Entecavir Research Articles

Lower Incidence of Hepatocellular Carcinoma with Tenofovir Alafenamide in Chronic Hepatitis B: Evidence from a Large-Scale Cohort

Background & AimsThe newer tenofovir alafenamide (TAF) lacks extensive research regarding its impact on hepatocellular carcinoma (HCC). This study aims to evaluate and compare the effects of TAF, tenofovir disoproxil fumarate (TDF), and entecavir (ETV) on HCC incidence using nationwide claim data. MethodsA total of 75,816 treatment-naïve chronic hepatitis B patients were included and divided into TAF (n=25,680), TDF (n=26,954), and ETV (n=23,182) groups after exclusions. Propensity score matching (1:1:1) resulted in 17,537 patients per group, and HCC incidence rates were compared. ResultsBefore matching, the incidence of HCC was significantly lower in the TAF group compared to the TDF and ETV groups (11.47 vs. 15.04 and 14.24 per 1,000 person-years). The incidence rate ratio for TDF was 1.31 (1.19-1.44) and for ETV was 1.24 (1.12-1.37). Before matching, the TAF group had a significantly lower HCC compared to TDF and ETV in both cirrhotic and non-cirrhotic patients. After matching, the TAF group had a lower HCC incidence compared to TDF (12.38 vs. 15.39, incidence rate ratio 1.24, p<0.001) but not ETV (incidence rate ratio 1.08, p=0.219). In cirrhotic patients, TAF had lower HCC incidence than TDF and ETV (30.25 vs. 39.56 and 38.51). In non-cirrhotic patients, TAF had lower HCC incidence than TDF (incidence rate ratio 1.19, p=0.030) but not ETV (incidence rate ratio 0.85, p=0.066). Cox regression analysis showed TAF had a significantly lower HCC incidence compared to TDF (hazard ratio 1.335, p<0.001) and ETV (hazard ratio 1.162, p=0.011), after adjusting for age, gender, and cirrhosis status. ConclusionsThe TAF group consistently demonstrated a lower incidence of HCC compared to the TDF and ETV groups, especially in patients with cirrhosis. IMPACT and IMPLICATIONSThe scientific justification for this work lies in its potential to fill the knowledge gap regarding the comparative efficacy of Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF), and Entecavir (ETV) in reducing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients. The study's findings are particularly crucial for healthcare providers and policymakers, as they highlight the significantly lower incidence of HCC associated with TAF, especially in patients with cirrhosis. These results suggest that TAF could be a preferable antiviral therapy option to mitigate HCC risk, thus influencing clinical decision-making and healthcare guidelines. Practically, these findings can guide physicians in prescribing more effective treatments, assist researchers in designing further studies to explore the mechanisms behind TAF's effectiveness, and inform policymakers in crafting healthcare policies that optimize patient outcomes while considering potential limitations such as the observational nature of the study and residual confounding factors.

A comparison of the therapeutic efficacy of Tenofovir Disoproxil Fumarate and Entecavir in patients with chronic Hepatitis-B

Objective: To compare the therapeutic efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients with chronic Hepatitis-B (CHB). Methods: This retrospective study included 110 patients with CHB who received treatment at The First People’s Hospital of Linping District, Hangzhou from January 2021 to January 2023. Clinical data of the patients were reviewed and the patients were classified according to the treatment received: TDF group (n=53, patients received TDF treatment) and ETV group (n=57, patients received ETV treatment). Hepatitis-B virus deoxyribonucleic acid (HBV DNA) levels, liver function indicators, hepatitis-B e antigen (HBeAg) seroconversion rate, alanine transaminase (ALT) normalization rate, HBV DNA negative conversion rate, overall efficacy, and incidence of adverse reactions were compared. Results: The total efficacy of the treatment in the TDF group was 94.33%, significantly higher than that in the ETV group (78.95%; P&lt;0.05). After the treatment, the HBV DNA levels in both groups decreased compared to pretreatment levels, and were significantly lower in the TDF group compared to the ETV group (P&lt;0.05). Both groups showed significant post-treatment improvement in liver function that was markedly better in the TDF group compared to the ETV group (P&lt;0.05). The HBeAg seroconversion rate, ALT normalization rate, and HBV DNA conversion rate in the TDF group were significantly higher compared to the ETV group (P&lt;0.05). There was no difference in the incidence of adverse reactions between the two groups. Conclusions: Compared with ETV, TDF has comparable adverse reaction profile but has more significant clinical effects in patients with CHB, improving HBeAg seroconversion rate, ALT normalization rate, and HBV DNA negative conversion rate. TDF is associated with lower HBV DNA levels after treatment and better improvements in liver function of patients. doi: https://doi.org/10.12669/pjms.40.10.10307 How to cite this: Wang H, Wu L. A comparison of the therapeutic efficacy of Tenofovir Disoproxil Fumarate and Entecavir in patients with chronic Hepatitis-B. Pak J Med Sci. 2024;40(10):2390-2394. doi: https://doi.org/10.12669/pjms.40.10.10307 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Effect of tenofovir versus entecavir on the long-term prognosis in hepatocellular carcinoma patients with concurrent metabolic dysfunction-associated steatotic liver disease and hepatitis B

BackgroundCurrently, there remains ongoing controversy about the selection of postoperative antiviral drugs for hepatocellular carcinoma (HCC) patients with concurrent metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis B virus (HBV) infection (HPMH) who underwent hepatectomy. MethodA multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were implemented to ensure equal baseline characteristics. The Kaplan‒Meier survival curves were employed for prognosis comparison between the two groups. ResultsThis study included 225 HPMH who all received post-hepatectomy antiviral therapy; with 107 in the tenofovir disoproxil fumarate (TDF) group and 118 in the entecavir (ETV) group. In the entire cohort, according to the multivariate analysis, patients in the TDF group showed better recurrence-free survival (RFS) (HR = 0.78; 95% CI, 0.55–0.95; p = 0.030) and overall survival (OS) (HR = 0.52; 95% CI, 0.30–0.97; p = 0.021) than those in the ETV group. After executing a PSM analysis, Kaplan‒Meier survival curve analysis disclosed significant differences for both RFS and OS between the two groups (p = 0.03 and p = 0.01, respectively). ConclusionsIn summary, our study suggests a more significant association of TDF in improving RFS and OS than ETV in HPMH who underwent hepatectomy through multivariate and PSM analysis. These findings indicate that the choice of antiviral drugs in HPHM holds crucial significance in guiding patient long-term prognosis.

Novel protocol for prevention from hepatitis B reactivation following living-donor liver transplantation.

Reactivation of hepatitis B virus (HBV) after liver transplantation (LT) remains a problem; thus, development of more effective HBV reactivation prophylaxis is desirable. We evaluated the efficacy of a combination of a long-term nucleotide analog (NA), such as entecavir (ETV) or tenofovir alafenamide (TAF), and short-term hepatitis B immunoglobulin (HBIG) in preventing HBV reactivation and compared it with conventional HBV prophylaxis. Between February 1999 and August 2023, 135 patients underwent living-donor liver transplantation for liver cirrhosis or acute liver failure caused by HBV infection or received an LT from a hepatitis B core antibody-positive donor. Recipients who had undergone LT were classified as being in the first or second era (namely until September 2017 and from October 2017), respectively, and outcomes of prophylaxis against HBV reactivation were compared between the two eras. In the second era, recipients with HBV-related disease or who had received hepatitis B core antibody-positive liver received combination therapy with short-term HBIG and an NA such as TAF and ETV long-term. The duration of HBIG treatment was markedly shorter than in the first era in both categories of patients and HBIG could be discontinued in all cases. Surprisingly, we observed HBV reactivation in the first era, but not in the second era, in both groups. We have established a protocol for prophylaxis against HBV reactivation using a combination of short-term HBIG and long-term NA. This protocol was found to be sufficient to prevent HBV reactivation after LT.

AI-Enabled Clinical Decision Support System Modeling for the Prediction of Cirrhosis Complications

Background and ObjectiveUtilizing artificial intelligence (AI), a clinical decision support system (CDSS), can help physicians anticipate possible complications of cirrhosis patients before prescribing more accurate treatments. This study aimed to establish a prototype of AI-CDSS modeling using electronic health records to predict five complications for cirrhosis patients who were controlled for oral antiviral drugs, lamivudine (LAM) or entecavir (ETV). MethodsOur modeling attained a web-based AI-CDSS with four steps – data extraction, sample normalization, AI-enabled machine learning (ML), and system integration. We designed the extract-transform-load (ETL) procedure to filter the analytics features from a clinical database. The data training process applied 10-fold cross-validation to verify diverse ML models due to possible feature patterns with medications for predicting the complications. In addition, we applied both statistical means and standard deviations of the realistic datasets to create the simulative datasets, which contained sufficient and balanced data to train the most efficient models for evaluation. The modeling combined multiple ML methods, such as support vector machine (SVM), random forest (RF), extreme gradient boosting, naive Bayes, and logistic regression, for training fourteen features to generate the AI-CDSS's prediction functionality. ResultsThe models achieving an accuracy of 0.8 after cross-validations would be qualified for the AI-CDSS. SVM and RF models using realistic data predicted jaundice with an accuracy of over 0.82. Furthermore, the SVM models using simulative data reached an accuracy of over 0.85 when predicting patients with jaundice. Our approaches implied that the simulative datasets based on the same distributions as that of the features in the realistic dataset were adequate for training the ML models. The RF model could reach an AUC of up to 0.82 for multiple complications by testing with the un-trained data. Finally, we successfully installed twenty models of the suitable ML methods in the AI-CDSS to predict five complications for cirrhosis patients prescribed with LAM or ETV. ConclusionsOur modeling integrated a self-developed AI-CDSS with the approved ML models to predict cirrhosis complications for aiding clinical decision making.

Risk factors related to low-level viraemia in chronic hepatitis B patients receiving entecavir treatment.

About 20% of on-treatment patients with chronic hepatitis B (CHB) experienced low-level viraemia (LLV), which is associated with persistent low-grade inflammation, fibrosis progression, and increased risk of hepatocellular carcinoma. We aimed to investigate the high-risk factors related to LLV. In this retrospective study, patients receiving entecavir (ETV) treatment from January 2018 to January 2023 were enrolled, and were divided into a LLV (HBV DNA 20-2000 IU/mL) cohort and a complete virological response (CVR) (HBV DNA < 20 IU/mL) cohort according to the virological response at week 48 posttreatment. Treatment baseline characteristics were retrieved from electronic medical records. Multivariate logistic regression was performed. Totally, 1653 patients were enrolled, male patients accounted for 73.0%; the median age was 44 years; the mean HBV DNA level was 5.9 Log10 IU/ml. Among them, 472 (28.6%) experienced LLV. Multivariate analysis showed that HBeAg positivity (OR = 2.650, 95% CI: 2.000-3.511, p < 0.001), HBV DNA ≥ 6.0 Log10 IU/mL (OR = 1.370, 95% CI: 1.054-1.780, p = 0.019), qHBsAg ≥ 9000 IU/mL (OR = 4.472, 95% CI: 3.410-5.866, p < 0.001), cirrhosis (OR = 1.650, 95% CI: 1.234-2.207, P = 0.001), LSM ≥ 13.0 kPa (OR = 1.644, 95% CI: 1.203-2.246, p = 0.002), and PLT < 100×109/L (OR = 1.450, 95% CI: 1.094-1.922, p = 0.010) at baseline were related to the development of LLV. High HBV DNA/HBsAg quantification/LSM, low PLT, HBeAg positivity, and liver cirrhosis were high-risk factors associated with LLV in patients receiving entecavir treatment.

Multi-spectral and docking assessments to explore the combination of an antiviral drug, entecavir with bovine serum albumin

Molecular interaction of entecavir (ETV) with the transport protein, albumin from bovine serum (BSA) was explored through multispectral and molecular docking approaches. The BSA fluorescence was appreciably quenched upon ETV binding and the quenching nature was static. The ETV–BSA complexation and the static quenching process were further reiterated using UV–visible absorption spectra. The binding constant (Ka) values of the complex were found as 1.47 × 104–4.0 × 103 M−1, which depicting a modarate binding strength in the ETV–BSA complexation. The experimental outcomes verified that the stable complexation was primarily influenced by hydrophobic interactions, hydrogen bonds and van der Waals forces. Synchronous and 3-D fluorescence spectral results demonstrated that ETV had significant impact on the hydrophobicity and polarity of the molecular environment near Tyr and Trp residues. Competitive site-markers displacement (with warfarin and ketoprofen) results discovered the suitable binding locus of ETV at site I in BSA. The molecular docking assessments also revealed that ETV formed hydrogen bonds and hydrophobic interactions with BSA, predominantly binding to site I (sub-domain IIA) of BSA.

Efficacy comparison of high-genetic barrier nucleos(t)ide analogues in treatment-naïve chronic hepatitis B patients: a network meta-analysis.

Four high-genetic barrier nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB), namely entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and besifovir dipivoxil maleate (BSV), have been established. The aim of this study is to investigate the efficacy of four high-genetic barrier NAs using a network meta-analysis of randomized trials and propensity score-matched cohorts. Systematic search was performed using PubMed, Cochrane library, and EMBASE and included randomized controlled trials and cohort studies that used propensity score matching. Studies on treatment-naïve CHB patients treated with ETV, TDF, TAF, or BSV were included. Outcomes included alanine aminotransferase normalization and hepatitis B e antigen seroclearance at week 48 and undetectable hepatitis B virus DNA at weeks 48 and 96. Network meta-analysis was performed to synthesize the results. In total, 15,000 patients from 16 studies were included. In terms of 48- and 96-week virologic response (VR), TDF outperformed ETV with statistical significance (48 weeks: odds ratio [OR], 1.38; p < 0.001; 96 weeks: OR, 1.57; p = 0.004). ETV was ranked first for 48-week biochemical response (BR) and outperformed TDF (OR, 0.76; p = 0.028). In the sensitivity analyses, 48-week VR from randomized-controlled trials were compiled, and the same trend toward the superiority of TDF over ETV was found (OR, 1.51; p = 0.030). Four high-genetic barrier NAs were compared, and TDF was more likely to achieve a VR after 48 weeks, while ETV provided a superior BR after 48 weeks.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors

This editorial commented on an article in the World Journal of Gastroenterology titled “Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis” by Colapietro et al In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

Entecavir vs. tenofovir disoproxil fumarate in the treatment of chronic hepatitis B patients with severe acute exacerbation.

The efficacy of different nucleos(t)ide analogs in the treatment of chronic hepatitis B virus (CHB) with severe acute exacerbation (SAE) remained unclear. Thus, this study aimed to compare the short-term efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients having CHB with SAE. We analyzed consecutive patients with treatment-naive CHB receiving TDF (n = 36) or ETV (n = 65) for SAE. The primary endpoint was overall mortality or receipt of liver transplantation (LT) by 24 weeks. The secondary endpoints are the comparison of ETV vs. TDF influences on renal function and virological and biochemical responses at 4, 12, 24, and 48 weeks. The baseline characteristics were comparable between the two groups. By 24 weeks, 8 (22%) patients in the TDF group and 10 (15%) patients in the ETV group had either died (n = 15) or received LT (n = 3) ( P = 0.367). Cox-regression multivariate analysis revealed age ( P = 0.003), baseline international normalized ratio of prothrombin time ( P = 0.024), and early presence of hepatic encephalopathy ( P = 0.003) as independent factors associated with mortality or LT. The two groups of patients achieved comparable biochemical and virological responses at 48 weeks. No significant difference was found in the estimated glomerular filtration rate (eGFR) between the TDF and the ETV groups. However, a significant reduction in the eGFR at 48 weeks, as compared with the baseline, was found in each group. TDF and ETV achieved similar short-term clinical outcomes and treatment responses in CHB patients with SAE.

Investigation of hepatitis B virus mutations associated with immune escape and drug resistance in human immunodeficiency virus-infected patients

Background Co-infection of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) has an impact on high HBV replication and progression to liver cancer. These may lead to cross-resistance of drugs due to therapeutic pressure or liver toxicity. These require continuous monitoring of HBV variants for better diagnosis and treatment strategies. Methods Convenience sampling was used to collect fifty archival sera from Inkosi Albert Luthuli Central Hospital. The Sera were subjected to HBsAg screening using ELISA, DNA extraction, PCR amplification, Sanger sequencing, phylogenetic and mutation analysis. A correlation test was performed to measure the association between polymerase and surface mutations. Results Of the 50 samples, 86% (N= 43/50) were HBsAg positive; 82% (N=41/50) PCR positive and 92% (N=38/41) sequenced. The HBV sequences showed similarity to genotype A (73% [N=19/26]) and (24% [N=7/26]) as genotypes B, C, D, E, F, and G. Prevalence of the mutations in the Surface region was (47% [N=18/38]); including diagnostic failure (K122R and T143S) and vaccines escape mutations (P127T, G145R, S207N, Y200T, E164D, Y206H and L209V). The mutations in the RT was at (36% [N=14/38]) with drug resistance mutations (DRM) at (50% [7/14]). Mutations showed resistance to lamivudine (LMV) at (35% [5/14]), telbivudine (LdT) at (29% [4/14]), (14% [2/14]) for entecavir (ETV) and (21% [3/14]) for adefovir (ADV). One sample had a combination of L180M, M204V, S202K, and M250I mutations. There was no statistical significance between S and RT mutations at P&gt;0.005 and the statistical correlation between RT and SHB mutations was weak at 0.877. Conclusions Our findings highlight the prevalence of HBV genotype A in HIV-infected patients in South Africa. We provide evidence of mutations linked to immune evasion and drug resistance. Mutations have no statistical significance but can have clinical Implication on the diagnosis and treatment of HBV in HBV/HIV co-infected individuals.

Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study.

Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

TDF and TAF inhibit liver cancer cell migration, invasion via p7TP3

Tenofovir disoproxil fumarate (TDF) seems to prevent hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV). However, the mechanism is still little known. This study aimed to investigate the the roles and mechanisms of TDF, tenofovir alafenamide fumarate (TAF), and entecavir (ETV) on the malignant characteristics of liver cancer cells. Using the wound-healing assays, transwell assays, matrigel transwell assays, and cell counting kit-8 (CCK-8) assays, it was possible to identify that TDF/TAF, inhibited migration, invasion, and proliferation of HepG2 cells and Huh7 cells. To investigate the mechanisms, we performed TOP/FOP-Flash system, Western blot, and RT-qPCR assays of liver cancer cells cultured with TDF/TAF and found a lower activity of Wnt/β-catenin signaling pathway compared with control cells. Finally, Hepatitis C virus p7 trans-regulated protein 3 (p7TP3), a tumor suppressor in liver cancers, was significantly increased in HepG2 cells and Huh7 cells that treated with TDF/TAF. However, entecavir (ETV)-treated liver cancer cells showed no significant difference in the malignant characteristics of liver cancer cells, activity of Wnt/β-catenin signaling pathway, and expression of p7TP3, compared with the control groups. To conclude, TDF/TAF maybe novel promising therapeutic strategy for liver cancers, including HCC and hepatoblastoma, via Wnt/β-catenin signaling pathway, by up-regulating expression of the tumor suppressor, p7TP3.

Beneficial Effects of Traditional Chinese Medicine Fuzheng Huayu on the Occurrence of Hepatocellular Carcinoma in Patients with Compensated Chronic Hepatitis B Cirrhosis Receiving Entecavir: A Multicenter Retrospective Cohort Study.

The application of antifibrotic drugs to treat patients with chronic liver diseases who are receiving antiviral therapies for hepatocellular carcinoma (HCC) has not been established. Here, we aimed to assess the impact of the Traditional Chinese Medicine Fuzheng Huayu (FZHY) on the occurrence of HCC in patients with hepatitis B virus-related compensated cirrhosis receiving the antiviral drug entecavir (ETV). A multicenter retrospective cohort study was performed. Compensated liver cirrhosis patients were divided into the ETV+FZHY group or the ETV group according to treatment. The cumulative incidence of HCC was analyzed using Kaplan-Meier and log-rank tests. Propensity score matching was used for confounding factors. Stratified analysis and Cox regression were used to determine the effects of FZHY on the occurrence of HCC and liver function decompensation. Out of 910 chronic hepatitis B patients, 458 were in the ETV+FZHY group and 452 were in the ETV group. After propensity score matching, the 5-year cumulative incidence of HCC was 9.8% in the ETV+FZHY group and 21.8% in the ETV group (p<0.01). The adjusted hazard ratio for HCC was 0.216 (0.108, 0.432) when FZHY treatment was >36 months. Age, diabetes, alanine aminotransferase, γ-glutamyl transpeptidase, albumin, hepatitis B e-antigen, and fibrosis 4 score were associated with the occurrence of HCC. FZHY decreased the risk of HCC in patients aged >45 years with a hepatitis B virus DNA level of ≥2,000 IU/l. Adjunctive FZHY treatment reduced HCC occurrence in patients with hepatitis B virus cirrhosis who were treated with ETV, possibly due to the antifibrotic properties of FZHY.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index>6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P<0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P<0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P=0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P<0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P=0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

COMPARATIVE EFFECTIVENESS OF ENTECAVIR VERSUS TENOFOVIR FOR PREVENTING HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B: A COMPREHENSIVE SYSTEMATIC REVIEW

COMPARATIVE EFFECTIVENESS OF ENTECAVIR VERSUS TENOFOVIR FOR PREVENTING HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B: A COMPREHENSIVE SYSTEMATIC REVIEW

Cost-Utility Analysis of Tenofovir Alafenamide and Entecavir in Chronic Hepatitis B Patients: A Markov Decision Model.

From the perspective of health economics, the evaluation of drug-related cost effectiveness and clinical utility is crucial. We conducted a cost-utility analysis of two first-line drugs, tenofovir alafenamide (TAF) and entecavir (ETV), in the treatment of chronic hepatitis B (CHB) patients. We performed inverse probability of treatment weighting (IPTW) to match the independent variables between the two treatment groups. The incremental cost effectiveness ratio (ICER) of the two treatment groups was simulated using a decision tree with the Markov annual-cycle model. A total of 54 patients treated with TAF and 98 with ETV from January 2016 to December 2020 were enrolled. The total medical cost in the TAF group was NT$76,098 less than that in the ETV group, and TAF demonstrated more effectiveness than ETV by 3.19 quality-adjusted life years (QALYs). When the time horizon was set at 30 years, the ICER of the TAF group compared with the ETV group was -NT$23,878 per QALY, suggesting more cost savings for TAF. Additionally, with the application of TAF, over NT$366 million (approximately US$12 million) can be saved annually. TAF demonstrates cheaper medical costs and more favorable clinical QALYs than ETV. To balance health insurance benefits and cost effectiveness, TAF is the optimal treatment for CHB.

Cost-effectiveness of switching from tenofovir disoproxil fumarate to tenofovir alafenamide versus entecavir for chronic hepatitis B patients in Greece.

Aim: This study assessed the clinical impact and cost-effectiveness of switching from tenofovir disoproxil fumarate (TDF) to either tenofovir alafenamide (TAF) or entecavir (ETV) in a Greek chronic hepatitis B (CHB) population. Patients & methods: A Markov model from the perspective of a third-party payer in Greece quantified the health and economic benefits of switching from TDF to either TAF or ETV over a lifetime horizon. Results: Over a lifetime, patients who switch from TDF to TAF versus patients who switch from TDF to ETV had an overall lower incidence of compensated cirrhosis (0.4% lower), decompensated cirrhosis (0.04% lower) and hepatocellular carcinoma (0.25% lower). Chronic kidney disease and end-stage renal disease were also lower in patients who switch to TAF; major osteoporotic fractures were similar for both groups. While total costs were higher for switching from TDF to TAF versus TDF to ETV due to the higher cost of TAF, switching from TDF to TAF versus ETV was cost effective with an incremental cost-effectiveness ratio of €17,113 per quality-adjusted life year. Conclusion: Switching from TDF to TAF in patients living with CHB is a cost effective strategy to reduce adverse liver disease outcomes, while improving bone- and renal-related safety outcomes.

Unveiling the molecular interaction of hepatitis B virus inhibitor, entecavir with human serum albumin through computational, microscopic and spectroscopic approaches

Molecular docking, molecular dynamics (MD) simulation, atomic force microscopy (AFM) and multi-spectroscopic techniques were selected to unveil the molecular association between the hepatitis B virus (HBV) inhibitor, entecavir (ETR), and the major blood plasma transporter, human serum albumin (HSA). The entire docking and simulation analyses recognized ETR binding to subdomain IIA (Site I) of HSA through hydrogen bonds, hydrophobic and van der Waals forces while maintaining the complex’s stability throughout the 100 ns. A gradual lessening in the Stern-Volmer quenching constant ( K sv ) with rising temperatures registered ETR-induced quenching of HBV fluorescence as static quenching, thus advising complexation between ETR and HSA. The further advocation of this conclusion was seen from a larger value of the biomolecular quenching rate constant (( kq ) > 1010 M−1s−1), changes in the spectra (UV-Vis absorption) of HSA following ETR inclusion and ETR-induced swelling of HSA in the AFM results. The ETR appeared to bind to HSA with moderate affinity ( K a = 1.87 − 1.19 × 10 4 M−1) at 290, 300 and 310 K. Significant alterations in the protein’s secondary and tertiary structures, including changes in the protein’s Tyr/Trp microenvironment, were also detected by circular dichroism and three-dimensional fluorescence spectra when the protein was bound to ETR. The findings of the drug displacement study backed the docking results of Site I as ETR's preferred binding site in HSA. Communicated by Ramaswamy H. Sarma

Tricaprylin-based drug crystalline suspension for intramuscular long-acting delivery of entecavir with alleviated local inflammation.

In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin-based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3-palmitate (EV-P), an ester lipidic prodrug for entecavir (EV), was employed. The EV-P-loaded TS was prepared by ultra-sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 μm), crystallinity (melting point of 160-165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS-injected site, drug aggregates of up to 500 μm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS-injected site, with >4 weeks remaining of the oily vehicle in micro-computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long-acting delivery, with improved local tolerability.