Entecavir Research Articles

Tenofovir versus entecavir for tertiary prevention of hepatocellular carcinoma in chronic hepatitis B infection after curative therapy: A systematic review and meta-analysis.

Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) are the first-line drugs for the treatment of chronic hepatitis B virus (HBV). However, the impact of these two antiviral agents on the outcome of HBV-related hepatocellular carcinoma (HCC) after curative therapy remains to be explored. The purpose of the present study was to compare the effect of ETV and TDF on recurrence and mortality after curative treatment for HBV-related HCC. A comprehensive literature search of multiple electronic databases was conducted from 2000 to January 2022 for studies comparing ETV and TDF for HBV-related HCC patients after curative therapy. The adjusted hazard ratios (aHR) were pooled using a random-effects model. A total of nine studies with 5298 patients were included in the final meta-analysis. TDF was associated with a lower risk of HCC recurrence [aHR 0.73, 95% confidence interval (CI) 0.65-0.81] compared to HCC. TDF reduced the risk of late recurrence compared to ETV (aHR 0.58, 95% CI 0.45-0.76) but not early recurrence (aHR 0.88, 95% CI 0.76-1.02). The mortality risk was also lower with TDF compared to ETV (aHR 0.62, 95% CI 0.50-0.77). TDF was associated with a lower risk of recurrence and mortality than ETV after resection or ablation of HBV-related HCC. Further prospective randomized controlled studies are warranted to validate these results.

ALT Is Not Associated With Achieving Subcirrhotic Liver Stiffness and HCC During Entecavir Therapy in HBV-Related Cirrhosis

We investigated whether baseline and on-treatment alanine aminotransferase (ALT) levels during entecavir (ETV) therapy are associated with achieving subcirrhotic liver stiffness (LS) and hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV)-related cirrhosis. We analyzed data from 347 treatment-naïve patients with HBV-related cirrhosis, who started ETV between 2006 and 2011 and were followed up for >5 years without developing HCC. The study outcomes were achieving subcirrhotic LS at 5 years of ETV, and risk of HCC development beyond 5 years of ETV. Subcirrhotic LS was defined as <12 kPa by transient elastography. After 5 years of ETV, 227 (65.4%) patients achieved subcirrhotic LS. During a median follow-up of 9.2 years, 49 (14.1%) patients developed HCC beyond 5 years of ETV. ALT levels at baseline, at 1 year of ETV therapy, and 5 years of ETV therapy were not associated with the probability of achieving subcirrhotic LS at 5 years of ETV therapy or risk of HCC development beyond 5 years of ETV therapy (all P > .05). Patients achieving subcirrhotic LS at 5 years of ETV therapy had significantly lower risk of HCC development than those who did not (adjusted hazard ratio, 0.33; 95% confidence interval, 0.17-0.64; P= .001). Baseline and on-treatment ALT levels were not associated with achieving subcirrhotic LS at 5 years of ETV therapy or with risk of HCC development beyond 5 years of ETV therapy in patients with HBV-related cirrhosis. Achieving subcirrhotic LS at 5 years of ETV therapy was independently associated with lower risk of HCC development beyond 5 years of ETV therapy.

The Efficacy of Antiviral Treatment for Chronic Hepatitis B Patients with Normal ALT Levels: A Systematic Review and Meta-analysis

Context: When nucleos(t)ide analogues (NAs) were applied clinically to manage chronic hepatitis B virus infection, the prognosis of chronic hepatitis B (CHB) patients greatly improved. However, certain CHB patients with normal alanine aminotransferase (ALT) levels were not used to be considered as the population with the need for antiviral treatment. Objectives: This systematic review and meta-analysis collected and analyzed data from clinical trials to assess and compare the efficacy of antiviral treatment among patients with elevated and normal ALT levels. Methods: A systematic search was performed to gather studies published from 1990.01 to 2022.08 in PubMed and Web of Science databases. The quality of the literature was assessed, and 16 studies were included for further analysis. Basic information on included studies and study populations was collected. A meta-analysis was carried out to evaluate three major outcomes of viral response, hepatitis B envelope antigen (HBeAg) loss, and HBeAg seroconversion after NAs treatment based on data extracted from these studies. Odds ratios (ORs) with 95% confidence intervals (CIs) for all outcomes were calculated using fixed-effects models. Results: In the 16 relevant studies, 5,345 patients met the inclusion criteria, including 3,687 patients receiving NAs treatment. All patients were grouped into one with elevated ALT and another with normal ALT based on whether their pretreatment ALT levels &gt; 1*upper limit of normal (ULN). For patients receiving lamivudine, the viral response showed no significant difference between the groups with elevated and normal ALT levels (pooled log OR: 0.51 [-0.23 - 1.26], P = 0.79); the pooled log OR for HBeAg loss was 1.19 (0.63 - 1.76, P = 0.03) and pooled log OR for HBeAg seroconversion was 2.19 (0.91 - 3.47, P = 0.40). For patients receiving first-line therapy with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), the viral response showed no significant difference between the two groups: Pooled log OR (0.38 [-0.22 - 0.97], P = 0.10). The pooled log OR for HBeAg loss and HBeAg seroconversion was (-0.07 [-0.81 - 0.67], P = 0.68) and (0.40 [-0.84 - 1.63], P = 0.88), respectively. Conclusions: The efficacies of first-line therapy with TDF and ETV treatments were similar in groups with elevated and normal ALT levels for the outcomes of viral response and HBeAg loss. These findings may support further treatment of CHB patients with normal ALT levels.

Baseline Circulating miR-125b Levels Predict a High FIB-4 Index Score in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Treatment.

The regulatory role of microRNAs (miRNAs) in HBV-associated HCC pathogenesis has been reported previously. This study aimed to investigate the association between serum miR-125b and liver fibrosis progression in chronic hepatitis B (CHB) patients after nucleos(t)ide analog (NA) treatment. Baseline serum miR-125b levels and other relevant laboratory data were measured for 124 patients who underwent 12-month NA therapy. Post-12-month NA therapy, serum miR-125, platelet, AST, and ALT levels were measured again for post-treatment FIB-4 index calculation. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for a higher post-treatment FIB-4 index. Results showed that baseline miR-125b levels were inversely correlated with the post-treatment FIB-4 index (ρ = -0.2130, p = 0.0082). In logistic regression analyses, age (OR = 1.17, p &lt; 0.0001), baseline platelet level (OR = 0.98, p = 0.0032), and ALT level (OR = 1.00, p = 0.0241) were independent predictors of FIB-index &gt; 2.9 post-12-month treatment. The baseline miR-125b level was not significantly associated with a higher post-treatment FIB-4 index (p = 0.8992). In 59 patients receiving entecavir (ETV) monotherapy, the alternation of serum miR-125b in 12 months and age were substantially associated with a higher post-treatment FIB-4 index (&gt; 2.9), suggesting that miR-125b is a reliable biomarker for detecting early liver fibrosis under specific anti-HBV NA treatments (e.g., ETV).

Clinical effect and influencing factors of pegylated interferon alfa-2a and entecavir monotherapy among children with HBeAg-positive chronic hepatitis B based on a real-world study

Objective: To compare the efficacy, safety, and influencing factors among children with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B (CHB) who received short-term therapy with pegylated interferon alfa-2a (Peg-IFNα-2a) or continuous therapy with entecavir (ETV). Methods: Quantitative data were compared using analysis of variance to compare the differences between groups. Enumeration data were compared by χ2 test (or Fisher's exact test). Univariate and multivariate logistic regressions were used to analyze the influencing factors. Results: Peg-IFNα-2a, ETV, and untreated group had HBsAg clearance rates of 46.2%, 5.3%, and 0 after 52 weeks of therapy, respectively. HBsAg clearance in the patients' group with Peg-IFNα-2a and ETV was all accompanied by anti-HBS positive conversion, and the difference was statistically significant (χ2=13.616, P=0.001). Peg-IFNα-2a group was followed-up for 104 weeks. Peg-IFNα-2a, ETV, and the untreated group had HBsAg clearance rates of 46.2%, 10.5%, and 0%, respectively, and the differences were statistically significant (χ2=11.056, P=0.004). Only one of the two children with HBsAg clearance in the ETV group had achieved anti-HBs antibodies, and the difference was statistically significant (χ2=13.616, P=0.001). Univariate and multivariate logistic regression analysis showed that HBsAg clearance was associated with age and antiviral therapy. During treatment, adverse events such as fever (n=4, 30.8%), rash (n=4, 30.8%), fatigue (n=1, 7.7%), leukopenia (n=7, 53.8%), arthritis (n=1, 7.7%), and alopecia (n=3, 23.1%) were observed in the Peg-IFNα-2a group, while none were observed in the ETV group. Conclusion: Peg-IFNα-2a antiviral therapy produced higher HBsAg clearance than ETV in five-year-old and younger children with HBeAg-positive CHB, while ETV had fewer adverse events and was safer than Peg-IFNα-2a.

S3176 Tenofovir Disoproxil Fumarate-Related Metabolic Syndrome and Steatohepatitis in a Case of Chronic Hepatitis B

Introduction: Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B virus infection (HBV). TDF is considered to have no direct hepatotoxicity. Herein we present a patient with HBV developing liver test abnormalities and biopsy-proven steatohepatitis (SH) after starting TDF, and the resolution of liver tests and SH after switching TDF to entecavir (ETV). Case Description/Methods: A 48-year-old female patient was admitted to our clinic with positive HBsAg and HBV-DNA level of 21600 copies/mL. Her Anti-HBe was positive and Anti-HDV was negative. Abdominal ultrasonography revealed 2 cm hepatomegaly; her AST was 74 U/L (5-40 U/L) and ALT 125 U/L (10-40 U/L). Her BMI was within normal limits, she had no comorbidities and was not on any medication. Her lipid panel was within the normal range. She was prescribed 245 mg/day TDF, and was scheduled for regular clinical follow-up. Six months later, her AST was 113 U/L, ALT 148 U/L, and her HBV-DNA was negative. The patient was advised to follow-up closely. Eighteen months after the initiation of TDF, her AST increased to 211 U/L and ALT to 216 U/L. Her HbA1c was 6.1% and HOMA-IR was 4.0. MRI showed fat accumulation in the liver, and a liver needle biopsy was performed. Histological evaluation revealed grade 2 steatosis with moderate ballooning degeneration and stage 3/4 fibrosis (Figure 1). Autoimmune serologies including antinuclear antibody and anti-smooth muscle antibody were negative, and ceruloplasmin phenotype was normal. The causation of TDF was hypothesized. TDF was stopped, and ETV 0.5 mg/day was initiated. Her follow-up at month 3 revealed a decreased trend in transaminase levels. The patient lost to follow-up for 2 years, but she used ETV regularly. Her control HbA1c was 5.5% at this last visit and a control abdominal ultrasonography showed no fat accumulation. Discussion: While it is known that TDF co-administration with other nucleoside analogs (e.g., didanosine, stavudine) can cause fatty infiltration of the liver, we present a rare case of metabolic syndrome and SH related with TDF monotherapy. Despite some reports suggesting tenofovir, specifically tenofovir alafenamide, might be associated with adverse metabolic changes in patients with HIV, our patient with HBV developed these changes while she was on TDF. We show that hepatic steatosis associated with TDF can be reversible with the medication change to ETV.Figure 1.: A: Hematoxylin-eosin staining shows 50% steatosis (grade 2), portal and lobular inflammation and moderate hepatocyte ballooning. B: Masson-trichrome staining shows portocentral and pericellular fibrosis (stage 3/4).

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.

Efficacy and Renal Safety of Prophylactic Tenofovir Alafenamide for HBV-Infected Cancer Patients Undergoing Chemotherapy.

There are no data comparing the efficacy and safety of prophylactic entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) for HBV-infected cancer patients undergoing chemotherapy. This study aimed to compare the efficacy and renal safety of ETV, TDF and TAF in this setting. HBsAg-positive cancer patients treated with ETV (n = 582), TDF (n = 200) and TAF (n = 188) during chemotherapy were retrospectively enrolled. Antiviral efficacy and risk of renal events were evaluated. The rate of complete viral suppression at 1 year was 94.7%, 94.7% and 96.1% in ETV, TDF and TAF groups, respectively (p = 0.877). A significant proportion of patients developed renal dysfunction during chemotherapy. The incidences of acute kidney injury (AKI) and chronic kidney disease stage migration were comparable among the ETV, TDF and TAF groups. TAF was relatively safe in patients with predisposing factors of AKI, including hypoalbuminemia and cisplatin use. In patients who were switched from TDF to TAF during chemotherapy, the renal function remained stable and viral suppression was well maintained after switching. In conclusion, TAF had good renal safety and comparable efficacy with ETV and TDF for HBV-infected cancer patients receiving chemotherapy. Switching from TDF to TAF during chemotherapy is safe, without a loss of efficacy.

Fuzheng Huayu Recipe and its active compounds inhibited HBeAg production by promoting TOMM34 gene expression in HBV-infected hepatocytes.

Background and aim: Fuzheng Huayu Recipe (FZHY) is a Chinese patent medicine (approval No. Z20020074) included in the national medical insurance catalogue, which is mainly used for anti-hepatic fibrosis treatment of hepatitis B virus (HBV) induced liver fibrosis and liver cirrhosis. In clinical practice, we discovered that FZHY might also have a direct anti-HBV effect on inhibiting HBeAg production, but the mechanism underlying was unclear. This study aimed to clarify the molecular mechanism of the inhibition effect of FZHY on HBeAg production. Methods: The decrease degree of serum HBeAg titer in FZHY + entecavir (ETV) group patients were analyzed through clinical data. C57BL/6N-Tg (1.28HBV)/Vst HBV transgenic mice were used for in vivo experiments. HepG2. 2.15 cells (wild-type HBV replication cells) were used for in vitro experiments. Results: The clinical study results showed that the decrease degree of serum HBeAg titer in FZHY+ETV group was significantly higher than that in ETV group after 48 weeks treatment. In vivo experiments results showed that FZHY could significantly reduce the serum HBeAg titer in HBV transgenic mice, and promote HBeAg seroconversion. In vitro experiments results showed that FZHY could reduce HBeAg titer dependently, but it did not significantly inhibit the expression of HBsAg and HBV-DNA. Further cell experiments in vitro discovered that TOMM34 might be the key target for FZHY to inhibit HBeAg production. The subsequent pharmacological screening experiment of 20 active compounds in FZHY showed that quercetin, baicalin and cordycepin could promote the expression of TOMM34 gene and reduce the production of HBeAg. Conclusion: In conclusion, FZHY and its active compounds quercetin, baicalin and cordycepin could inhibit HBeAg production by promoting the expression of TOMM34 gene in HBV-infected hepatocytes.

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B.

ObjectiveThe aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.MethodsHBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-β1, TGF-β2, TGF-β3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed.ResultsA total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-β1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001–1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046–0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972–0.999, p = 0.040).ConclusionCytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment.

Comparing the efficacy and safety of tenofovir and adefovir or combined drug treatment for the treatment of chronic hepatitis B infection: a systematic review and meta-analysis.

BackgroundChronic hepatitis B (CHB) affects a vast population globally. A variety of drugs are available for the treatment of CHB, including tenofovir (TDF) and adefovir (ADV). However, the efficacy of monotherapy drug treatment is inconclusive, the safety and efficacy of TDF remain unclear, more data are needed to be included and combined drug treatment is considered to exhibit higher efficacy. To explore this issue, we performed a current literature review and meta-analysis to compare the efficacy and safety of ADV vs. TDF, TDF vs. ADV + lamivudine (LAM); TDF vs. ADV + entecavir (ETV).MethodsWe systematically searched China National Knowledge Infrastructure, the Cochrane Library, Embase, PubMed, Chinese VIP, and Wanfang Data, for relevant clinical trials since July 2015, all included studies were based on PICOS principles and evaluated independently by the reviewers in accordance with the Cochrane Handbook (Rob2.0). A meta-analysis was performed by using Review Manager 5.4.ResultsWe included a total of 32 studies, including 31 randomized controlled trials and one retrospective study involving 2,473 patients. The results revealed a low risk of bias in included studies, that the virologic response of TDF was superior to ADV (P<0.05). And TDF was also superior to ADV in Serum creatinine levels, Immunologic function, and safety profile. However, when ADV was combined with other medications, it was superior to TDF in alanine aminotransferase (ALT) level and Tbil level and adverse reactions, but on other indicators, TDF was superior to drug combination therapy.ConclusionsResults showed that TDF was superior to ADV in the parameters of ALT, hepatitis B virus (HBV)-DNA reduction, HBeAg-negative conversion rate, safety, and total bilirubin levels in patients with CHB. However, when ADV was combined with LAM or ETV, they often showed the same therapeutic effect as TDF in parameters such as ALT level and Tbil level and combined therapy can effectively reduce the occurrence of adverse reactions. In this study, because the sample source countries were limited, a greater number of global studies are needed in the future to verify the current findings.

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

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. 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. 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. 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.

Predictive value of serum HBV RNA for therapeutic effect of entecavir in patients with chronic hepatitis B

To investigate the value of HBV RNA for predicting the therapeutic effect of long-term entecavir (ETV) antiviral therapy in patients with chronic hepatitis B (CHB). Serum samples were collected from 59 CHB patients treated with ETV for 96 or 108 months. HBV RNA levels, HBV DNA levels, and serological marker (HBeAg) levels were measured at baseline and 3, 6, 9, 12, 36, 72, and 96 (or 108) months during the therapy. Although HBV RNA level decreased after 12 and 36 months of ETV antiviral therapy, no significance changes occurred in HBV RNA negative conversion rate (P>0.05). After 72 months of treatment or longer, 33 patients had HBV RNA levels lower than 100 copies/mL, and among them 29 patients had HBV RNA levels lower than the detection limit, and HBV RNA negative conversion rate was statistically significant (P < 0.05). A lower HBV RNA level was associated with a higher HBeAg negative conversion rate (P < 0.05). Age and HBV RNA level were positively correlated with HBeAg negative conversion rate (P < 0.05). Prolonged ETV antiviral therapy results in better clearance of HBV RNA and a higher negative conversion rate in CHB patients. The length of antiviral therapy and age are positively correlated with the negative conversion rate of HBV RNA, and earlier administration of the antiviral treatment achieves better therapeutic effect. Serum HBV RNA level can be used as an indicator for predicting conversion to negative HBeAg in CHB patients receiving ETV therapy.

The decline of HBV RNA associated with HBeAg seroconversion and double-negative HBV DNA and RNA in chronic hepatitis B patients who received entecavir therapy: a 10-year retrospective cohort study.

BackgroundWhether the decline of hepatitis B virus (HBV) RNA was associated with antiviral efficacy in chronic hepatitis B (CHB) patients receiving long-term nucleos(t)ide analogues (NAs) therapy remains unclear. We observed the levels of serum HBV RNA in CHB patients treated with entecavir (ETV) for 10 years and explored the clinical significance of HBV RNA during long-term antiviral treatment.MethodsA total of 33 hepatitis B surface antigen (HBsAg)-positive CHB patients treated with ETV for up to 10 years were recruited for this study. Liver function, HBsAg, hepatitis B envelope antigen (HBeAg), HBV DNA, and HBV RNA were measured at the baseline and each follow-up points. Antiviral efficacy was defined as negative HBV DNA (<20 IU/mL) and HBV RNA (<300 Copies/mL).Results(I) Serum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years (P<0.001). (II) There were positive correlations between serum HBV DNA and HBV RNA at each follow-up point (r=0.62 and P<0.001 at baseline, r=0.77 and P<0.001 at week 24, r=0.71 and P<0.001 at week 48, r=0.81 and P<0.001 at week 96, r=0.60 and P<0.01 at year 5 and r=0.77 and P<0.001 at year 10). (III) HBeAg and HBsAg levels at baseline and 10th year after ETV treatment have significant difference (P<0.05 and P<0.01). (IV) The decline of HBV RNA after ETV treatment was associated with HBeAg seroconversion, the area under the ROC curves (AUROCs) of the declines of HBV RNA were 0.25 at the baseline, 0.62 at week 24, 0.78 at week 48 and 0.86 at week 96, respectively. (V) The decline of HBV RNA after ETV treatment was associated with antiviral efficacy, the AUROCs of the declines of HBV RNA were 0.33 at the baseline, 0.74 at week 24, 0.83 at week 48 and 0.86 at week 96, respectively.ConclusionsSerum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years. The decline of HBV RNA was associated with HBeAg seroconversion and antiviral efficacy in CHB patients receiving long-term ETV therapy, and the earliest prediction point was week 24.

The efficacy of pegylated interferon alpha-2a and entecavir in HBeAg-positive children and adolescents with chronic hepatitis B

Background and objectivesPegylated interferon alpha-2a (peg-IFN α-2a) and entecavir (ETV) are both recommended as the first-line antiviral drugs for chronic hepatitis B (CHB) at present. We aimed to compare the efficacy and safety between peg-IFN α-2a and ETV initial therapy in children and adolescents with CHB and investigate the potential factors affecting the treatment response during the first 48 weeks.MethodsWe retrospectively selected 70 treatment-naïve children and adolescents with CHB who received peg-IFN α-2a(n = 26) or ETV(n = 44) as initial therapy and completed 48-week follow-up for data analysis. Blood samples before treatment were collected from 26 patients of the cohort to assess the cytokine profiles.ResultsWe found that initial peg-IFN therapy results in higher rates of hepatitis B surface antigen (HBsAg) serological response (SR) but lower rates of virological and biochemical response rates compared to ETV at week 48. As for achieving hepatitis B e antigen (HBeAg) SR, peg-IFN was comparable to ETV in the univariate analysis and turned out to be better than ETV after adjustment for important baseline factors. We also found that elevated pre-treatment IL-18 level was significantly associated with HBeAg SR, and remained as the only independent factor of predicting HBeAg SR after adjustment for other important factors. No serious adverse effects of the 2 drugs were reported during the 48-week follow-up.Conclusionscomparing to ETV, peg-IFN was superior in achieving HBsAg and HBeAg SR; higher baseline IL-18 levels were independently associated with HBeAg SR in this study of children and adolescents with CHB.

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

Background and AimsWhether 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. MethodsThis 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. ResultsDuring 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. ConclusionsTDF 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.

Real-life impact of tenofovir disoproxil fumarate and entecavir therapy on lipid profile, glucose, and uric acid in chronic hepatitis B patients.

The impact of long-term nucleos(t)ide analogs treatment on host metabolism is a concern. Hence, we conducted this study to compare the effect of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on metabolic parameters among chronic hepatitis B(CHB) patients.In this real-life retrospective study, 2030 CHB outpatients treated with ETV or TDF at Nanfang Hospital, China, were included. For treatment-naïve patients, pretreatment and semiannual metabolic parameters were collected. For treatment-experienced patients, metabolic parameters were collected at the first visit. Propensity score matching (PSM) was used to balance the effects of potential confounding factors.Among 122 treatment-naïve patients and 1908 treatment-experienced patients, ETV-treated patients were older with a higher percentage of metabolic syndrome. After PSM, the characteristics were comparable between the two groups. For treatment-naïve patients, four lipid parameters, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglyceride levels showed a decreasing trend during the 42-month TDF treatment, while they remained relatively stable or increased during ETV treatment. At Month 30, the levels of TC and LDL among TDF-treated patients were significantly lower than those among ETV-treated patients (TC: 4.7 mmol/L vs. 3.9 mmol/L, p = 0.004; LDL: 3.0 mmol/L vs. 2.4 mmol/L, p = 0.009). For treatment-experienced patients, we also observed lower levels of lipid parameters in patients with different durations of TDF treatment. The levels of glucose and uric acid were similar among ETV- and TDF-treated patients.TDF has a lipid-lowering effect in CHB patients, which provides a basis for the selection of antiviral drugs for aging CHB patients.

Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir.

Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs inhibit HBV DNA synthesis by targeting the reverse transcriptase (RT) domain of HBV polymerase. Several mutations in the RT domain which lead to drug resistance against NAs have been reported, even for TDF and TAF which are highly potent with very low resistance rate. Besifovir (BFV) is a new antiviral dGMP analogue able to be used as a new NA drug for the control of CHB infection. Drug resistance to BFV is not well known due to its shorter duration of clinical use. Recently, we reported that rtL180M (M) and rtM204V (V) mutations, already resistant to LMV, are associated with BFV resistance. However, the susceptibility to BFV of previously known HBV mutants resistant to various drugs has not been studied. To investigate this, we performed in vitro drug susceptibility assays using natural and artificial mutants that are associated with resistance to LMV, ADV, ETV or TDF. As a result, LMV-resistant mutants were not susceptible to BFV and ETV-resistant clones showed partial resistance against BFV as well. However, ADV-resistant mutants were highly sensitive to BFV. In case of tenofovir-resistant mutations, the HBV mutants harboring primary mutations to tenofovir resistance were susceptible to BFV. Therefore, our study revealed that BSV may serve as an alternative drug for patients with ADV-, ETV-, TDF- or TAF-resistance.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double‐blind, double‐dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty‐seven (71 in group A) patients with HBeAg‐positive CHB and 46 (21 in group A) patients with HBeAg‐negative CHB completed the 240‐week treatment and follow‐up. Baseline characteristics were well balanced between the two groups. For the HBeAg‐positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg‐negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long‐term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Prognostic value of plasma level of superoxide dismutase in HBV-related acute-on-chronic liver failure

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is the most prevalent type of ACLF in China. The mortality rate of HBV-ACLF has decreased in recent years due to advances in treatment therapies; however, it is still above 50%. Many cases of HBV-ACLF are caused by HBV reactivation due to discontinuation of nucleoside analog treatment. The present study focused on plasma levels of superoxide dismutase (SOD) in HBV-ACLF patients and investigated whether the plasma level of SOD is a useful biomarker in assessing disease severity and predicting outcomes of HBV-ACLF patients, including patients treated with Entecavir (ETV) and patients who were withdrawn from ETV treatment.MethodsPlasma samples and clinical data from 200 HBV-ACLF patients and from age- and sex-matched cirrhotic and healthy controls were collected and analyzed. Plasma levels of SOD were measured using an ELISA commercial kit.ResultsAmong the HBV-ACLF patients, in the ETV withdrawal group, the mortality rate was higher than in the ETV group (69.95% vs 46.71%, P < 0.05). Moreover, HBV-DNA and SOD plasma levels were higher in the ETV withdrawal group than in the ETV group (Log10(HBV-DNA): 6.49 ± 0.24 vs 4.79 ± 0.14, P < 0.01; SOD: 463.1 ± 27.61 U/mL vs 397.2 ± 10.97 U/mL, P < 0.05). The mortality and liver transplantation rates were significantly higher in HBV-ACLF patients with plasma levels of SOD > 428 U/mL than in patients with plasma SOD levels ≤ 428 U/mL.ConclusionsReactivation of HBV and elevated oxidative stress caused by discontinuation of ETV treatment are crucial factors in the pathogenesis of HBV-ACLF. Plasma level of SOD may serve as a useful biomarker in estimating disease severity and predicting outcomes of HBV-ACLF patients who stop ETV treatment.