Tenofovir versus entecavir on long-term prognosis in hepatocellular carcinoma patients with concurrent metabolic dysfunction-associated steatotic liver disease and hepatitis B.

BACKGROUND: Currently, 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. METHOD: A 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. RESULTS: This 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). CONCLUSIONS: In 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.

Effects of Bushen Huayu Decoction combined with entecavir on liver function and hepatic fibrosis in patients with compensated cirrhosis.

OBJECTIVE: To analyze the effect of Bushen Huayu Decoction combined with entecavir on alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (Alb) in patients with hepatitis cirrhosis. METHODS: A retrospective study was conducted on 102 patients with compensated hepatitis cirrhosis treated at the No. 2 Hospital of Baoding from February 2020 to April 2023. These patients were divided into two groups based on different treatment modalities: a control group treated with entecavir (n=51) and an observation group treated with Bushen Huayu decoction plus entecavir (n=51). The Traditional Chinese Medicine (TCM) syndrome scores, level of liver function indicators, and liver fibrosis symptoms were compared between the two groups before treatment and after 2 weeks and 4 weeks of treatment. RESULTS: Before treatment, the two groups differed insignificantly in liver fibrosis indicators (HA, IV-C, and PCIII), liver function indices (ALT, AST, TBil, and Alb) and TCM syndrome scores (all P>0.05). After 2 weeks and 4 weeks of treatment, HA, IV-C, and PCIII in both groups decreased. Those in the observation group were significantly lower than those in the control group (P<0.05). The levels ALT, AST, and TBil decreased significantly in both groups. The level of Alb increased significantly, and the alterations in the observation group was more prominent compared with those in the control group (all P<0.05). The scores of TCM syndromes across various aspects all decreased significantly. The scores in the observation group were significantly lower than those of control group (P<0.05). CONCLUSION: The combined treatment of Bushen Huayu Decoction and entecavir is helpful to improve the TCM symptoms, reduce the levels of ALT, AST, and TBil, increase the level of Alb, improve the state of liver fibrosis, and promote the recovery of liver function in patients with compensatory hepatitis cirrhosis.

Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a reconstructed individual patient data meta-analysis.

Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.

A systematic review and meta-analysis comparing the impact of tenofovir and entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma patients undergoing liver resection.

Background: Tenofovir (TDF) and entecavir (ETV) are highly effective and well-tolerated nucleos(t)ide analogs commonly prescribed for hepatitis B virus (HBV) treatment. Yet, it is unclear whether survival outcomes differ for HBV-related hepatocellular carcinoma (HCC) patients treated with ETV and TDF. Thus, this meta-analysis aimed to compare the prognostic effectiveness of ETV and TDF in HBV-related HCC patients. Methods: We comprehensively searched four databases, PubMed, Web of Science, Embase, and the Cochrane Library, to identify pertinent studies utilizing keywords "entecavir," "tenofovir," "hepatocellular carcinoma," and "liver resection." Our primary outcomes of interest encompassed overall survival (OS), recurrence-free survival (RFS), early recurrence, and late recurrence. The statistical effect size for these measures was expressed in terms of hazard ratios (HRs). Results: Our search yielded 10 studies encompassing 11 datasets involving 7,400 patients. Our meta-analysis revealed that patients treated with TDF achieved better OS (HR = 0.53; 95% confidence interval [CI] = 0.40-0.70, p < 0.0001), RFS (HR = 0.68; 95% CI = 0.57-0.80; p < 0.0001), early recurrence (HR = 0.80; 95% CI = 0.67-0.94; p < 0.0077), and late recurrence (HR = 0.64; 95% CI = 0.43-0.97; p = 0.0368). We detected publication bias potentially affecting OS but not RFS. Conclusion: Our findings demonstrated that TDF outperformed ETV regarding RFS for HBV-related HCC patients. However, to bolster the evidence and establish more conclusive conclusions, further validation via extensive and high-quality randomized controlled trials is essential. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD 42024542579.

Successful Treatment of Hepatitis B Virus Reactivation With a Combination of Entecavir and Short-Term Administration of Interferon-ß Twice per Day.

Hepatitis B virus (HBV) reactivation-related hepatitis is likely to progress to acute liver failure, with high morbidity and mortality, even when nucleoside analogs are administered after the onset of hepatitis. We report a case of adult T-cell leukemia/lymphoma (ATLL) with the development of HBV reactivation-related hepatitis during chemotherapy and successful treatment by a combination of entecavir and short-term intravenous administration of interferon (IFN)-ß 3 MIU twice per day. This outcome suggests that this combination therapy has a potent effect in rapidly suppressing HBV replication in the early phase of hepatitis and may be effective and safe for the treatment of HBV reactivation-related hepatitis.

A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) resistance in people treated with entecavir or tenofovir.

BACKGROUND: As nucleos/tide analogue (NA) therapy (e.g. entecavir and tenofovir) for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. A systematic review to quantify resistance to these agents has not previously been undertaken. METHODS: We performed a systematic review and random-effects meta-analysis to estimate the risk of HBV resistance to entecavir and tenofovir. We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting treatment ≥48 weeks, with assessment of HBV resistance based on viral sequence data. Data were analysed according to prior exposure history to NA, and choice of NA agent. Analyses were performed in R. FINDINGS: 62 studies involving a total of 12,358 participants were included. For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), resistance increased over time to 0.9 % at ≥5 years (95 %CI 0.1-2.3 %), and resistance was increased in NA-experienced individuals (18 studies; 1112 individuals), to 20.1 % (95 %CI 1.6-50.1 %) at ≥5 years. For tenofovir, pooled resistance risk was 0.0 % at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis. INTERPRETATION: We have generated the first pooled estimates of HBV entecavir and tenofovir resistance over time. HBV resistance to entecavir in treatment-experienced groups in particular may represent a clinical and public health challenge. To date, tenofovir appears to have an excellent resistance profile, but due to data gaps, we caution that existing studies under-estimate the true real-world risk of resistance. Robust prospective data collection is crucial to reduce health inequities and reduce blind-spots in surveillance as treatment is rolled out more widely.

Lack of association between early on-treatment HBeAg seroclearance and development of hepatocellular carcinoma or decompensated cirrhosis.

Background & Aims: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue (NA) treatment and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) remains unclear. Here, we aimed to investigate the association of HBeAg seroclearance during potent NA treatment with the development of HCC and decompensated cirrhosis. Methods: Using a multicenter historical cohort including 2,392 non-cirrhotic adult patients with HBeAg-positive CHB who initiated NA treatment with tenofovir or entecavir, the risk of HCC and decompensated cirrhosis was compared between patients who achieved HBeAg seroclearance within 36 months of NA treatment (the HBeAg-loss group) and those who did not (the HBeAg-maintained group), using inverse probability of treatment weighting. Results: Over a median of 6.6 years of NA treatment, 1,077 patients achieved HBeAg seroclearance (HBeAg loss rate = 6.0 per 100 person-years), 64 patients developed HCC (HCC incidence rate = 0.39 per 100 person-years), and 46 patients developed decompensated cirrhosis (decompensation incidence rate = 0.28 per 100 person-years). The HBeAg-loss and HBeAg-maintained groups had a similar risk of developing HCC (hazard ratio 0.89; 95% CI 0.47-1.68; p = 0.72) and decompensated cirrhosis (hazard ratio 0.98; 95% CI 0.48-1.81; p = 0.91). Compared with delayed HBeAg seroclearance beyond 10 years of NA treatment, the risk of HCC was comparable in those who achieved earlier HBeAg seroclearance at any time point within 10 years, regardless of baseline age and fibrotic burden. Conclusions: Early HBeAg seroclearance during NA treatment was not associated with a reduced risk of development of HCC or decompensated cirrhosis in non-cirrhotic HBeAg-positive patients with CHB. Impact and implications: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue treatment and the risk of hepatocellular carcinoma in patients with chronic hepatitis B remains unclear. Our findings indicate that early on-treatment HBeAg seroclearance within 3 years was not associated with the development of hepatocellular carcinoma or decompensated cirrhosis. Achieving HBeAg seroclearance may not be an appropriate surrogate endpoint for preventing the development of liver-related outcomes in non-cirrhotic patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues.

Excessive Dynamic Airway Collapse After Entecavir Use in a Patient With Pegylated Interferon-Induced Undifferentiated Connective Tissue Disease and Entecavir Use to Prevent Hepatitis B Virus Reactivation Upon Giving Rituximab.

Pegylated interferon-alpha (PEG-IFN-α) is an antiviral medication used to treat chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. It may result in rare but severe side effects, such as undifferentiated connective tissue disease (UCTD) and excessive dynamic airway collapse (EDAC), which can occur as delayed complications of PEG-IFN-α-induced UCTD. In cases where these complications arise, entecavir, employed for treating HBV infection, may be considered. A 49-year-old female patient, monitored for nine years with HCV and a viral load of 1.5 million, genotype 3, and normal liver function tests (LFTs), possibly acquired the infection from her HCV-positive husband. The patient was initially treated with PEG-IFN-α (IFN-α-2b, 100 µg/week subcutaneously) and ribavirin (RBV, 500 mg/twice daily). Following the sixth injection, the patient exhibited symptoms, including shortness of breath and cough, leading to limited daily activities. Subsequent high-resolution computed tomography (HRCT) showed interstitial pneumonitis (IP) signs. She was given a high dose of steroids. Over the next two to four weeks, the patient experienced Raynaud's phenomenon, skin tightening, joint pains, and dryness of the eyes and mouth. The antinuclear antibody (ANA) test was negative, while the extractable nuclear antigen (ENA) test showed equivocal anti-Smith antibodies (6.38). Rheumatoid factor (RA) factors were mildly positive, and pulmonary function tests (PFTs) indicated a restrictive pattern. The patient was intolerant to hydroxychloroquine (HCQ) and azathioprine (Imuran) 500 mg, subsequently receiving mycophenolate mofetil 500 mg/thrice daily. Despite four years of treatment, UCTD due to PEG-IFN-α remained difficult to control; however, IP responded well to steroids. Rituximab pulse therapy was planned before the initiation; serological tests showed positive anti-HBs with a titer of 17.02, positive anti-HBc, but negative HBsAg and undetectable HBV viral load, indicating immunity to HBV due to natural infection. Given the potential for rituximab to cause immunosuppression and HBV reactivation, entecavir treatment was started and continued for 18 months. The patient was followed for another five years, during which her LFTs and viral markers showed stability. However, after nine years of PEG-IFN-α-induced UCTD disorder, she experienced a reoccurring cough but was unresponsive to steroids that were against her suspicion of a flare of IP. A subsequent dynamic CT scan detected a 75% trachea collapse while in a supine position, indicating a potential complication termed EDAC. This EDAC could not be linked to PEG-IFN-α-induced UCTD disorder or EDAC after the use of entecavir in a patient with PEG-IFN-α-induced UCTD disorder. Treatment of such complex patients requires flexible, specific treatment plans and continuous monitoring. This case emphasizes the need for caution in patients with a history of IFN-induced disease and the possibility of late effects and possible effects of the use of entecavir in a patient with PEG-IFN-α-induced UCTD. To the best of our knowledge, this is the first case reported as EDAC, a possible delayed complication of PEG-IFN-α plus ribavirin or entecavir in a patient with PEG-IFN-α-induced UCTD.

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.

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

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

Mac-2 binding protein glycosylation isomer at 5 years of antiviral therapy predict hepatocellular carcinoma and mortality beyond year 5 in chronic hepatitis B patients with cirrhosis.

Whether serum Mac-2 binding protein glycosylation isomer (M2BPGi) level at year 5 of treatment could predict hepatocellular carcinoma (HCC) development and mortality beyond year 5 of entecavir or tenofovir disoproxil fumarate (TDF) treatment in chronic hepatitis B (CHB) patients with cirrhosis remain unclear. This retrospective study investigated the role of M2BPGi level at year 5 of treatment in predicting HCC and mortality beyond year 5 in CHB patients with cirrhosis. This study analyzed 1385 cirrhotic patients receiving entecavir or TDF treatment. Of them, 899 patients who did not develop HCC within the first 5 years of treatment were enrolled. In the entire cohort, there was no significant difference in the annual incidence of HCC before and after year 5 of entecavir or TDF treatment (P = 0.455). Multivariable Cox analysis identified old age, higher AFP and M2BPGi levels at 5 years of treatment as independent predictors of HCC occurrence beyond year 5. We developed the HCC risk prediction model, AMA, based on age, M2BPGi and AFP levels at 5 years of treatment, with the total score ranging from 0 to 8. The AMA model accurately categorized patients into low (≤2), medium (2-5), and high (≥5) risk groups in the development and validation groups (P<0.001) and exhibited good discriminant function in predicting HCC beyond year 5 in cirrhotic patients (AUROC: 0.743 at 5 years). The M2BPGi of 1.0 COI at 5 years of treatment stratified the risk of all-cause and liver-related mortality beyond year 5 (P<0.001). In conclusions, M2BPGi level at 5 years of treatment is a useful marker for predicting HCC development and mortality beyond year 5 of entecavir or TDF therapy in CHB patients with cirrhosis.

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.

Background and Aims: 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). Methods: 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. Results: 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. Conclusion: 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.

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

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Prospects for Controlling Hepatitis B Globally.

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission.

Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

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

BACKGROUND & AIMS: Factors predicting HBsAg seroclearance after treatment cessation, irrespective of nucleos(t)ide analogue (NA) resumption, have important clinical implications. We evaluated predictors of long-term HBsAg seroclearance after entecavir cessation. METHODS: This study followed-up Chinese patients with chronic hepatitis B from two previous studies of entecavir cessation. All patients were non-cirrhotic, HBeAg-negative, with undetectable HBV DNA (<20 IU/ml) at end-of-treatment (EOT). They were monitored closely for 48 weeks with regular HBV DNA, quantitative HBsAg (qHBsAg) and alanine aminotransferase (ALT) measurements. Entecavir was resumed at HBV DNA >2,000 IU/ml, irrespective of ALT levels. After the initial 48 weeks, patients were assessed every 6 months, regardless of entecavir resumption, to monitor for HBsAg seroclearance. RESULTS: A total of 194 patients (63.4% male, mean age 49.9 years, on entecavir for a median of 47.2 months) were recruited; 94 (48.5%) and 158 (81.4%) patients had EOT qHBsAg <100 IU/ml and <1,000 IU/ml, respectively; 151 (77.8%) patients were eventually resumed on entecavir. After follow-up for a median of 70.7 (51.0-118.2) months, 28 (14.4%) patients had HBsAg seroclearance. qHBsAg levels at weeks 36 and 48 after EOT independently predicted HBsAg seroclearance (both p <0.01), whereas qHBsAg from EOT to week 24 only trended towards statistical significance. The ratio of ALT/qHBsAg at all time points from EOT to week 48 independently predicted HBsAg seroclearance (hazard ratios ranging from 1.003-1.028, all p <0.01) with excellent diagnostic performance (area under the receiver-operating characteristic curve 0.799-0.933, negative predictive value >90% at different time points), regardless of whether entecavir was resumed. CONCLUSIONS: The ALT/qHBsAg ratio after entecavir cessation predicts HBsAg seroclearance, even in patients who were resumed on treatment. Its use may mitigate the risk of severe hepatitis flares in patients managed by observation without treatment resumption. IMPACT AND IMPLICATIONS: Current predictors of HBsAg seroclearance after finite nucleos(t)ide analogue (NA) therapy have suboptimal predictive value. We demonstrated that the ALT/qHBsAg ratio may be able to reflect the balance between host control and virological activity. The ALT/qHBsAg ratio at different time points from end-of-treatment till week 48 independently and accurately predicted HBsAg seroclearance in patients who have stopped entecavir. The ALT/qHBsAg ratio may be utilized by clinicians for patient selection and retreatment decisions in finite NA therapy.

HBsAg kinetics after 7 years of therapy with tenofovir disoproxil fumarate in a cohort of naïve patients affected by chronic hepatitis B with different genotypes.

The role of different genotypes in nucleos(t)ide analogs (NAs) treatment is still debated. Previous studies conducted on special populations evidenced that the E genotype had the lower virological and serological response. This descriptive study aims to recognize the hepatitis B "s" antigen (HBsAg) decline during tenofovir disoproxil fumarate (TDF) treatment in a cohort of patient affected by chronic hepatitis B (CHB). We retrospectively included all patients with CHB treated with TDF between April 2007 and March 2012 with a duration of treatment of 7 years. Kinetics of HBsAg was determined as serological response in this cohort. We include 110 subjects; virological response was observed in all subjects with genotypes A, B, and D; in 17 patients with C genotype (94.4%) and 24 with E genotype (96%). HBeAg loss was observed in 2 patients with genotype A (50%), 3 with B (100%), 0 with C (0%), 1 with D (20%), and 1 with E genotype (25%). In multivariate analysis we observed as predictive factors of HBsAg decline the baseline level of HBsAg (OR = 1.467; 95%CI: 1.221-5.113; p = 0.017) and viral genotypes (OR = 11.218; 95%CI: 5.441-41.138; p < 0.001). This study confirmed higher HBsAg decline after 7 years of treatment in A and B genotypes, and lower in C, E, and D genotypes. However, no evidence is enough to choose a single NAs, but in special populations, as well as in genotype E, the use of TDF should be preferred to entecavir.

Long-Term HBsAg Titer Kinetics with Entecavir/Tenofovir: Implications for Predicting Functional Cure and Low Levels.

The long-term kinetics of quantitative HBsAg levels in HBV-infected patients treated with entecavir or tenofovir, as well as the role of quantitative HBsAg in predicting functional cure (HBsAg loss) and low HBsAg levels (<2 log IU/mL) remain unclear. Of some 1661 consecutively enrolled patients newly treated with entecavir or tenofovir, we analyzed 852 patients who underwent serial HBsAg level checks every 6-12 months. The primary outcomes included long-term kinetics in HBsAg levels and the rate of functional cure and achieving low HBsAg levels. Over a mean 6.3-year follow-up, the functional cure rate was 2.28% (n = 19), and 12.9% (n = 108) achieved low HBsAg levels. A significant HBsAg level reduction was seen in the first treatment year (p < 0.05), with another stepwise decrease between year 6-7. These trends were pronounced in patients with chronic hepatitis and HBeAg-positivity compared to those with cirrhosis and HBeAg-negativity, respectively. Baseline HBsAg of ≤3 log IU/mL and the first-year HBsAg reduction were key predictors for both functional cure and low HBsAg levels (p < 0.05). In conclusion, our findings elucidate the stepwise reduction in quantitative HBsAg dynamics during high-potency NA therapy (entecavir or tenofovir) along with variations based on different conditions. We also underscore the significance of quantitative HBsAg titer in predicting functional cure and low-HBsAg levels.

Risk of hepatocellular carcinoma after curative treatment when switching from tenofovir disoproxil fumarate or entecavir to tenofovir alafenamide: A real-world multicenter cohort study.

AIM: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. METHODS: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods. RESULTS: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings. CONCLUSIONS: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment.

[Diagnosis and treatment of viral hepatitis B and D in 2024]. / Diagnostik und Therapie der Virushepatitis B und D im Jahr 2024.

Despite the availability of vaccines, hepatitis B remains a significant cause of fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The increase in reported hepatitis B cases in Germany is attributed to factors such as immigration and the hepatitis B surface antigen (HBsAg) screening introduced in 2020 as part of health check-ups. The indication for treatment depends on various factors, including the level of hepatitis B virus (HBV) DNA and inflammatory activity. Nucleos(t)ide analogues are the preferred treatment option, but functional cure, defined as HBsAg loss, is rare. In principle, treatment with nucleos(t)ide analogues should usually be discontinued after loss of HBsAg, but can be stopped earlier under certain conditions and is currently the subject of ongoing research. Pregnancy and immunosuppression in the context of hepatitis B require special attention. In addition, a possible hepatitis D virus co-infection must always be taken into account, which is why every HBsAg-positive person should be tested for anti-HDV. Since 2020, the entry inhibitor bulevirtide has become a new treatment option alongside pegylated interferon alfa, which represents a significant advance in the treatment landscape.