Hepatitis B Surface Antigen Decline Research Articles

Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ Tcell immunity to inhibit hepatitis B virus.

The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ+CD4+ Tcell immune response. Depletion of CD4+ Tcells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ+CD4+ Tcell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ+CD4+ Tcell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.

Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989

Background and aimsRNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis...

CXCR7 genetic variant predicts treatment response of pegylated-interferon α in HBeAg-positive chronic hepatitis B patients

ObjectivesCXC chemokine receptor 7 (CXCR7) plays pivotal roles in different virus infections. However, no research focused on the role of CXCR7 in hepatitis B virus (HBV)-infected patients. The primary aim of this study is to elucidate the role of CXCR7 in predicting the treatment response of chronic hepatitis B (CHB) patients undergoing pegylated interferon-alpha (PegIFNα) therapy. MethodsTwo cohorts with a total of 945 Chinese CHB patients (Cohort 1, n = 238; Cohort 2, n = 707) were enrolled in this retrospective study, all the patients were positive for hepatitis B e antigen (HBeAg) and received PegIFNα treatment for 48 weeks and followed-up for 24 weeks post-treatment. Nineteen tag single-nucleotide polymorphisms (SNPs) were selected within and surrounding the CXCR7 gene region. The associations of CXCR7 SNPs and polygenic score (PGS) with PegIFNα treatment response were investigated in the two cohorts. ResultsAmong the 19 candidate SNPs of CXCR7, rs2952665 (A > G) was significantly associated with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <3.3log10IU/mL, P = 0.002) and hepatitis B surface antigen (HBsAg) decline (P = 0.015) in the two cohorts at week 72. Furthermore, a PGS comprising CXCR7_rs2952665 and five additional SNPs, which were previously recognized as biomarkers of PegIFNα treatment response, demonstrated a robust correlation with both CR (P = 1.38 × 10−12) and HBsAg decline (P = 0.003) in all the patients. ConclusionThis research illustrated that CXCR7_rs2952665 is a promising predictor of the PegIFNα therapy efficiency in Chinese HBeAg-positive CHB patients. A PGS consisting of CXCR7_rs2952665 and five previously reported SNPs predicts treatment response to PegIFNα better.

HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B

ObjectiveSelected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess...

Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy

Immune checkpoint inhibitors (ICIs) can restore exhausted T-cell immunity not only for cancer treatment but also potentially to cure chronic hepatitis B (CHB). Thus, we aimed to determine the previously unclear impact of ICIs on hepatitis B surface antigen (HBsAg) seroclearance in patients with cancer. Consecutive patients with cancer from 2016 to 2020 (cohort 1, n= 118), and hepatocellular carcinoma from 2020 to 2022 (cohort 2, n= 44, as validation) receiving ICIs and positive for HBsAg were retrospectively recruited. An additional HBV-HCC cohort (cohort 3, n= 85) not receiving ICIs served as a control group. Factors associated with HBsAg loss or a HBsAg decline >1 log were analyzed. With median follow-up of 17.5 months, 8 (6.8%) patients in cohort 1 and 4 (9.1%) in cohort 2 achieved HBsAg seroclearance, and an additional four in cohort 1 and one in cohort 2 had a HBsAg decline >1 log. In multivariate analysis, HBsAg <100 IU/ml was associated with HBsAg seroclearance (hazard ratio 6.274, p= 0.028). In the validation cohort, the cumulative incidences of HBsAg loss at months 12 and 24 were 13.0% and 38.4%, respectively, for baseline HBsAg <100 IU/ml, which were significantly higher than those in the control group (p= 0.0267). No case in cohort 3 achieved HBsAg loss within 24 months. Of the 17 cases who achieved HBsAg loss or a decline >1 log, 16 (94.1%) received nucleos(t)ide analogue treatment. The median time to HBsAg loss or HBsAg decline was 16.5 (range 9.6 to 27.5) months. ICIs may accelerate HBsAg seroclearance in patients with cancer and baseline HBsAg <100 IU/ml. This finding provides important information for the design of future trials evaluating the ability of ICIs to induce functional cure in patients with CHB. Immune checkpoint inhibitors (ICIs) can restore exhausted T-cell immunity not only for cancer treatment but also potentially to cure chronic hepatitis B. Functional cure of hepatitis B was observed in patients with cancer or HCC undergoing ICI treatment, and the cumulative incidence of HBsAg loss was higher compared with controls without ICIs. ICIs may accelerate the HBsAg loss in patients with baseline HBsAg levels <100 IU/ml. This finding provides important information for the design of future ICI trials evaluating the ability of ICIs to induce functional cure in patients with CHB.

Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy.

For chronic hepatitis B (CHB) patients, there is still a need to improve hepatitis B surface antigen (HBsAg) clearance rates. This study aimed to assess the predictive effectiveness of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for HBsAg clearance in HBeAg-negative CHB patients undergoing peginterferon (Peg-IFN)-based antiviral treatment. This study encompassed 280 patients undergoing treatment with Peg-IFNα. Serum levels of sPD-1 and sPD-L1 were measured using ELISA kits at baseline, as well as at 12, 24 and 48 weeks. The primary endpoint of the study was the determination of HBsAg clearance at 48 weeks. Logistic regression analysis was employed to identify predictors of HBsAg clearance. The clearance group demonstrated significantly lower serum sPD-L1 levels compared to the non-clearance group. While both groups exhibited an increase in sPD-1 levels, only the clearance group showed a rise in sPD-L1 levels. Multivariate analysis identified sPD-L1 increase at 24 weeks, and HBsAg decline at 24 weeks as predictors for HBsAg clearance at 48 weeks. The combined use of these indicators showed a predictive performance for HBsAg clearance with an AUROC of 0.907 (95% CI: 0.861-0.953, p < 0.001). The study revealed an inverse relationship between the trends of sPD-1/sPD-L1 and HBsAg clearance during combined IFN and NAs treatment. Moreover, the magnitude of HBsAg reduction and sPD-L1 increase emerged as significant predictors for HBsAg clearance.

Interferon-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

A genetic variant of CXCR4 predicts pegylated interferon-alpha treatment response in HBeAg-positive chronic hepatitis B patients.

Chemokine receptor 4 (CXCR4) plays a vital role in immunoregulation during hepatitis B virus (HBV) infection. This study aimed to screen single-nucleotide polymorphisms (SNPs) of CXCR4 for predicting pegylated interferon-alpha (PegIFNα) therapy response in chronic hepatitis B (CHB) patients. This retrospective cohort study enrolled a total of 945 CHB patients in two cohorts (Cohort 1, n = 238; Cohort 2, n = 707), and all the patients were hepatitis B e antigen (HBeAg)-positive and treated with PegIFNα for 48 weeks and followed up for 24 weeks. Twenty-two tag SNPs were selected in CXCR4 and its flanking region. A polygenic score (PGS) was utilized to evaluate the cumulative effect of multiple SNPs. The relationships between CXCR4 SNPs and PGS and PegIFNα treatment response were explored in the two cohorts. Among the 22 candidate SNPs of CXCR4, rs28367495 (T > C) was significantly linked to PegIFNα treatment response in both cohorts. In patients with more number of rs28367495 C allele, a higher rate of combined response (CR, defined as HBeAg seroconversion and HBV DNA level < 3.3 log10 IU/mL; P = 1.51 × 10-4), a lower mean hepatitis B surface antigen (HBsAg) level (P = 4.76 × 10-4), and a higher mean HBsAg decline (P = 3.88 × 10-4) at Week 72 were achieved. Moreover, a PGS integrating CXCR4_rs28367495 and five previously reported SNPs was strongly correlated with CR (P = 1.26 × 10-13), HBsAg level (P = 4.90 × 10-4), and HBsAg decline (P = 0.005) in all the patients of the two cohorts. CXCR4_rs28367495 is a promising indicator for predicting the responsiveness to PegIFNα treatment for HBeAg-positive CHB patients. The new PGS may further improve the prediction performance.

A high functional cure rate was induced by pegylated interferon alpha-2b treatment in postpartum hepatitis B e antigen-negative women with chronic hepatitis B virus infection: an exploratory study.

Limited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure. A total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks. At week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p<0.001) and higher HBsAg seroconversion rate (38.10% vs 2.38%,p<0.001). Baseline HBsAg levels (Odds Ratio [OR]: 0.051, 95% Confidence Interval [CI]: 0.003-0.273, P=0.010), HBsAg at week 24 (OR:0.214, 95%CI:0.033-0.616, P=0.022), HBsAg decline at week 24 (OR:4.682, 95%CI: 1.624-30.198, P=0.022) and postpartum flare (OR:21.181, 95%CI:1.872-633.801, P=0.030) were significantly associated with HBsAg loss at week 48 after Peg-IFN alpha-2b therapy. Furthermore, the receiver operating characteristic curve (ROC) showed that the use of baseline HBsAg<182 IU/mL, HBsAg at week24 < 4 IU/mL and HBsAg decline at week24>12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported. Peg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.

Higher BST2 Expression Promotes the Anti-HBV Effect of IFN-α and BST2 Genetic Variant Predicts PegIFNα Treatment Response of HBeAg-Positive Chronic Hepatitis B Patients.

We previously reported that an interferon (IFN)-inducible protein, BST2, was regulated by the JAK-STAT pathway activated by CD40, and subsequently suppressing hepatitis B virus (HBV) repliaction and transcription. The current research attempted to assess the impact of BST2 on the IFN-treated anti-HBV effect, and explore BST2 variants for predicting pegylated IFN alpha (PegIFNα) therapy response of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Using an HBV-transfected cell model, the function of BST2 on HBV DNA replication and transcription driven by IFN was studied. The potentially functional BST2 variants were selected through a strategy of gene-wide screening. The associations of BST2 variants and polygenic score (PGS) model, which was used to quantify the combined influence of several genetic variants, with treatment response were examined in 2 separate PegIFNα-treated cohorts of 238 and 707 patients with CHB, respectively. We found that overexpression of BST2 improved the anti-HBV activity triggered by IFN-α. Among PegIFNα-treated patients with CHB, BST2_rs9576 was screened out to be significantly correlated with combined response (CR; i.e., HBeAg seroconversion along with HBV DNA level <3.3log10 IU/mL, P = 7.12 × 10-5 ). Additionally, there was a strong correlation between the PGS incorporating BST2_rs9576 and other 5 genetic variations (previously described predictors of therapy response to PegIFNα) and CR (P = 1.81 × 10-13 ), hepatitis B surface antigen (HBsAg) level (P = 0.004), as well as HBsAg decline (P = 0.017). In conclusion, higher BST2 expression responded better to IFN-α treatment. BST2_rs9576 is an effective indicator to forecast therapy response of PegIFNα-treated patients with CHB. The PGS possesses the potential to boost the ability of PegIFNα therapy response.

Predictors of therapeutic response to peginterferon α‑2a and nucleos(t)ide analog combination therapy for HBeAg‑negative chronic hepatitis B: 1‑year follow‑up after treatment.

Chronic hepatitis B (CHB) is a major global health concern. Guidelines for the management of hepatitis B virus (HBV) indicate that the loss of hepatitis B surface antigen (HBsAg) is a key endpoint of interest. The present study aimed to examine long-term changes in HBsAg levels in HBV-DNA-negative, hepatitis B e-antigen (HBeAg)-negative patients treated with peginterferon (Peg-IFN) α-2a and nucleos(t)ide analog (NA), and to examine the conditions that make them susceptible to HBsAg decline. A total of 17 patients with CHB treated with NA and Peg-IFN were observed for 96 weeks (48 weeks of Peg-IFN therapy and 48 weeks of post-treatment follow-up). In this study, responders were defined as those with a 50% or greater decrease in HBsAg levels from baseline at week 96. Beginning at week 16 of Peg-IFN therapy, there was a significant difference in the decrease in HBsAg levels from baseline between the responders and non-responders. In responders, HBsAg levels tended to be >60% lower 16 weeks after Peg-IFN initiation than before initiation. Age at the start of NA use and the duration of NA use before Peg-IFN treatment initiation were significant pretreatment factors associated with HBsAg response. In conclusion, Peg-IFN was revealed to be more effective in HBeAg-negative patients with CHB who started NA at a young age and have been on long-term treatment, particularly if the HBsAg levels decreased to less than 60% of the starting level at week 16 after starting Peg-IFN treatment.

Association of Alanine Aminotransferase Flares to Hepatitis B Surface Decline During Tenofovir Alone or With Pegylated Interferon Alfa.

We aimed to determine whether the intensity of alanine aminotransferase (ALT) flares during antiviral therapy is associated with the level of hepatitis B surface antigen (HBsAg) decline. Quantitative HBsAg was determined during tenofovir monotherapy or tenofovir plus peginterferon alfa-2a in 201 participants with hepatitis B e antigen-positive or -negative chronic hepatitis B. A multivariable analysis identified factors associated with a shorter time to reduction in HBsAg. Fifty flares occurred during treatment of which 74% were moderate (ALT >5-10 × upper limit of normal) or severe (ALT >10 × upper limit of normal). These flares were associated with greater HBsAg decline compared with no flares. Significantly faster times to HBsAg decline >1 log 10 IU ( P = 0.04) and to HBsAg level <100 IU/mL ( P = 0.01) were observed with severe flares. Flare severity is a potentially important factor associated with shorter time to HBsAg reduction. These findings can be useful when evaluating HBsAg response to evolving hepatitis B virus therapies.

CD4+ T cell counts and soluble programmed death-1 at baseline correlated with hepatitis B surface antigen decline in HIV/HBV coinfection during combined antiretroviral therapy.

Several studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART. A total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log10 IU/ml at 6 months from the baseline after initiation of cART. HBsAg declined faster (0.47 log10 IU/mL) in the first six months and attained a decrease of 1.39 log10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4+ T cell levels (OR=6.633, P=0.012) and sPD-1 level (OR=5.389, P=0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation. Lower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection.

Rapid Decline Rather Than Absolute Level of HBsAg Predicts Its Seroclearance in Untreated Chronic Hepatitis B Patients From Taiwanese Communities.

Hepatitis B surface antigen (HBsAg) clearance leads to favorable outcomes in patients with chronic hepatitis B. HBsAg levels <200 IU/mL with HBsAg decline >0.5 log 10 IU/mL in 1 year have been reportedly predictive of HBsAg loss. This study aimed to use the REVEAL-hepatitis B virus cohort to validate and simplify this prediction rule and verify whether the simplified algorithm can be used among various clinical subgroups. We analyzed 707 patients with untreated chronic hepatitis B who had 3 or more HBsAg measurements within 5 years before HBsAg seroclearance or last visit, greater than 1 year apart from one another. Rapid HBsAg decline was defined as HBsAg decline >0.5 log 10 IU/mL in 1 year or >1 log 10 IU/mL in 2 years. Sensitivity, specificity, positive predictive values, and negative predictive values were compared to assess the predictability of HBsAg seroclearance. During a median follow-up of 10.7 years, 41 of the 707 patients cleared serum HBsAg. HBsAg levels at all measurements were lower ( P < 0.0001) and HBsAg decline was greater ( P < 0.0001) in patients with seroclearance compared with non-seroclearance patients. The predictive accuracy of predicting 1-year HBsAg loss using only the rapid decline algorithm (sensitivity = 0.4412, specificity = 0.9792, positive predictive value = 0.5172, negative predictive value = 0.972) was the same as the model combining rapid HBsAg decline and HBsAg levels <200 IU/mL. The simplified algorithm including only the rapid decline performed similarly among various levels of HBsAg, hepatitis B virus DNA, and alanine aminotransferase and was independent of inactive carrier state. HBsAg decline >0.5 log 10 IU/mL/yr was a practical predictor of HBsAg seroclearance within 1 year in our community-based untreated cohort.

Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial.

Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn. Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <10 3 IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria. Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal. Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.

Long-term Hepatitis B Surface Antigen Profile and Seroclearance after Severe Acute Flares of Chronic Hepatitis B.

Hepatitis B surface antigen (HBsAg) seroclearance remains uncommon in chronic hepatitis B (CHB) infection. During acute flares of CHB (AFOCHB), alanine aminotransferase elevation reflects a mounting immune response toward viral clearance. We hypothesized that severe AFOCHB is associated with a greater quantitative HBsAg (qHBsAg) decline and HBsAg seroclearance rate. A total of 75 patients with severe AFOCHB with alanine aminotransferase 10× the upper limit of normal were matched to a control group by age and sex in a 1:2 ratio. qHBsAg levels were measured at the time of flare and annually (for both cases and controls) until the last follow-up. The median follow-up times for patients with severe AFOCHB and controls were 8.8 and 10.5 years, respectively. The cumulative rate of HBsAg seroclearance was higher in the severe AFOCHB group than in the control group (11.8% vs 5.0%, p=0.04) despite the former group having a trend of a higher baseline median qHBsAg (3,127 IU/mL vs 1,178 IU/mL, p=0.076). Compared with the control group, the severe AFOCHB group had a greater annual qHBsAg reduction (-242.4 IU/mL/yr vs -47.3 IU/mL/yr, p=0.002). Increasing age (p=0.049), lower baseline qHBsAg (p=0.002), and severe AFOCHB (p=0.014) were independently associated with HBsAg seroclearance. However, the cumulative rate of hepatocellular carcinoma was significantly higher in the severe AFOCHB group than in the control group (15.8% vs 1.9%, p<0.001). Severe AFOCHB was associated with a greater incidence of HBsAg seroclearance and qHBsAg decline. However, it was associated with a higher incidence of hepatocellular carcinoma.

Switching to tenofovir alafenamide versus continued therapy in chronic hepatitis B patients who were treated with entecavir: A prospective, multicenter, randomized controlled study.

Backgrounds:Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) have been used widely to treat patients with chronic hepatitis B virus (HBV) infection, but it is still unclear how best to use these drugs. Although some studies compared the efficacies of treatment switch from ETV to TAF, there has been no randomized study.Methods:We performed a prospective multicenter randomized controlled study in which subjects were enrolled from April 2018 to June 2019 and observed for 2 years until March 2021 to clarify the efficacy and safety of switching from ETV to TAF.Results:Thirty-three patients were enrolled and randomized into 2 groups, and a total of 30 patients were evaluated; a TAF-switching group (n = 16) and an ETV-continuing group (n = 14). The mean age of the 30 patients was 61 years old and 18 patients (60%) were male. The serum HBV DNA in all patients were below detection limit. The mean change in hepatitis B surface antigen (HBsAg) levels after 2 years was not significantly different between the TAF and ETV groups (–0.08 vs –0.20 log IU/mL, P = .07). Comparing the group with a HBsAg decline (≤ –0.1 log IU/mL) and a group without a HBsAg decline in an overall analysis, the prior ETV duration was significantly shorter in the HBsAg-declined group (49 vs 92 months, P = .03). Although the eGFR levels tended to decrease in the TAF group compared to ETV (–6.15 vs –2.26 mL/min/1.73 m2, P = .09), no significant differences were observed in patients with baseline eGFR < 60 (–2.49 vs 0.40 mL/min/1.73 m2, P = .25).Conclusion:The efficacy and safety were comparable in the TAF-switching group and the ETV-continuing group. Because the present study was conducted in limited patients, a larger study will be required.

An optimized mode of interferon intermittent therapy help improve HBsAg disappearance in chronic hepatitis B patients.

BackgroundTo investigate the effect of intermittent interferon therapy mode on the disappearance of hepatitis B surface antigen (HBsAg) in chronic hepatitis B (CHB) patients.MethodsThis is a retrospective cohort study in CHB patients who were suspended from pegylated interferon α (PEG-IFNα) therapy due to a plateau in HBsAg decline during the initial treatment period, and resumed interferon therapy after an interval of 3–6 months. Patients received entecavir or tenofovir during the interval period. Hepatitis B virus (HBV) virological and serological indexes, clinical biochemical indexes, and blood routine tests were performed at the baseline and every 3 months during follow-up of initial interferon treatment. A functional cure was analyzed as a primary outcome.ResultsA total of 304 patients treated with intermittent PEG-IFNα were included in the statistical analysis, including 215 men and 89 women, aged 37.97 ± 8.53 years, and 73 hepatitis B e antigen (HBeAg)-negative and 231 HBeAg positive patients. In total 59 patients (19.41%) achieved HBsAg disappearance through the initial, intermittent, and retreatment of PEG-IFNα treatment, of whom 43 patients (14.14%) achieved HBsAg seroconversion. Early HBsAg response to initial treatment was significantly associated with HBsAg response at 12 and 24 weeks of retreatment. After the intermission period, the incidence of HBsAg disappearance in patients with early HBsAg response in the retreatment period was 43.87%. The baseline HBsAg and 12-week HBsAg response in the retreatment period had higher predictive value than the initial treatment HBsAg response.ConclusionThe initial, intermittent, and retreatment mode of interferon can help to improve the HBsAg disappearance rate in CHB patients.Clinical trial registration[www.ClinicalTrials.gov], identifier [NCT04028856].

Effect of switching from nucleos(t)ide maintenance therapy to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomized trial.

Induction of a durable viral response is difficult to achieve in patients with chronic hepatitis B (CHB), even from long-term use of a nucleos(t)ide analogue (NA). This study investigated whether switching to peginterferon (PegIFN) alfa-2a after long-term NA therapy induced a durable viral response. Patients with hepatitis B e antigen (HBeAg)-positive CHB who received any NA for at least 72 weeks and had a low level of HBV DNA (≤100 IU/mL) were randomized (1:1) to receive PegIFN alfa-2a (180 μg/week) or NA for 48 weeks. The primary endpoint was change in the hepatitis B surface antigen (HBsAg) titer during antiviral therapy. We randomized 149 CHB patients to the two groups. Compared to baseline, the HBsAg levels in both groups were not lower at week 12, but were lower after 24, 36, and 48 weeks (all p<0.001). The maximal HBsAg decline in the PegIFN alfa-2a group was at week 36 (0.50±0.88 log10 IU/mL), and this decline was smaller in the NA group (0.08±0.46 log10 IU/mL). The percentage of patients with HBeAg seroconversion at week 48 was also greater in the PegIFN alfa-2a group (15/75 [20.0%] vs. 5/74 [6.8%], p = 0.018). Multivariable analysis indicated the PegIFN alfa-2a group had a greater change in HBeAg seroconversion at week 48 (p = 0.027). Patients had relatively good tolerance to PegIFN alfa-2a therapy. CHB patients who switched to PegIFN alfa-2a for 48 weeks had a significantly lower HBsAg titer and increased HBeAg seroconversion relative to those who remained on NA therapy. (ClinicalTrials.gov; NCT01769833).

Robust antiviral responses in severe hepatitis flare persist after early retreatment cessation and lead toward hepatitis B surface antigen loss: A proof‐of‐concept study

Hepatitis B flare has been interpreted as result of immune response against upsurging hepatitis B virus (HBV) and its antigen(s) that may lead to HBV decline/clearance spontaneously. It has been speculated that antiviral therapy could halt the effective immune response with viral persistent as a consequence. A proof-of-concept study was conducted to investigate this issue. Serial biochemical, quantitative hepatitis B surface antigen (HBsAg), interferon-γ (IFN-γ) and tumor-necrosis factor-α (TNF-α) assays were performed in four patients with severe hepatitis flare who had achieved precipitous HBsAg decline within 4weeks of antiviral therapy. TNF-α and IFN-γ were found to be elevated in parallel to upsurging HBV DNA and HBsAg levels in all patients. Higher levels of TNF-α and IFN-γ and levels relative to qHBsAg were observed during and after early termination of therapy within 4weeks in two patients and were followed by further HBsAg decline to <5 IU/ml and even achieved HBsAg loss in one patient. The patient who had stopped therapy on day 44 showed minimal HBsAg decline afterward and the patient who continued therapy showed a 10-fold rebound of qHBsAg from its nadir. The subsequent IFN-γ and TNF-α activity of these two patients was minimal. The results suggest that patients with severe hepatitis flare who achieved precipitous HBsAg decline may have robust immune response to clear the virus, and early termination of antiviral therapy may allow the protective immune response to continue and accelerate HBV decline toward HBsAg loss.