Entecavir Combination Research Articles

Roles Played by DOCK11, a Guanine Nucleotide Exchange Factor, in HBV Entry and Persistence in Hepatocytes

HBV infection is challenging to cure due to the persistence of viral covalently closed circular viral DNA (cccDNA). The dedicator of cytokinesis 11 (DOCK11) is recognized as a guanine nucleotide exchange factor (GEF) for CDC42 that has been reported to be required for HBV persistence. DOCK11 is expressed in both the cytoplasm and nucleus of human hepatocytes and is functionally associated with retrograde trafficking proteins Arf-GAP with GTPase domain, ankyrin repeat, and pleckstrin homology domain-containing protein 2 (AGAP2), and ADP-ribosylation factor 1 (ARF1), together with the HBV capsid, in the trans-Golgi network (TGN). This opens an alternative retrograde trafficking route for HBV from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. DOCK11 also facilitates the association of cccDNA with H3K4me3 and RNA Pol II for activating cccDNA transcription. In addition, DOCK11 plays a crucial role in the host DNA repair system, being essential for cccDNA synthesis. This function can be inhibited by 10M-D42AN, a novel DOCK11-binding peptide, leading to the suppression of HBV replication both in vitro and in vivo. Treatment with a combination of 10M-D42AN and entecavir may represent a promising therapeutic strategy for patients with chronic hepatitis B (CHB). Consequently, DOCK11 may be seen as a potential candidate molecule in the development of molecularly targeted drugs against CHB.

Predictive role of early treatment dynamics of HBV RNA and HBcrAg for HBeAg seroconversion in children with chronic hepatitis B.

This study aimed to assess the predictive capacity of emerging serological markers, serum HBV RNA and HBcrAg, for HBeAg seroconversion in children with HBeAg-positive chronic hepatitis B (CHB). Treatment-naïve HBeAg-positive CHB children who admitted to the Liver Disease Center of Hunan Children's Hospital between April 2021 and September 2022 and received treatment with the combined entecavir and interferon-alpha treatment were recruited. Serum HBV RNA and HBcrAg were measured at baseline and Weeks 12, 24, and 48 of treatment. Our study showed that serum HBV RNA (HR = 0.71, 95% CI: 0.56-0.91, p = 0.006), HBcrAg (HR = 0.60, 95% CI: 0.43-0.84, p = 0.003), and HBsAg (HR = 0.49, 95%CI: 0.36-0.69, p < 0.001) at Week 12 were independent predictors of HBeAg seroconversion. ROC curve analysis presented that serum HBV RNA decline value (ΔHBV RNA) at Week 36 and HBcrAg decline value (ΔHBcrAg) at Week 12 (AUC = 0.871, p = 0.003 and AUC = 0.810, p = 0.003, respectively) could effectively predict HBeAg seroconversion. Furthermore, the optimal critical values were determined and the children with ΔHBV RNA > 3.759 log10 copies/mL at Week 36 or ΔHBcrAg >0.350 log10 U/mL at Week 12 more likely to achieve HBeAg seroconversion. The serum HBV RNA and HBcrAg provide new insights into the treatment of CHB in children. Early assessment of serum HBV RNA and HBcrAg during treatment can assist clinical decision-making and optimize individualized therapeutic approaches.

Comparative effectiveness of glycyrrhizic acid preparations aimed at improving liver function of patients with chronic hepatitis B: A network meta-analysis of 53 randomized controlled trials

Background and objectivesEntecavir (ETV) has disadvantages, such as poor improvement in liver function, during the treatment of Chronic hepatitis B (CHB). Thus ETV is often used in clinical therapy with glycyrrhizic acid (GA) preparations. However, due to the lack of reliable and direct clinical studies, it remains controversial whether glycyrrhizic acid preparations have the best efficacy in CHB. Therefore, we aimed to compare and rank the different GA preparations in the treatment of CHB using network meta-analysis (NMA). MethodsWe systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Science, China national knowledge internet (CNKI), Wanfang, VIP, and SinoMed databases as of August 4, 2022. Literature was screened according to predefined inclusion and exclusion criteria to extract meaningful information. A Bayesian approach was used for random effects model network meta-analysis, and Stata 17 software was used for data analysis. ResultsFrom 1074 papers, we included 53 relevant randomized clinical trials (RCTs). For the primary outcome, we used the overall effective rate in assessing the effectiveness of treatment for CHB (31 RCTs including 3007 patients): CGI, CGT, DGC and MgIGI significantly reduced the incidence of overall response compared to controls (RRs range from 1.16 to 1.24); SUCRA results showed that MgIGI was the best (SUCRA 0.923). In terms of secondary outcomes, we assessed the effect of treatment for CHB according to the level of reduction in ALT and AST: for ALT (37 RCTs including 3752 patients), CGI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to controls (MD range from 14.65 to 20.41); SUCRA results showed that CGI was the best (SUCRA 0.87); for AST, GI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to the control group (MD range from 17.46 to 24.42); SUCRA results showed that MgIGI was the best (SUCRA 0.871). ConclusionIn this study, we verified that the combination of GA and Entecavir is more effective than entecavir monotherapy in the treatment of hepatitis B. MgIGI and CGI showed clinically significant effects on liver function recovery compared with other GA preparations. MgIGI appeared to be the best choice among all GA preparations for the treatment of CHB. Our study provides some references for the treatment of CHB.

Effect of entecavir plus peginterferon α-2a on hepatitis B virus-RNA, IL-21 expression level, immune function and prognosis in patients with hepatitis B

Combination of interferon and nucleotide analogues might be more effective in inhibiting replication of hepatitis B virus (HBV), thereby alleviating hepatic fibrosis and hepatocyte necrosis. Herein, we explored the impact of co-treatment of entecavir (ETV) and PEG-IFNα-2a on HBV-RNA, IL-21 level, immune function and prognosis in HBeAg-positive patients with low HBsAg level. Patients treated with ETV over 12 months received PEG-IFNα-2a treatment. Serum HBV markers and HBV-DNA were examined at 12, 24 and 48 weeks, and disappearance of HBsAg were measured at 24 weeks as an evaluation index for efficacy. Besides, levels of IL-21, serum albumin, and complement C3 were measured. During follow-up, we found that, HBsAg serological conversion appeared in 6.0% of all patients, with HBsAg disappearance in 18.1% and HBsAg &lt;10 IU/mL in 10.8%. The HBeAg level in non-disappearing group was lower than HBsAg disappearing group (P &lt;0.05) with AUC score of 0.720 for HBsAg suggested by HBeAg conversion rate (P &lt;0.05). Of note, HBsAg levels decreased at 12 weeks of treatment (≥0.5 log IU/mL) and HBsAg was prone to disappearance (P &lt;0.05). AUC of HBsAg disappearance predicted by the HBsAg levels at 12 weeks and 24 weeks were 0.810 (95% CI: 0.686–0.935, P = 0.000) and 0.842 (95% CI: 0.736–0.947, P = 0.000) compared with baseline. Combination of ETV and PEG-IFNα-2a resulted in enhancement of serum IL-21 level (210.803±72.477) and reduction of IL-21 expression (157.084±38.697). The IL-21 level was negatively correlated with immune function indicators serum albumin and serum complement C3. HBsAg conversion rate and early HBsAg changes are crucial to prediction of HBsAg disappearance. With ETV achieving great virological response, combination of ETV with PEG-IFNα-2a enhanced HBsAg loss, reducing IL-21 expression, and improving immune function in patients.

Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients

The combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT. This retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV. Only 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA-positive patients remained at a lower level than that of HBV-DNA-negative patients. Entecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.

Analysis of efficacy and factors influencing sequential combination therapy with tenofovir alafenamide fumarate after treatment with entecavir in chronic hepatitis B patients with low-level viremia

Objective: To observe the efficacy and factors influencing sequential or combined tenofovir alafenamide fumarate (TAF) after treatment with entecavir (ETV) in patients with chronic hepatitis B (CHB) with low-level viremia (LLV). Methods: 126 CHB cases treated with ETV antiviral therapy in the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 2020-September 2022 were retrospectively collected. Patients were divided into a complete virologic response (CVR) group (n = 84) and a low-level viremia (LLV) group (n = 42) according to the HBV DNA level during treatment. Clinical characteristics and laboratory indicators of the two groups at baseline and 48 weeks were analyzed by univariate analysis. Patients in the LLV group were divided into three groups according to their continued antiviral treatment regimen until 96 weeks: continued use of ETV as a control group; replacement of TAF as a sequential group; and combination of ETV and TAF as a combined group. The data of the three groups of patients were analyzed by one-way analysis of variance for 48 weeks. HBV DNA negative conversion rate, HBeAg negative conversion rate, alanine aminotransferase (ALT), creatinine (Cr), and liver stiffness test (LSM) were compared among the three groups after 96 weeks of antiviral treatment. Multivariate logistic regression was used to analyze the independent factors influencing the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Receiver operating characteristic curve (ROC) was used to evaluate the effectiveness of predicting the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Kaplan-Meier was used to analyze the cumulative negative rate of DNA in LLV patients, and the Log-Rank test was used for comparison. HBV DNA and HBV DNA negative conversion rates during treatment were observed dynamically. Results: Univariate analysis showed statistically significant differences in age, BMI, HBeAg positivity rate, HBV DNA, HBsAg, ALT, AST, and LSM at baseline between the CVR group and the LLV group (P < 0.05). Univariate analysis of variance revealed no statistically significant difference among the three groups of LLV patients at 48 weeks (P > 0.05). HBV-DNA negative conversion rate in the sequential group and the combination group was significantly higher than that in the control group after 96 weeks of treatment (88.89% vs. 41.18%, 85.71% vs. 41.18%, χ (2) = 10.404, P = 0.006). HBeAg negative conversion rate was higher than that of the control group, with no statistically significant difference (P > 0.05).Compared with the control group, ALT, Cr, and LSM in the sequential group and the combined group were equally improved to varying degrees, with a statistically significant difference (P < 0.05). Subsequent use of ETV and HBV DNA at 48 weeks were independent risk factors for HBV DNA positivity at 96 weeks in LLV patients (P < 0.05). The AUC of HBV DNA at 48 weeks was 0.735 (95%CI: 0.578 ~ 0.891), the cut-off value was 2.63 log(10) IU/ml, and the sensitivity and specificity were 76.90% and 72.40%, respectively. DNA conversion rate was significantly lower in LLV patients receiving 48-week ETV and 48-week HBV DNA≥2.63 log10 IU/mL than in patients receiving sequential or combined TAF and 48-week HBV DNA < 2.63 log(10) IU/mL. HBV DNA negative conversion rates in the sequential group and combined group at 72 weeks, 84 weeks, and 96 weeks were higher than those in the control group during the period from 48 weeks to 96 weeks of continuous treatment, and the differences were statistically significant (P < 0.05). Conclusion: Sequential or combined TAF antiviral therapy could more effectively improve the 96-week CVR rate, as well as hepatic and renal function, and alleviate the degree of hepatic fibrosis in CHB patients with LLV following ETV treatment. Subsequent use of ETV and HBV DNA load at 48 weeks were independent predictors of HBV DNA positivity at 96 weeks in LLV patients.

H3K9 acetylation modification and TLR9 immune regulation mechanism in patients after anti-HBV treatment

To improve the curative effect of anti-hepatitis B virus (HBV) drugs, methods such as thymosin and entecavir combination have become a focus of clinical investigation. The aim of this retrospective experimental study was to explore the potential mechanism of action of thymosin a1 (Ta1) combined with entecavir in the treatment of HBV infection. A total of 28 patients with chronic hepatitis B, 29 patients treated with thymosin a1 and entecavir combination, and 15 healthy individuals were enrolled in this study. RT-qPCR was conducted to evaluate the mRNA levels of TLR9 in peripheral blood mononuclear cells (PBMCs). The serum level of TLR9 protein was analyzed by ELISA. The binding of TLR9 gene to the protein H3K9Ac in PBMCs was assessed by chromatin immunoprecipitation, and serum inflammatory factors were detected by Luminex technology. The expression levels of TLR9 mRNA and serum TLR9 protein in patients with HBV infection were significantly lower than those in subjects in the control group before treatment but increased after treatment with the Ta1 and entecavir combination. Moreover, the acetylation protein H3K9Ac was significantly bound to the promoter region of the TLR9 gene in patients with HBV infection treated with the Ta1 and entecavir combination compared to that in patients with HBV infection without treatment. Furthermore, the expression levels of interleukin 6 (IL-6), interleukin 12 (IL-12), interferon gamma, and necrosis factor alpha in patients with HBV infection after the combination treatment were slightly decreased compared to those in patients with HBV infection without treatment. In conclusion, the histone acetylation modification of TLR9 was significantly improved in patients with HBV infection after treatment with the Ta1 and entecavir combination, which elevated the expression of TLR9 at the mRNA and protein levels and further regulated the expression of IL-6, IL-12, and other cytokines.

A meritorious integrated medical regimen for hepatic fibrosis and its complications via the systematic review and meta-analysis for Dahuang Zhechong pill-based therapy

BackgroundHepatic fibrosis is a health challenge due to the absence of satisfactory therapy, especially at the cirrhosis stage. Dahuang Zhechong pill (DHZCP)-based therapy is reportedly a successful treatment for hepatic fibrosis and is even beneficial for the treatment of cirrhosis. Hence, a systematic review and clinical evidence assessment of DHZCP-based therapy should be performed, and clinical recommendations based on its efficacy for the treatment of hepatic fibrosis should be generated. With respect to potential indicators, the comparative value of the hepatic function, spleen thickness, and portal vein internal diameter should be evaluated.Materials and methodsPubMed, the Excerpta Medica Database, the Cochrane Library, the Web of Science, the WanFang Database, the Chinese Scientific Journal Database, and the Chinese National Knowledge Infrastructure database were searched to identify clinical trials. Three subgroup analyses were performed based on the stage of disease, medication use, and the course of treatment. Statistical analyses were performed using Review Manager 5.4.ResultsA total of 18 studies including 1,494 patients were evaluated. The DHZCP-based therapy was effective in reducing the plasma levels of hyaluronic acid, and laminin, procollagen III, and IV collagen were also reduced irrespective of the hepatitis stage or the presence of hepatic cirrhosis. Abnormalities in alanine aminotransferase, aspartate aminotransferase, albumin, and total bilirubin were reversed. A 6-month course of treatment was the most beneficial DHZCP-based therapy regimen. Alanine aminotransferase improvement was more obvious in patients with cirrhosis, and alanine aminotransferase was reduced significantly in patients with hepatic cirrhosis. With respect to pharmacological mechanisms, DHZCP-based therapy could inhibit hepatic stellate cell growth and activation, reduce inflammation, and prevent extracellular matrix formation. Hepatic portal hypertension and splenomegaly were ameliorated significantly in the DHZCP-based therapy group.ConclusionDahuang Zhechong pill-based therapy has demonstrated efficacy as a treatment for hepatic fibrosis and cirrhosis. A 6-month course of treatment is the recommended option for DHZCP-based therapy in clinical practice. The combination of DHZCP-based therapy and entecavir is a favorable treatment for hepatic cirrhosis.

The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.

The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. ClinicalTrials.gov Identifier NCT03062813.

Bushen Jianpi Formula Combined with Entecavir for the Treatment of HBeAg-Negative Chronic Hepatitis B: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background Bushen Jianpi formula (BSJPF, also known as Lingmao formula) is a traditional Chinese medicine for chronic hepatitis B (CHB). The previous study has suggested that the treatment combination of BSJPF and entecavir (ETV) can achieve a significant loss of hepatitis B e antigen (HBeAg) and a significant decrease in serum level of hepatitis B virus (HBV) DNA in HBeAg-positive CHB patients with mildly elevated alanine aminotransferase. Objective This study aimed to evaluate the efficacy and safety of BSJPF combined with ETV for treating HBeAg-negative CHB patients. Methods A total of 640 patients were assigned randomly to the treatment group (receiving BSJPF combined with ETV for 96 weeks) or the control group (receiving a placebo combined with ETV for 96 weeks) in a 1 : 1 ratio. The primary endpoints are the rate of loss of hepatitis B surface antigen (HBsAg). The secondary outcomes included the rate of decrease in the HBsAg concentration to ≥1 lg·IU/mL, the HBV DNA suppression, the decline of the level of covalently closed circular DNA (cccDNA) in the liver, histological improvements, and the rate of ALT normalization. Results The rate of HBsAg loss in the treatment group was significantly higher than that of the control group (5.5% versus 1.8%, P=0.031). There were 11.1% of patients in the treatment group who recorded a reduction in HBsAg ≥1 lg·IU/mL, which is better than 5.9% of patients in the control group (P=0.043). There was no significant difference between the two groups with regard to the rate of HBV DNA clearance, the reduction in intrahepatic cccDNA, and the rate of ALT normalization (P > 0.05). The rate of liver fibrosis improvement in the treatment group was better than that of the control group (35.5% versus 11.8%, P=0.031), but there was no difference in necroinflammatory improvement (P > 0.05). The adverse events (AEs) were similar between the two groups, except for the abnormal kidney function, with 2.2% in the control group and 0.0% in the treatment group (P=0.028). Conclusion The combination of BSJPF and ETV can increase the rate of HBsAg loss and the rate of histological fibrosis improvement without serious adverse events in CHB patients. Trial Registration. This trial is registered with ChiCTR-IOR-16009880 on November 16, 2016—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=16836.

Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy.

Seroclearance of hepatitis B surface antigen (HBsAg) (“functional cure”) is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into “simultaneous” combination (“de novo” strategy); “sequential” combination, which involved starting with one therapy followed by the other (“switch-to” strategy); “add-on” combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.

The clinical efficacy and adverse effects of Entecavir plus Thymosin alpha-1 combination therapy versus Entecavir Monotherapy in HBV-related cirrhosis: a systematic review and meta-analysis

BackgroundPrevious studies have demonstrated the benefits of thymosin alpha-1 (Tα1) in anti-virus, immunological enhancement and anti-inflammation. However, it is controversial about the efficacy and safety of entecavir (ETV) plus Tα1 combination therapy versus ETV monotherapy in cirrhotic patients with hepatitis B virus (HBV) infection.MethodsThe systematic review and meta-analysis of randomized clinical trials (RCTs) were performed to evaluate the efficacy and safety of ETV plus Tα1 combination therapy versus ETV monotherapy in HBV-related patients with cirrhosis. We performed a systematic literature search via PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), and Chinese Biological Medicine database (CBM). Relative risk (RR) and standardized mean difference (SMD) with a fixed- or random- effect model were calculated. Heterogeneity was assessed through a Cochrane Q-test and I2 values.ResultsSeven RCTs involving 1144 subjects were included in the systematic review and meta-analysis. Compared with ETV monotherapy, ETV plus Tα1 combination therapy led to a higher complete response (RR = 1.18; 95% CI, 1.07–1.30). In post treatment for 24 weeks, the HBV DNA undetectable rate and HBeAg loss rate were higher in ETV plus Tα1 group than in ETV alone group (RR = 1.91; 95% CI, 1.56–2.35; RR = 2.05; 95% CI, 1.62–2.60). However, after 48 and 52 weeks of treatment, there was no significant difference between the combination therapy and ETV monotherapy (RR = 1.07; 95% CI, 0.96–1.18; RR = 1.17; 95% CI, 0.89–1.55). At week 52 of treatment, the HBsAg loss rate of ETV plus Tα1 group was no significance with that of ETV alone group (RR = 1.03; 95% CI, 0.15–7.26). In comparison with ETV alone, the some biochemical parameters and liver fibrosis were obviously improved by ETV plus Tα1, and there was significant heterogeneity. In addition, the number of adverse events was significantly reduced by ETV plus Tα1, compared to ETV alone (RR = 0.48; 95% CI, 0.24–0.95).ConclusionsETV plus Tα1 might lead to a higher clinical response and a lower comprehensive adverse reaction rate in HBV-related patients with cirrhosis, compared to ETV alone. However, the whole patients included in this meta-analysis were from Chinese mainland, so that more worldwide RCTs with a larger sample size are needed to verify the current findings.

Peginterferon and Entecavir Combination Therapy Improves Outcome of Non-Early Response Hepatitis B e Antigen-Positive Patients.

BackgroundThe efficacy of nucleot(s)ide analogs (NAs) and pegylated interferon (PegIFN) combination therapy for hepatitis B e antigen–positive (HBeAg+) patients is still controversial. Whether PegIFN and entecavir (ETV) combination therapy could provide a greater benefit for HBeAg+ patients was assessed.MethodsTreatment-naïve HBeAg+ patients initiated on PegIFN alfa-2a (PegIFNα-2a) for 24 weeks without early response (early response: HBsAg <1500 IU/mL and hepatitis B virus [HBV] DNA <105 copies/mL) were recruited in the current study. Among total of 94 patients, 51 were continued on PegIFNα-2a monotherapy, and 43 were offered PegIFNα-2a and ETV combined therapy.ResultsBetter outcomes in response to the combined therapy, compared with that of the monotherapy, were demonstrated, including more HBsAg decline and loss and HBV DNA decline and HBeAg clearance. Importantly, the patients with HBsAg levels between 1500 and 20 000 IU/mL initially or between 5000 and 20 000 IU/mL after 24 weeks of PegIFNα-2a benefitted more from the combined therapy, compared with those on monotherapy.ConclusionsCombined therapy of PegIFNα-2a and ETV is more efficacious for HBeAg+ patients without early response to PegIFN monotherapy, and HBsAg levels are a good predictor of treatment outcomes.

Histological Outcome of Fuzheng Huayu plus Entecavir Combination Therapy in Chronic Hepatitis B Patients with Significant Liver Fibrosis.

Background and Aims: To evaluate the efficacy of Fuzheng Huayu (FZHY), a Chinese herbal formula, plus entecavir (ETV) in regression of liver fibrosis in chronic hepatitis B (CHB) patients with significant fibrosis/cirrhosis.Methods: The current study was a two-center, randomized, double-blind and placebo-controlled pilot study. Fifty-two currently untreated chronic hepatitis B patients with Ishak fibrosis score ≥3 points were identified and 1:1 randomized into FZHY plus ETV combination and placebo plus ETV groups. The second liver biopsy was performed after 48-week treatment. Necroinflammatory improvement and regression of fibrosis were assessed. Fine changes in different collagen features in paired liver biopsies were evaluated by dual-photon microscopy for both groups.Results: Forty-nine patients completed the full course of treatment; forty-six of them underwent second liver biopsy (for which twenty-two were in the combination group and twenty-four were in the control group). Compared to those in the control group, patients in the combination group had significantly higher rate of fibrosis regression (82% vs. 54%) (p<0.05). Furthermore, the necroinflammatory improvement was greater in the combination group than in the control group (59% vs. 25%, p<0.05). Among the more than 80 collagen parameters in the dual-photon analysis, 5 decreased significantly in the combination group compared to the control group (p<0.05). However, no significant improvement was detected in either biochemical, virologic or serologic responses between these two groups at week 48.Conclusions: The combination therapy of FZHY plus ETV for 48 weeks resulted in a higher rate of necroinflammatory improvement and fibrosis regression than ETV alone in chronic hepatitis B patients with significant fibrosis/cirrhosis. The clinical trial number is ChiCTR-TRC-11001377.

Is tenofovir and entecavir combination therapy still the optimal treatment for chronic hepatitis B patients with prior suboptimal response?

Is tenofovir and entecavir combination therapy still the optimal treatment for chronic hepatitis B patients with prior suboptimal response?

Analysis and Simulation of a Fractional Order Optimal Control Model for HBV

In this paper, we propose a fractional optimal control model of anti-HBV infection based on saturation incidence and logistic proliferation of uninfected cells for the first time. We derive the basic reproduction number R0 and the cytotoxic T lymphocyte immune response reproductive number R1 and give the stable analysis based on R0 and R1. We analyse the optimal control condition and give two optimal control strategies about entecavir monotherapy and combination therapy of traditional Chinese medicine and entecavir with different fractional orders by simulation. The simulation shows that combination therapy may be a good choice in anti-HBV infection therapy. We also compare the objective function values of the optimal control strategies with other constant control strategies; the comparison shows that the optimal therapy can get similar or better treatment effect with less drug dose and side effects.

Treating Chronic Hepatitis B Liver Fibrosis with a Combination of Biejiaruangan Compound Tablet and Entecavir with the aid of Real-time Shear Wave Elastography

The aim of the present study was to observe clinical effect of the combination of Biejiaruangan compound tablet and entecavir under the assistance of real-time shear wave elastography for treating chronic hepatitis B liver fibrosis. About 180 patients who had been treated for chronic hepatitis B liver fibrosis at the Second Hospital of Yinzhou were enrolled. The real-time shear wave elastography was applied. The patients were randomized into the research group and the control group, each containing 90 patients. The control group was treated with entecavir, while the research group was treated with a combination of Biejiaruangan compound tablet and entecavir. The therapeutic efficacy was compared between both groups. Patients’ liver stiffness was obviously decreased after treatment (p<0.05). The research group had better hepatic function index than the control group (p<0.05). Moreover, a greater decrease in the hepatic fibrosis index and abdominal ultrasonography was observed in both groups after treatment, compared to those before therapy. The therapeutic efficacy of the research group was significantly better as well (p<0.05). For treating chronic hepatitis B liver fibrosis, a combination of Biejiaruangan compound tablet and entecavir with the aid of real-time shear wave elastography could achieve good clinical efficacy as well as significantly improve the therapeutic efficiency.

Clinical Efficacy and Safety of Eight Traditional Chinese Medicine Combined with Entecavir in the Treatment of Chronic Hepatitis B Liver Fibrosis in Adults: A Network Meta-Analysis.

Background Traditional Chinese medicine (TCM) is used as an adjuvant drug for the treatment of chronic hepatitis B liver fibrosis and is used frequently. We still do not know which TCM has the best curative effect as an adjuvant drug. Therefore, we decided to use network meta-analysis to solve this problem. Methods We used the RevMan software (5.3) and Stata software (13.0) to achieve this network meta-analysis (NMA). The primary outcomes of this study were HA, LN, PCIII, and IV-C; the secondary outcomes of this study were AST, ALT, and HBV-DNA negative conversion rate, and the Cochrane risk-of-bias tool was used to assess the quality of the included studies. For all outcomes, the scissors funnel plot, Egger test, and Begg test were used to detect publication bias, and sensitivity analysis was used to investigate the stability of the results. And the meta-regression was used to explore the source of heterogeneity. Results A total of 34 articles were included in this study. The study involved a total of 3199 patients, of which 1578 were assigned to the control group and 1621 patients were assigned to the experimental group. The number of men and women is roughly equal, and the average age is about 43 years old. In addition, nine treatment strategies were involved in this study. The combination of TCM and entecavir can significantly improve the patients' HA, LN, PCIII, IV-C, AST, ALT, and HBV-DNA negative conversion rates. The comprehensive evaluation results showed that FHC combined with entecavir has more advantages than other treatment strategies. Conclusion For improving the HBV-DNA negative conversion rates, adding TCM to the therapeutic strategies does not seem to show absolute superiority. Finally, FHC combined with entecavir is the best therapeutic strategy.

Advances in anti hepatic fibrotic therapy with Traditional Chinese Medicine herbal formula.

The process of liver fibrogenesis includes a number of common and etiology-dependent or independent mechanisms and events. Up to now, there are still insufficient approved biological or chemical therapies directly targeting and reversing advanced fibrosis. The key is that once liver fibrosis is triggered, it presents a complex network control model with the activation of HSCs as the core, resulting in poor efficacy of treatment. Traditional Chinese medicine (TCM) has unique advantages in treating hepatic fibrosis because of its syndrome differentiation and treatment and comprehensive pharmacological effects of multi-channel, multi-level and multi-target. However, TCM's advantages were rarely discussed as previous reviews focused on the active ingredients of TCM and single Chinese Medicine. Therefore, this paper focuses on TCM herbal formulae's pharmacological role, target and related mechanisms in the treatment of liver fibrosis. This paper will focus on the pharmacological role, target and related mechanisms of TCM herbal formulae in the treatment of liver fibrosis. We collect English literatures or Chinese literatures with English Abstract on the treatment of liver fibrosis with TCM herbal formulae from databases including PubMed, Wiley InterScience, Science Direct OnSite/Elsevier, Ovid, Excerpta Medica Database, SpringLink, CNKI and China Biomedical Literature Database. Based on previous literatures, we summarize the TCM herbal formulae with definite anti-hepatic fibrosis effects. To some extent, classical or modern TCM herbal formulae including Yinchenhao Decoction (YCHD), Xiayuxue Decoction (XYXD), Xiaochaihutang (XCHT), Yiguanjian Decoction (YGJ), Huangqi Decoction (HQD), Dahuang Zhechong Pills (DHZC), Fuzheng Huayu Formula (FZHY), Fufang Biejia Ruangan Tablets (FFBJRG), Anluo Huaxian Pills (ALHX) and Compound 861 (Cpd861) have anti-hepatic fibrosis effect both on patients with liver fibrosis and animal models with liver fibrosis. According to the principle of syndrome differentiation and treatment, Liver fibrosis patients with different syndromes are treated with different herbal formula, which increases the difficulty of clinical efficacy research. YCHD and XYXD research lack randomized and controlled clinical trials. XCHT, YGJ and HQD research has small sample sizes despite randomized and controlled clinical trials. In contrast, most modern herbal formulae have randomized and controlled clinical trials. For instance, FZHY and ALHX recently published the research results of the combination of entecavir in the treatment of patients with chronic hepatitis B liver fibrosis or cirrhosis. Compared to anti-viral treatment with entecavir alone, this method has improved the reversion rate of liver fibrosis but still needs syndrome classification therapy of TCM. TCM Herbal formulae have a good prospect in treating liver fibrosis, but its composition of multiple drugs and a wide range of targets intensify the difficulty of studying their anti-hepatic fibrosis mechanisms. Future research needs to further study the anti-hepatic fibrosis mechanisms and select corresponding TCM herbal formula to treat patients with different syndromes of liver fibrosis or the same patient with different syndromes at different stages to achieve better curative results.

Tenofovir monotherapy versus tenofovir plus entecavir combination therapy in HBeAg-positive chronic hepatitis patients with partial virological response to entecavir.

The aim of this retrospective study was to compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) monotherapy and TDF + entecavir (ETV) combination therapy for chronic hepatitis B (CHB) patients with the partial virological response (PVR) to ETV. CHB patients with PVR to ETV were switched to TDF monotherapy or TDF + ETV combination therapy. The primary efficacy outcome was a virological response (VR), and the secondary efficacy outcomes were hepatitis B e antigen (HBeAg) seroconversion and alanine aminotransferase (ALT) normalization. The primary safety outcomes were changes in serum creatinine and serum phosphorus levels. A total of 143 patients were investigated, including 63 patients in the TDF monotherapy group and 80 patients in the TDF + ETV combination therapy group. Baseline demographics and clinical characteristics were comparable between groups. The median age of patients was 44.5 years, and 76.2% of them were male. The VR rate in TDF + ETV group was higher than that of the TDF group at 48 weeks (88.8% vs 71.4%; P = .009). At 48 weeks, the HBeAg seroconversion rate of TDF + ETV group was higher than that of the TDF group (30% vs 15.9%; P = .049). There was no significant difference in the proportion of patients with elevated ALT in the TDF group and TDF + ETV group at 48 weeks (9.5% vs 7.5%; P = .665). After adjusting the treatment regimen, serum creatinine levels increased slightly and serum phosphorus level decreased slightly in both groups. TDF + ETV combination therapy for 48 weeks had a higher VR rate than TDF monotherapy in CHB patients with PVR to ETV.