ALT Normalization Rate Research Articles

Efficacy and safety of tenofovir amibufenamide in the treatment of patients over 65 years of age with chronic hepatitis B

Objective: To investigate the efficacy and safety of tenofovir amibufenamide in patients over 65 years old with chronic hepatitis B and liver cirrhosis. Methods: We recruited 45 patients in Linyi People's Hospital with chronic hepatitis B and liver cirrhosis who were treated with TMF antiviral therapy for 48 weeks, compared the virologic response rate and HBV DNA decrease level at 12, 24 and 48 weeks, and the changes in hepatitis B surface antigen, alanine aminotransferase, glomerular filtration rate, creatinine, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum phosphorus and blood lipids, and the changes in ALT normalization rate at 48 weeks. P<0.05 was statistically significant. Results: The age of the enrolled patients was 69.0 (67.0, 72.5) years. At 12, 24, and 48 weeks of treatment, the complete virological response rates were 32.4% (12/37), 70.0% (28/40), and 84.6% (33/39) respectively, and the level of HBV DNA decreased from baseline (P＜0.05). After 48 weeks of treatment, the level of HBsAg decreased (P<0.05), and there was no negative HBsAg conversion and seroconversion. After 48 weeks of treatment, the level of ALT decreased (P<0.05). At 48 weeks of treatment, the rates of ALT reverted to normality were 88.9% (16/18) and 70.4% (19/27), respectively. There was no significant difference in the levels of glomerular filtration rate, creatinine, phosphorus, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol estimated at baseline before and after treatment (P＞0.05), and no serious adverse events were observed. Conclusions: For patients over 65 years old with chronic hepatitis B and liver cirrhosis, TMF can significantly inhibit HBV DNA replication, and the ALT normalization rate is high and well tolerated.

Real-world study on the efficacy and safety of different treatment regimens in treatment-naïve CHB patients with high viral load

Evaluate the real-world effectiveness and safety of different treatment regimens for treatment-naïve high viral load chronic hepatitis B (CHB) patients. Between January 2021 and August 2022, CHB patients with HBV DNA ≥ 107 IU/mL were collected from four medical centers in Shenzhen. Patients treated with mono or combine antiviral therapy. The primary endpoint was the cumulative incidence of virological response at 48 weeks, and other endpoints included changes in HBsAg, HBeAg, ALT, and eGFR at 48 weeks. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the bias. Weighted logistics regression was used to estimate the factors affecting virological response. A total of 391 patients were included in the study, with 296 patients undergoing statistical analysis after IPTW. The patients were distributed into four groups: ETV (n = 62), TDF (n = 89), TAF (n = 36), TDF + LdT/ETV (n = 109). The 48-week cumulative incidence of virological response was significantly lower in ETV group (52.3%) compared to TDF (71.7%), TAF (74.2%), and TDF + LdT/ETV groups (77.9%) (P < 0.05). There were no significant differences in HBsAg loss among the four groups, but the HBeAg seroconversion rate was significantly higher in the TAF group. The ALT normalization rate was significantly higher in the TAF group (72.2%) compared to the others at 48 weeks (P < 0.05). In treatment-naïve CHB patients with high viral load, combination therapy was not superior to TDF or TAF monotherapy in virological response. Patients treated with TDF or TAF showed superior virological response compared to those treated with ETV. The TAF group demonstrated superiority in terms of ALT normalization and HBeAg seroconversion.

Comparative efficacy and safety of tenofovir amibufenamide vs tenofovir alafenamide in the initial 48-week treatment of high viral load chronic hepatitis B: A single-centre retrospective study.

Tenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB). We retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed. Baseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups. TMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.

Real-world study on the efficacy and safety of first-line antiviral therapy for chronic hepatitis B

Objective: To clarify the clinical efficacy of first-line oral antiviral drugs tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), and entecavir (ETV) in the treatment of chronic hepatitis B (CHB) and their safety profiles with lipid, bone, and kidney metabolism. Methods: 458 CHB cases diagnosed and treated at the Department of Hepatology of Integrated Traditional Chinese and Western Medicine of the Third Hospital of Hebei Medical University from February 2010 to November 2022 were selected. TAF (175 cases), TDF (124 cases), and ETV (159 cases) were used as therapies. At 24 and 48 weeks, the virology, biochemical response, changes in liver stiffness measurement (LSM), and bone, kidney, and blood lipid metabolism safety profiles were compared and analyzed. Results: After 24 and 48 weeks of TAF, TDF, and ETV therapy, HBV DNA load decreased by 3.28, 2.69, and 3.14 log10 IU/ml and 3.28, 2.83, and 3.65 log10 IU/ml, respectively, compared with the baseline, and the differences between the three groups were statistically significant, P < 0.001. The complete virological response rates were 73.95%, 66.09%, 67.19%, and 82.22%, 72.48%, and 70.49%, respectively. The incidence rates of low-level viremia were 16.67%, 21.70%, and 23.08%, while poor response rates were 1.11%, 3.67%, and 4.10%. ALT normalization rates were 64.00%, 63.89%, 67.96%, and 85.33%, 80.56%, 78.64%, respectively, and there was no statistically significant difference among the groups. LSM was significantly improved in patients treated with TAF for 48 weeks, P = 0.022. Serum phosphorus level gradually decreased with the prolongation of TDF treatment. The TAF treatment group had a good safety profile for kidney, bone, and phosphorus metabolism, with no dyslipidemia or related occurrences of risk. Conclusion: There are some differences in the therapeutic effects of first-line anti-HBV drugs. TAF has the lowest incidence of low-level viremia after 48 weeks of treatment and has a good safety profile in kidney, bone, and blood lipid metabolism.

The efficacy and safety of Chinese patent medicine LWWL combined with nucleoside/nucleotide analogues in treatment of chronic hepatitis B: A systematic review and meta-analysis

BackgroundHBV infection is still one of the serious public health problems in the world. NAs as the first line drugs effectively inhibit viral replication, whereas the suppressive effects are much weaker on HBV antigen expression. Chinese patent medicine Liuweiwuling tablet (LWWL) has been used for chronic hepatitis B (CHB) patients for more than 10 years as an adjuvant treatment. Objective. This study aimed to assess the efficacy and safety of LWWL combined with NAs in treating CHB by meta-analysis. Methods. Systematic searches for randomized controlled trials (RCT) were conducted in four databases (up to December 2020) without language restrictions. Data were analyzed using Cochrane RevMan software version 5.3.0 and Stata software version 13.1, and reported as weight mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CIs). The primary outcomes were negative conversion rate of serum HBV DNA and HBeAg. The secondary outcomes were improvement of liver function including ALT and AST, and adverse drug reactions. The quality of evidence was evaluated according to criteria from the Cochrane risk of bias. Results. A total of 201 potentially relevant publications were identified, and 20 RCTs were eligible for inclusion. For the negative rate of HBV DNA (OR ​= ​2, 95%CI:1.64–2.45, P ＜0.05) and HBeAg (OR ​= ​1.83, 95%CI:1.46–2.30, P＜0.05), there were both statically significant benefit in favor of LWWL combined with NAs. In addition, Meta-analysis also showed that LWWL combined with NAs significantly reduced ALT (WMD ​= ​−17.73, 95%CI: 21.37∼-14.09, P ​< ​0.01), AST (MD ​= ​-23.49, 95%CI: −30.52∼-16.45, P ​< ​0.05), and increased the normalization rate of ALT (OR ​= ​3.89, 95%CI:2.82–5.36, P ​< ​0.01). Conclusion. The negative conversion rates of HBV DNA, HBeAg, and improvement of liver function in patients treated with LWWL combined with NAs were significantly higher than those treated with NAs alone, and no serious ADRs were identified. This work provides a reference to the evidence, for the beneficial effects of LWWL combined with NAs in treating CHB.

Evaluation of the efficacy of tenofovir disoproxil fumarate in the treatment of chronic hepatitis B combined with nonalcoholic fatty liver disease by high-sensitivity detection of HBV DNA levels

Objective: To observe the efficacy of tenofovir disoproxil fumarate (TDF) antiviral therapy in patients with chronic hepatitis B (CHB) combined with nonalcoholic fatty liver disease (NAFLD), so as to provide evidence-based evidence in these special populations. Methods: Data from 91 CHB cases who received TDF 300 mg/d antiviral therapy for 96 weeks were analyzed retrospectively. Among them, 43 cases with NAFLD were included in the study group, and 48 cases without NAFLD were included in the control group. The virological and biochemical responses of the two groups of patients at 12, 24, 48, and 96 weeks were compared. Among them, 69 patients underwent highly sensitive detection of HBV DNA. The t-test and χ (2) test were performed on the data. Results: ALT normalization rate was lower in the study group (42%, 51%) at 12 and 24 weeks of treatment than that in the control group (69%, 79%), and the difference was statistically significant (P < 0.05). However, there was no statistically significant difference between the two groups at 48 and 96 weeks. HBV DNA concentration below the lower limit of detection (200 IU/ml) was lower in the study group at 12 weeks of treatment than in the control group (35% vs. 56%), and the difference was statistically significant (P < 0.05). However, there was no statistically significant difference between the two groups at 24, 48, and 96 weeks. Furthermore, HBV DNA concentration below the lower limit was significantly lower in the study group than that in the control group at 12, 24, 48, and 96 weeks of treatment when the lower limit of HBV DNA detection was set at 20IU/ml, and the difference was statistically significant (P < 0.05). The HBeAg serological negative conversion rate was gradually higher in the study group at 48 and 96 weeks of treatment than in the control group, and the difference was not statistically significant. Conclusion: TDF antiviral treatment can affect the virological and biochemical responses of NAFLD in chronic hepatitis B.

Retreatment Efficacy and Renal Safety of Tenofovir Alafenamide, Entecavir, and Tenofovir Disoproxil Fumarate After Entecavir or Tenofovir Cessation.

We aimed to compare the one-year retreatment efficacy and renal safety of entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) after HBV relapse in patients who discontinued entecavir or TDF. This retrospective study included 289 chronic hepatitis B (CHB) patients without cirrhosis who received entecavir (n = 93), TDF (n = 103), or TAF (n = 86) retreatment for at least 12months after entecavir or TDF cessation. The rate of virological response (HBV DNA < 20IU/mL) at 12months of retreatment was 79/93 (84.9%) in the entecavir group, 92/103 (89.3%) in the TDF group, and 72/86 (83.7%) in the TAF group. The rate of ALT normalization (ALT ≤ 40 U/L) after 12months of retreatment was 76/93 (81.7%) in the entecavir group, 77/103 (74.7%) in the TDF group , and 73/86 (84.9%) in the TAF group. There was no significant difference in the rates of virological response (p = 0.495) and ALT normalization (p = 0.198) among the three groups. Multivariate analysis showed thatlower HBV DNA and HBsAg levels at baseline were independently associated with virological response at 12months of retreatment. The TDF group (37.8 ± 34.8 U/L) had higher ALT levels at 12months of retreatment than the TAF (27. ± 17.9 U/L, p = 0.015) and entecavir (28.3 ± 19.3 U/L, p = 0.022) groups. In patients with eGFR 60-90mL/min/1.73 m2, eGFR change between baseline and 12months of retreatment increased in the entecavir and TAF groups and decreased in the TDF group. TAF could be one of the retreatment options for retreatment of HBV relapse after entecavir or TDF cessation.

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.

Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients

BackgroundEntecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue.MethodsPatients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups.ResultsThe rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups.ConclusionsTDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

Nucleos(t)ide analogue therapy: The role of tenofovir alafenamide.

Chronic hepatitis B virus (HBV) infection remains an important global health problem, and may be difficult to manage in clinical practice. Nucleos(t)ide analogues (NAs) with a high barrier to resistance (entecavir [ETV], tenofovir disoproxil fumarate [TDF] and tenofovir alafenamide [TAF]) are the most frequently used HBV treatments because of their long-term effectiveness and tolerability. ETV may be less effective in patients with lamivudine-resistant strains, and TDF is associated with impaired renal function and reductions in bone mineral density. TAF, a new tenofovir prodrug, has been developed to overcome the less favourable safety profile of TDF. TAF is more stable in plasma, and higher tenofovir levels are achieved within cells at lower doses than with TDF. Several registration and real-life studies, performed up to week 144 of treatment, have shown that TAF is at least as effective as TDF, with higher rates of ALT normalization and significantly fewer kidney disturbances and changes in bone mineral density. No emergence of drug resistance has been found with TAF use. The main limitation to prescribing TAF is its price. The European Association for the Study of the Liver has suggested selecting TAF or ETV instead of TDF in patients >65years old and in those with a risk of osteoporosis or renal abnormalities, and to prescribe TAF rather than ETV in patients previously exposed to NAs.

Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice.

Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. We analyzed 834 patients with CHB previously treated with TDF for ≥12months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA<20IU/mL), biochemical (alanine aminotransferase [ALT]<35/25U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96weeks after switch. Viral suppression (P<0.001) and ALT normalization (P=0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend >0.44) or mean eGFR (P>0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR<90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P=0.029) but not after TAF switch (P=0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

Systematic review and Meta-analysis of efficacy and safety of Compound Glycyrrhizin Injection in improving chronic hepatitis B liver damage

To evaluate the efficacy and safety of Compound Glycyrrhizin Injection(CGI) in improving liver damage in chronic hepatitis B(CHB). PubMed, Web of Science, SinoMed, CNKI, Wanfang and VIP databases were retrieved from their inception to February 10, 2020. The randomized controlled trial(RCT) of CGI in the treatment of CHB was included. Data were independently extracted by two authors, and the methodological quality was evaluated using the Cochrane bias risk assessment tool by other two authors. Statistical analysis was performed using RevMan 5.3 software. A total of 18 two-armed RCTs were included, involving 1 915 participants. The methodological quality of all studies included was generally low. In the comparison between CGI and diammonium glycyrrhizinate, the results showed that CGI was superior to the control group in improving the overall clinical effectiveness, but there was no statistical difference between the two groups in increasing ALT normalization rate, reducing ALT and AST level. In the comparison between CGI and diammonium glycyrrhizinate+other general hepatoprotective drugs, the results showed that CGI was superior to the control group in reducing AST level, while there was no statistical difference between the two groups in reducing ALT level and increasing overall clinical effectiveness. In the comparison between CGI+other commonly used drugs(including energy mixture, glutathione, vitamins, potassium magnesium aspartate) and diammonium glycyrrhizinate+other commonly used drugs, the results showed that CGI combined with other commonly used drugs was better than the control group in reducing ALT and AST level and improving the clinical total effective rate, and there was no statistical difference between the two groups in increasing the rate of ALT normalization. In the comparison between CGI+other commonly used drugs and other commonly used drugs, the results showed that CGI combined with other commonly used drugs was superior to the control group in reducing ALT and AST level and improving the overall clinical effectiveness. In the comparison between CGI+vitamins and diammonium glycyrrhizinate+potassium magnesium aspartate+vitamins, the results showed no statistical difference between the two groups in reducing AST level. A small number of studies included reported that CGI caused mild adverse reactions when used alone or in combination with other drugs. Based on the results, CGI has a certain effect in improving CHB liver damage, but the evidence is not enough to prove that CGI would cause serious adverse events. In the future, more well-designed and strictly-enforced RCT with an adequate sample size are needed to further evaluate the effect CGI in alleviating CHB liver damage.

Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase

Background & aimsNormal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. MethodsCHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). ResultsThere was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg− patients. HBsAg at baseline and week 24 were strong predictors of “low HBsAg at week 48”. ConclusionLong term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg− patients with baseline HBsAg<2.66 log IU/ml to achieve “low HBsAg at week 48”.

Efficacy of peg-interferon-nucleoside analog sequential optimization therapy in HBeAg-positive patients with CHB.

This study aimed to evaluate the efficacy of Peg-interferon (Peg-IFN)-nucleoside analog (NA) sequential optimization therapy (SOT) in HBeAg-positive patients with chronic hepatitis B (CHB). In this prospective two-center study, 132 CHB patients were assigned to receive Peg-IFN standard therapy for 48weeks (65 patients) or Peg-IFN monotherapy for 12-24weeks and NA add-on for those without early virological response (EVR) (67 patients). Both patient groups were monitored and followed for 24weeks after treatments stop. At week 24 after treatments stop, the Peg-IFN-NA SOT group achieved more HBsAg levels drop (- 1.35 vs - 0.67 log10 IU/mL, p = 0.016), higher HBsAg ≤ 100IU/mL (32.8% vs 9.2%, p = 0.001), HBV DNA undetectable (79.1% vs 49.2%, p < 0.001), and ALT normalization (80.6% vs 38.5%, p < 0.001) rates compared with Peg-IFN monotherapy. At week 24 after treatments stop, nosignificantdifference was found in HBeAg seroconversion (35.8% vs 27.7%, p = 0.316), HBsAg loss (8.9% vs 4.6%, p = 0.323) and HBsAg seroconversion rates (4.5% vs 1.5%, p = 0.325) between Peg-IFN monotherapy group and Peg-IFN-NA SOT group. Starting with Peg-IFN followed by addition of NA achieved more HBsAg levels drop, and higher HBsAg ≤ 100IU/mL, HBV DNA undetectable, and ALT normalization rates compared with Peg-IFN monotherapy.

Comparison of 48‐week efficacy of tenofovir vs entecavir for patients with chronic hepatitis B: A network meta‐analysis

Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are accepted as first-line treatments for chronic hepatitis B (CHB). However, there are few randomized studies comparing their efficacy. The primary aim of this study was to compare the efficacy of TDF and ETV using a network meta-analysis of randomized trials. The secondary aim was to additionally include propensity-matched cohort studies in a conventional meta-analysis. We systematically searched PubMed, EMBASE, Cochrane Library and Web of Science for published English-language randomized and propensity-matched studies between 1/1/2000 and 4/2/2020. Outcomes included undetectable HBV DNA, ALT normalization and HBeAg seroconversion at 48weeks. We excluded patients who had co-infection or significant prior treatment with antivirals. 13517 participants from 16 studies (11 RCTs, n=2675; five propensity-matched cohort studies, n=10842) were included. Virological response at 48weeks was higher in patients receiving TDF compared to ETV using both the network meta-analytic approach (OR 1.69, P<.001) and the conventional meta-analysis including propensity-matched cohort studies (OR 1.40, P<.001). On subgroup analysis, this difference was only significant in HBeAg-positive patients (OR 1.81, P=.037). There was limited evidence to suggest a higher rate of ALT normalization with ETV (OR 0.74, P=.07). There was no difference in rates of HBeAg seroconversion between the two antivirals. TDF is more likely than ETV to induce virological response at 48weeks in treatment-naïve CHB patients. Future studies should focus on elucidating associations between early and sustained virological response with adverse patient outcomes including development of HCC or cirrhosis.

Histological response to combination therapy with nucleos(t)ide analogs and peginterferon alpha in treatment-naïve chronic hepatitis B patients.

Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P=0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.

Antiviral and antifibrotic therapies reduce occurrence of hepatocellular carcinoma in patients with chronic hepatitis B and liver fibrosis: a 144-week prospective cohort study

To compare the efficacy and safety of different antiviral and antifibrotic regimens in patients with chronic hepatitis B (CHB) and hepatic fibrosis and the incidence of hepatocellular carcinoma (HCC) associated with these therapies. A total of 840 patients with CHB and concurrent hepatic fibrosis, who received antiviral therapy in Nanfang Hospital between June, 2010 and June, 2018, were enrolled in this follow-up cohort study. The patients were assigned to 3 cohorts matched for gender, age (difference≤5 years), HBeAg status and liver stiffness measurement (LSM) for treatment with one of the 3 antiviral drugs, namely entecavir, tenofovir dipivoxil and adefovir dipivoxil; each cohort was divided into 2 groups, with one of the groups having a combined treatment with Fufang Biejiaruangan tablet. The cumulative negative conversion rate of HBV DNA, normalization rate of ALT, hepatic fibrosis regression and the incidence of HCC were compared among the 3 cohorts and across the 6 groups at 144 weeks. A total of 749 patients were available to follow-up at 144 weeks. Compared with the baseline data, the cumulative negative conversion rate of HBV DNA increased gradually and the abnormal rate of ALT decreased significantly over time during the treatment in all the 6 groups (all P &lt; 0.001). Compared with the any of the antiviral drugs used alone, the combined treatments all resulted in significantly better antifibrotic effects (χETV cohort2=11.345, χTDF cohort2=10.160, χADV cohort2=6.358; all P &lt; 0.05). At 144 weeks, the incidence of HCC were 2.2%, 1.7%, 1.7% and 3.3% in enecavir group, enecavir with Biejiaruangan tablet group, adefovir group, and adefovir with Biejiaruangan tablet group, respectively, showing no significant difference between the two cohorts (4 groups; χ2=6.813, P=0.138). None of the patients in the 2 groups with tenofovir treatment had HCC by the end of the observation. Antiviral therapy combined with antifibrotic therapy can effectively reverse hepatic fibrosis and reduce the incidence of HCC in patients with CHB; among the 3 antiviral drugs, tenofovir dipivoxil can be a better option for reducing the incidence of HCC in these patients.

Histological improvement in chronic hepatitis B patients treated with bicyclol: real world experience

BackgroundBicyclol, the most commonly-used liver hepatoprotective drug in China, is often selected to control disease progression in CHB patients who refuse anti-viral treatment. However, data on histological changes after bicyclol treatment in these patients are scarce. Therefore, this study has been conducted to find out whether bicyclol has good benefits of histological improvement in CHB patients who refuse anti-viral agents.MethodsThe demographic, clinical and pathological data were collected from CHB patients who received bicyclol from January 2010 to June 2016. Improvement in liver inflammation or fibrosis is defined as at least one-grade or one-stage decrease as measured by the Scheuer scoring system. Thirty patients treated with ETV for 48 weeks were chosen as a control group to compare the histological improvement between bicyclol and entecavir (ETV) after 48-week treatment.ResultsA total of 123 patients with CHB treated with bicyclol were included in this study. Paired liver biopsies were performed in 70 patients. Inter-biopsy interval was 17.44 ± 8.90 months (12–60 months). As shown by facts, 41.4% patients achieved liver inflammation improvement, while only 10.0% patients showed liver inflammation progression after bicyclol treatment. In regarding to liver fibrosis, as shown by facts, 28.6% patients achieved fibrosis improvement. More importantly, It was found that the proportions of patients with liver inflammation and fibrosis improvement were both not significantly lower than those in ETV group (53.3% vs 63.3 and 36.7% vs 43.4%). Most of patients (82.4%) with elevated baseline ALT became normal after bicyclol treatment. More importantly, as shown by the multi-variate analysis, the treatment course of bicyclol was an independent factor for liver inflammation improvement. With the HBeAg status adjusted, ALT and HBV-DNA quantity, the odds ratio (95% confidence interval) of patients with ≥48-week treatment was 5.756 (1.893,17.500) when compared with patients via < 48-week treatment.ConclusionBicyclol can improve liver inflammation and the ALT normalization rate of CHB patients, especially when the treatment course is prolonged. This has confirmed that bicyclol could control hepatitis activity, which might be a good choice for CHB patients who refuse anti-viral treatments.

Higher efficacy of pegylated interferon-α2b add-on therapy in hepatitis B envelope antigen-positive chronic hepatitis B patients on tenofovir monotherapy.

Monotherapy with pegylated interferon-α (Peg-IFNα) or the nucleos(t)ide analogs (NA) currently approved for treating chronic hepatitis B (CHB) has limited efficacy. Studies on the combination of Peg-IFNα/NA have shown conflicting results. We investigated whether sequentially adding on Peg-IFNα to tenofovir enhances serological response rates. Treatment-naïve, hepatitis B envelope antigen (HBeAg)-positive CHB patients with moderately elevated alanine aminotransferase (ALT; 48-200IU/mL) were started on tenofovir (300mg/day) and enrolled at week 12 in a 1:1 ratio to either receive Peg-IFNα2b add-on (1.5μg/kg/week) from week 12 to 36 (n = 53) or continue tenofovir monotherapy (n = 53). Both treatment arms received tenofovir consolidation therapy until week 72. The primary end-point was HBeAg loss at week 72. At week 72, the rate of HBeAg loss was higher in the Peg-IFNα2b add-on group (35.8%) compared to the tenofovir monotherapy group (17%) (P = 0.028; odds ratio, 2.73, 95% confidence interval, 1.09-6.79), and considerably higher in patients with a baseline hepatitis B virus (HBV)-DNA level >6logIU/mL (32.6% vs 11.4%; P = 0.021). Rates of HBV-DNA loss (77.4% vs 71.7%; P = 0.51), ALT normalization (62.3% vs 52.8%; P = 0.32), and sustained virologic response (20.8% vs 11.3%; P = 0.18) at week 72 were comparable between the two groups. Significantly more patients in the add-on group had >3log HBV-DNA reduction at week 36 (92.5% vs 66%; P = 0.001). Four patients treated with Peg-IFNα2b add-on achieved hepatitis B surface antigen (HBsAg) loss compared with one patient receiving tenofovir monotherapy. Decline of HBV-DNA of >2log at week 4 led to higher HBeAg loss at week 72, independent of treatment arm. No patient had treatment-related adverse effects requiring treatment discontinuation. Twenty-fourweeks of Peg-IFNα2b as an add-on sequential regimen to tenofovir is safe and resulted in greater loss of HBeAg and HBsAg compared to tenofovir monotherapy in selected HBeAg-positive patients. Viral load reduction followed by immune modulation is a potentially useful approach.

Tenofovir alafenamide in the treatment of chronic hepatitis B: design, development, and place in therapy

Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has been approved for the treatment of chronic hepatitis B virus (HBV) infection. TAF has been shown to be a potent inhibitor of HBV replication at a low dose, with high intracellular concentration and more than 90% lower systemic TFV concentration than tenofovir disoproxil fumarate (TDF). In two randomized, double-blind, multinational, Phase 3, non-inferiority trials for hepatitis B e antigen (HBeAg)-positive and -negative patients (primary analysis: 48 weeks), TAF 25 mg orally once-daily was not inferior to TDF 300 mg in achieving an HBV DNA level <29 IU/mL at week 48. No amino-acid substitutions associated with viral breakthrough were detected by deep sequencing, and no resistance to TAF was found through week 96. In addition, no difference in the frequency of HBeAg or hepatitis B surface antigen loss was observed. However, TAF was associated with a significantly higher ALT normalization rate than was TDF, based on the American Association for the Study of Liver Diseases criteria (male: ALT ≤30 U/L and female: ALT ≤19 U/L). An analysis of renal safety showed that patients treated with TAF had a significantly lower decrease in the estimated glomerular filtration rate level than did patients treated with TDF. Similarly, the declines of hip and spine bone mineral density were significantly less in the TAF group. These trends of efficacy and renal/bone safety continued through week 96. Longer term follow-up and real-world data will be required to determine if the differences in viral/biochemical response and renal/bone safety seen with TAF in comparison with TDF are clinically relevant.