing patients under treatment with NAs. Serum AKR1B10 levels measured by ELISA were higher in HCC cases under NA treatment compared with non-HCC cases and were associated with lamivudine- and adefovir pivoxil-, but not entecavir- or tenofovir alafenamide-treated cases. The latter drugs did not increase AKR1B10 values even in HCC cases, suggesting that they influence the reduction of AKR1B10 in any cases. This analysis was supported by in-vitro examination, which showed reduced AKR1B10 expression by entecavir and tenofovir via immunofluorescence staining. In conclusion there was a relationship between HBV-related HCC incidence and AKR1B10 under nucleos(t)ide analogues, especially in the use of lamivudine and adefovir pivoxil, but entecavir and tenofovir had suppressive effects of AKR1B10.

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

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

Higher HBeAg-reversion virological relapse and lower sustained remission after treatment cessation in tenofovir-treated HBeAg-positive patients.

A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.

Serum cytokine profiles predict outcomes of chronic hepatitis B patients discontinuing entecavir or tenofovir therapy.

BACKGROUND/PURPOSE: Distinct hepatitis relapse has been observed after discontinuing entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients. End-of-therapy (EOT) serum cytokines were compared and used for outcome prediction. METHODS: A total of 80 non-cirrhotic CHB patients in a tertiary medical center in Taiwan who discontinued ETV (n = 51) or TDF (n = 29) therapy after fulfilling the APASL guidelines were prospectively enrolled. Serum cytokines were measured at EOT and 3rd month afterwards. Multivariable analysis was performed to predict virological relapse (VR, HBV DNA >2000 IU/mL), clinical relapse (CR, VR and alanine aminotransferase > 2-fold upper limit of normal) and hepatitis B surface antigen (HBsAg) seroclearance. RESULTS: Compared with TDF group, ETV stoppers had greater interleukin 5 (IL-5), IL-12 p70, IL-13, IL-17 A and tumor necrosis factor alpha (TNF-alpha) (all P < 0.05) at EOT. Older age, TDF use, higher EOT HBsAg and IL-18 (Hazard ratio [HR], 1.01; 95% CI, 1.00-1.02) levels at EOT predicted VR, while older age, higher EOT HBsAg and IL-7 (HR, 1.25; 95% CI, 1.00-1.56) levels predicted CR. In TDF stoppers, higher IL-7 (HR, 1.29; 95% CI, 1.05-1.60) and IL-18 (HR, 1.02; 95% CI, 1.00-1.04) levels predicted VR, while IL-7 (HR, 1.34; 95% CI, 1.08-1.65) and interferon-gamma (IFN-gamma) (HR, 1.08; 95% CI, 1.02-1.14) levels predicted CR. A lower EOT HBsAg level was associated with HBsAg seroclearance. CONCLUSION: Distinct cytokine profiles were observed after stopping ETV or TDF. Higher EOT IL-7, IL-18, and IFN-gamma could be probable predictors for VR and CR in patients discontinuing NA therapies.

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.

Early virologic relapse predicts alanine aminotransferase flares after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B.

When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) therapy before achieving HBsAg loss, flares often ensue which are challenging to predict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 patients from an external, prospective cohort were used for validation. Retreatment criteria were pre-defined. Pre- and post-treatment predictors of alanine aminotransferase (ALT) flare (>5× ULN) were evaluated by Cox proportional-hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5× ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2-8.9]; p = 0.03) and serum HBV DNA (1.2 [1.0-1.8]; p = 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5× ULN (3.4 [1.4-8.4]; p = 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment.

Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies.

BACKGROUND & AIMS: Clinical relapse occurs much earlier and more frequently in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients after stopping tenofovir (TDF) therapy than those off-entecavir (ETV). Clinical relapse may subside or progress to hepatitis flare which poses a safety concern. This study compared the incidence, timing and severity of hepatitis flares after stopping TDF and ETV. METHODS: HBeAg-negative CHB patients who had stopped ETV or TDF were included in the study. Off-therapy hepatitis flare patterns were compared between off-ETV and off-TDF patients before and after propensity score matching (PSM). RESULTS: The off-therapy hepatitis flares occurred more frequently (2-year: 58% vs 38%, P < .001) and much earlier (12 vs. 38 weeks, P < .001) in TDF group, with higher alanine aminotransferase (ALT) levels (after PSM: 536 vs. 419 U/L, P = .020) and two times rate of hepatic decompensation (4.0% vs. 2.1%, P = .322). The cirrhotic status [aHR: 20.531 (2.645-159.365), P = .004] and off-TDF [aHR: 5.530 (1.728-17.694), P = .004] were two independent predictors for hepatic decompensation. CONCLUSIONS: Hepatitis flare occurred more frequently, earlier, and more severe in off-TDF than off-ETV patients. More stringent off-therapy monitoring within 6 months off-TDF is mandatory whereas more attention is needed after 6 months off-ETV.

Low anti-HBc levels are associated with lower risk of virological relapse after nucleos(t)ide analogue cessation in HBe antigen-negative patients.

BACKGROUND AND AIMS: Low anti-HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg-positive cohorts. We investigated the association of anti-HBc levels with relapse in HBeAg-negative patients. METHODS: Serum levels of anti-HBc, HBsAg and HBcrAg were determined in 136 HBeAg-negative patients, participating in a vaccination trial (ABX-203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated. RESULTS: After therapy cessation 50% (N = 68) of patients relapsed. Median anti-HBc prior to treatment stop was significantly higher among relapsers compared to off-treatment responders (520 IU/ml vs. 330 IU/mL, p = .0098). The optimal anti-HBc cut-off to predict relapse was 325 IU/ml according to the Youden-Index. About 35% of patients with anti-HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p = .0103; sensitivity 50%, specificity 75%). Combining the optimal cut-offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti-HBc increased the proportion of patients with relapse to 80% (p < .0001) and 74% (p = .0006), respectively. CONCLUSION: In contrast to predominantly HBeAg-positive cohorts, in our cohort of HBeAg-negative patients lower anti-HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti-HBc level as an indicator of the host response might be prospectively further explored for prediction models.

A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study.

BACKGROUND AND AIM: In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off-Nuc hepatitis flare can be alleviated by switching from one Nuc to another. METHODS: HBeAg-negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed-up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono-ETV), TDF monotherapy (mono-TDF), switched to ETV (switch-ETV), and switched to TDF (switch-TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off-Nuc CR and flares. RESULTS: A total of 1309 patients (1022 mono-ETV, 219 mono-TDF, 40 switch-ETV and 28 switch-TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono-ETV, mono-TDF, switch-ETV and switch-TDF respectively (P < 0.001). After PSM, the mono-ETV (adjusted HR: 0.39, P < 0.001) and switch-ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare. CONCLUSION: In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non-ETV-Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR.

Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients.

BACKGROUND & AIMS: Factors associated with a successful outcome upon nucleos(t)ide analogue (NA) treatment withdrawal in HBeAg-negative chronic hepatitis B (CHB) patients have yet to be clarified. The objective of this study was to analyse the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation. METHODS: Twenty-seven patients without cirrhosis with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analysed at baseline and longitudinally throughout follow-up. RESULTS: After a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1,000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses. CONCLUSIONS: Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal. LAY SUMMARY: Nucleos(t)ide analogue therapy can be discontinued in a high proportion of chronic hepatitis B patients without cirrhosis. The strength of HBV-specific immune T cell responses may contribute to successful viral control after antiviral treatment interruption. Our comprehensive study provides in-depth data on virological and immunological factors than can help guide individualised therapy in patients with chronic hepatitis B.

Association between nucleos(t)ide analogue therapy for hepatitis B and Sjögren's syndrome: 15-year analysis of the national database of Taiwan.

Hepatitis B virus (HBV) infection has been proposed to play a role in the development of Sjögren's syndrome. However, to date, there are no reports on the risk of SS in HBV-infected patients following nucleos(t)ide analogue therapy. Due to Taiwan has higher prevalence of HBV infection and therapy was well recorded in the Taiwan's single-payer national health insurance database, we hypothesized that a long-term retrospective analysis of the risk of Sjögren's syndrome in HBV-infected patients following nucleotide therapy will increase our understanding of Sjögren's syndrome development following HBV infection. We identified 26,147 adults diagnosed with HBV infection between 1997 and 2012 in claims data. Finally, a total of 3268 HBV-infected patients who ever received nucleotide therapy (treated cohort) were frequency-matched on age and sex at 1:4 ratios to select a control group of 13,072 counterparts without therapy (untreated cohort). To identify Sjögren's syndrome risk, competing risk analysis adjusted for all covariates was performed. The risk was significantly lower in the treated cohort (15-year cumulative incidence, 2.4%; 95% confidence interval [CI], 1.4%-3.7%) than in the untreated cohort (7.1%; 95% CI, 2.5%-15.2%) (p = .015), and the adjusted HR was 0.6 (95% CI, 0.41-0.88; p = .009). Multivariable stratified analysis further verified the consistent associations between nucleoside therapy and risk reduction of Sjögren's syndrome across all strata. Our finding suggests that HBV infection treated with nucleotides is associated with lower risk of Sjögren's syndrome, implying a potential role of HBV infection in the development of Sjögren's syndrome.

Tenofovir disoproxil fumarate on the risk of hepatocellular carcinoma in chronic hepatitis B patients with failure to preceding treatments: A nationwide cohort study.

Tenofovir disoproxil fumarate (TDF) monotherapy is recommended for the treatment of chronic hepatitis B (CHB) patients who are refractory to other drugs. Yet, little data are available for the effectiveness of TDF monotherapy compared with TDF-based combination therapy on the risk of hepatocellular carcinoma (HCC) and death/transplantation. This nationwide population-based cohort study included 11,289 CHB patients who initiated TDF rescue therapy after failure of preceding treatments between 2012 and 2014 in Korea. The risks of HCC and death/transplantation were compared between TDF combotherapy (n = 2,499) and TDF monotherapy (n = 8,790) groups. The findings were validated in a hospital cohort of 1,163 CHB patients. In the nationwide cohort, during 44.2 months of overall treatment duration, 529 patients developed HCC and 190 died or received transplantation. In the 2,499 propensity score-matched pairs, compared with TDF combotherapy, TDF monotherapy showed no significantly different risks of HCC (1.11/100 person-year [PY] vs. 1.32/100 PY; HR 1.23, 95% CI 0.95-1.60, p = .12) and death/transplant (0.43/100 PY vs. 0.42/100 PY; HR 1.04, 95% CI 0.67-1.60, p = .87). However, in the 469 propensity score-matched pairs of cirrhosis subcohort, TDF monotherapy was associated with a higher risk of HCC than TDF combotherapy (HR 1.46, 95% CI 1.002-2.12, p = .049). In the validation hospital cohort, TDF monotherapy was not associated with significantly different risks of HCC and death/transplant in the entire cohort and cirrhosis subcohort. In CHB patients with failure to preceding treatments, TDF monotherapy showed no higher risks of HCC and death/transplantation compared with TDF combotherapy. However, the comparative effectiveness of rescue TDF monotherapy should be further clarified in cirrhotic patients since the findings were not consistent in the nationwide and hospital cohorts.

Comparison of Serum Hepatitis B Virus RNA Levels and Quasispecies Evolution Patterns between Entecavir and Pegylated-Interferon Mono-treatment in Chronic Hepatitis B Patients.

Hepatitis B virus (HBV) RNA may independently predict virological and serological response. This study aimed to compare dynamic changes in serum HBV RNA levels and HBV quasispecies evolution patterns between entecavir and pegylated-interferon mono-treatment in chronic hepatitis B patients and to determine the clinical significance during treatment. TaqMan real-time PCR was used for quantitative analysis. HBV RNA levels were retrospectively determined in serial serum samples from 178 chronic hepatitis B patients who received either entecavir or pegylated-interferon treatment. Both serum HBV DNA and RNA quasispecies were analyzed via next-generation sequencing. Receiver operating characteristics (ROC) analysis was performed to evaluate the prediction value of individual biomarkers for hepatitis B e antigen (HBeAg) seroconversion. Patients who received pegylated-interferon treatment showed stronger declines in HBV RNA levels than did those who received entecavir treatment. Serum HBV RNA levels were lower in patients with subsequent HBeAg seroconversion. At baseline, the level of HBV RNA was better than other indicators in predicting HBeAg seroconversion. Moreover, the predictive value of serum HBV RNA levels was better in the entecavir group. Baseline HBV RNA exhibited a significantly higher genetic diversity than HBV DNA and had a significant decline after 4 weeks of entecavir treatment. Higher baseline genetic diversity may result in a better outcome in pegylated-interferon-treated patients. Serum HBV RNA levels showed different decline kinetics, and HBV RNA quasispecies showed different evolution patterns in entecavir and pegylated-interferon mono-treatment. Taken together, serum HBV RNA may serve as a promising biomarker of HBeAg seroconversion in patients during antiviral treatment.

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.

Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue-treated HBeAg-positive chronic hepatitis B: a retrospective study.

BACKGROUND: The impact of hepatic steatosis (HS) on treatment response following nucleos(t)ide analogue (NA) treatment for chronic hepatitis B (CHB) patients has not been clearly elucidated. We aimed to investigate the difference in HBeAg seroclearance between NA-treated HBeAg-positive CHB patients with and without HS. METHODS: We retrospectively recruited HBeAg-positive CHB patients receiving liver biopsy and NA monotherapy. The baseline clinical characteristics and cumulative incidence of HBeAg seroclearance were compared between patients with and without HS and age/gender-matched subgroup analysis was performed. RESULTS: A total of 196 patients were enrolled from 2003 April to 2016 October. The mean age was 39.6 ± 11.2 years, 142 (72.4%) were males and 94 (48%) had histological evidence of HS. Median treatment duration and follow-up period were 24.3 months and 54.9 months, respectively. HBeAg seroclearance was achieved in 56/102 (54.9%) and 54/94 (57.4%) patients with and without HS, respectively (p = 0.830). The 5-year cumulative incidence of HBeAg seroclearance in patients with and without HS was 62.8 and 67.7% in overall population (p = 0.398) and 62.4 and 66.9% in age/gender-matched subgroups (p = 0.395), respectively. The rate of HBeAg seroclearance was comparable between patients with or without HS in different NA monotherapy (all p > 0.05). CONCLUSIONS: HS had no significant impact on HBeAg seroclearance in HBeAg-positive CHB patients with NA monotherapy during long-term follow-up.