Nucleoside/nucleotide Analogues Research Articles

Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis.

The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. Of the 464 articles considered, 18 articles recruiting 10320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR=3.12, 95% CI: 2.40-4.06, P<0.001, I2=43.2%, P=0.043; OR=5.65, 95% CI: 3.44-5.82, P<0.001, I2=0.00%, P=0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR=1.71, 95% CI: 1.26-2.32, P<0.001, I2=7.89%, P=0.031). For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.

Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy.

A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown. A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy. Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53logIU/mL; p=0.047), HBsAgGi/HBsAg ratio (≥1.10; p=0.035), and HBV DNA (≤6.3logcopies/mL; p=0.012) at baseline and HBsAg (≤3.19logIU/mL; p=0.033) and HBsAgGi/HBsAg ratio (≥1.09; p=0.003) at 48weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88×103 /mm3 (p=0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48weeks after NA therapy ≥1.09 (p=0.040; HR, 10.099) were independently and significantly associated with the development of HCC. Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.

Effects of entecavir and tenofovir alafenamide fumarate treatment on renal function in Japanese elderly patients with chronic hepatitis B.

Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are considered safe nucleoside/nucleotide analogs (NA) for the kidney. This study aimed to investigate the long-term effects of ETV or TAF on renal function in elderly patients with chronic hepatitis B (CHB) in Japan. The study included 246 CHB patients treated with ETV (184 patients) or TAF (62 patients) for at least 2years. These patients were divided into two groups: those <65years of age (130 patients) and those ≥65years of age (116 patients). The effects of the NAs on renal functions were examined by comparing the estimated glomerular filtration rates (eGFR) from baseline to 2years between the two groups. The change in eGFR from baseline to 1 or 2years after treatment was significantly decreased in both groups. However, the amount of change at 1 and 2years was significantly greater in the group aged ≥65years than in the group aged <65years. The amount of change in eGFR from baseline to 1 and 2years after treatment was significantly greater in the group aged ≥65years than in the group aged <65years, regardless of the type of NA, the prior treatment history, cirrhosis/chronic hepatitis, hypertension, dyslipidemia, and diabetes. Additionally, logistic regression analysis showed that age ≥65years was independently associated with a decreased eGFR after 2years of NA treatment. Long-term administration of NA to CHB patients over 65years of age should be carefully monitored for renal impairment.

Hepatitis C virus/Hepatitis B virus coinfection: Current prospectives.

In endemic areas, hepatitis C virus (HCV)/hepatitis B virus (HBV) coinfection is common, and patients with coinfection have a higher risk of developing liver disease such as hepatocellular carcinoma, liver fibrosis and cirrhosis. In such cases, HCV predominates, and HBV replication is suppressed by HCV. HCV core proteins and interferons that are activated by HCV are responsible for the suppression of HBV. Immunosuppression is also seen in patients with HCV and HBV coinfections. A decrease in HCV-neutralizing antibody response and circulation of Th1-like Tfh cells is observed in patients with HCV and HBV coinfection. Both viruses interacted in the liver, and treatment of HCV/HBV coinfection is genotype-based and complex due to the interaction of both viruses. In HCV-dominant cases, direct-acting antiviral drugs and peg interferon plus ribavirin are used for the treatment, with continuous monitoring of AST and ALT. HBV-dominant cases are less common and are treated with peg interferon and nucleoside nucleotide analogues with monitoring of AST and ALT. The SVR rate in HCV-HBV coinfection is higher than that in monoinfection when treated with direct-acting antiviral drugs. But there is a risk of reactivation of HBV during and after therapy. The rate of reactivation is lower in patients treated with direct-acting antiviral drugs as compared to those treated with peg interferon plus ribavirin. Biomarkers of HBV such as HBcrAg, HBV DNA and HBVpg RNA are not effective in the prediction of HBV reactivation; only the hepatitis B surface antigen titre can be used as a biomarker for HBV reactivation. HCV can also be reactive, but this is found in very rare cases in which HBV is present and is treated first.

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes.

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

The potential effect of HBV vaccination on off-treatment HBsAg reversion after interferon-induced HBsAg clearance

ABSTRACT Off-treatment HBsAg reversion occurs in a considerable number of chronic hepatitis B(CHB) patients after IFN(interferon)-induced HBsAg clearance. HBV vaccination protects the general population against HBV infection. However, it remains unclear whether HBV vaccination could prevent off-treatment HBsAg reversion in CHB patients with HBsAg clearance. CHB patients (n = 199) with HBsAg clearance were included in the current study, comprising spontaneous HBsAg clearance group (n = 51), NA (nucleoside/nucleotide analogues)-induced group (n = 36) and IFN-induced group (n = 112). Log-rank test was performed to compare the cumulative incidences of HBsAg reversion between groups. Cox regression model was used to identify the factors associated with off-treatment HBsAg reversion. The 5-year cumulative incidence of HBsAg reversion in IFN-induced group was significantly higher than that in NA-induced group or spontaneous group (27.6% vs. 3.3% vs. 8.1%, both p < .05). In IFN-induced group, 66.7% of CHB patients received HBV vaccination. The cumulative incidence of HBsAg reversion in individuals with strong responses to HBV vaccination (HBsAb level >100mIU/ml) was significantly lower than that in those with weak responses to HBV vaccination (HBsAb level ≤100mIU/ml) or without HBV vaccination in IFN-induced group (7.7% vs. 58.5% vs. 31.9%, both p < .05). Multivariate Cox regression analysis confirmed strong responses to HBV vaccination were independently associated with a lower cumulative incidence of HBsAg reversion after IFN-induced HBsAg clearance (HR = 0.246, 95%CI: 0.066–0.907, p = .035). HBV vaccination has potential to prevent off-treatment HBsAg reversion in CHB patients after IFN-induced HBsAg clearance via a sufficiently high level of HBsAb, helping clinicians optimize the clinical management of such patients.

Intranasal therapeutic vaccine containing HBsAg and HBcAg for patients with chronic hepatitis B; 18months follow-up results of phase IIa clinical study.

HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18months, and their HBsAg reduction and anti-HBs induction assessed as endpoints. Among the patients with CHB treated with NAs (n=27) and HBV carriers without NAs (n=36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log10 IU/ml (p<0.05) and -0.2677 log10 IU/ml (p<0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment. Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

Some HBeAg-negative chronic hepatitis B patients treated with nucleos(t)ide analogue can achieve HBsAg loss after drug withdrawal: stop-to-cure may be coming

Nucleoside/Nucleotide analogues (NAs) are widely used for the antiviral treatment of chronic hepatitis B (CHB), however, it is difficult to achieve serum hepatitis B surface antigen (HBsAg) loss with NAs therapy. In recent years, several prospective trails have reported that HBsAg loss (functional cure or clinical cure) also occurs in a small number of hepatitis B e antigen (HBeAg) negative CHB patients who discontinued long-term treatment with NAs. Accordingly, the "stop-to-cure" strategy is proposed. Although the mechanism has not been fully elucidated, the known factors related to serum HBsAg loss with NAs withdrawal include HBV genotype, duration of NAs treatment, serum HBsAg and HBV RNA levels at end-of-treatment, and ethnic differences. In the review, we discuss the best time to stop NAs therapy, the potential markers for predicting relapse after cessation of NAs and the possible mechanism of "stop-to-cure" in HBeAg-negative CHB patients, and propose some suggestions on the time of retreatment.

Effectiveness of antiviral treatment in HBeAg-negative chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase: a retrospective study

BackgroundThere are inadequate data and no histological evidence regarding the effects of antiviral treatment for hepatitis B e-antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT). This study investigated the effects of antiviral treatment on these patients.MethodsWe retrospectively analysed the outcomes of antiviral treatment for HBeAg-negative CHB patients with normal or mildly elevated ALT who were treated with nucleoside/nucleotide analogues (NAs) for up to 96 weeks.ResultsA total of 128 patients were enrolled; 74 patients had normal ALT and 54 patients had mildly elevated ALT. The total cumulative rates of viral suppression were 64.06%, 81.97%, and 96.39%, at weeks 24, 48, and 96, respectively. The cumulative rates of viral suppression for the normal and mildly elevated ALT groups were 67.85% and 58.97%, 86.39% and 76.31%, and 93.13% and 97.04% at weeks 24, 48, and 96, respectively. The serum HBV DNA levels at week 12 and hepatitis B surface antigen (HBsAg) levels at week 24 were significant predictors of the 96-week virological response. Of the 128 patients, 54 with normal ALT and 33 with mildly elevated ALT underwent FibroScan at baseline. Significant fibrosis (F ≥ 2) was found in 44.4% (n = 24) and 51.5% (n = 17) of the patients in the normal ALT group and mildly elevated ALT group, respectively. Compared with the values at baseline, liver stiffness values significantly decreased at week 48 (8.12 kPa vs. 6.57 kPa; p < 0.001) and week 96 (8.87 kPa vs. 6.43 kPa; p < 0.001), respectively.ConclusionsHBeAg-negative CHB patients with normal ALT could benefit from antiviral therapy with NAs, similar to patients with mildly elevated ALT. Antiviral treatment is strongly recommended for HBeAg-negative CHB patients with normal ALT. Additionally, significant liver fibrosis is not rare in HBeAg-negative CHB patients with ALT less than two-times the upper limit of normal, and FibroScan should be performed regularly for these patients.

Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection.

ABSTRACTHepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications.IMPORTANCE A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. However, the neutralizing effect of these MAbs may be muted by a large excess of HBsAg-positive noninfectious particles in the blood of infected patients. The advantage of NTCP-targeted HBV entry inhibitors is that they remain effective regardless of viral genotype, viral mutations, and the presence of subviral particles. Although N6HB426-20 requires a higher dose than myrcludex to obtain equivalent suppression of HBV in a model mouse system, it maintained the inhibitory effect for a long time postadministration in proportion to the half-life of an IgG MAb. We believe that further improvements will make this antibody a promising treatment option for patients with chronic hepatitis B.

Traditional Chinese medicine Yiqi Huoxue recipe attenuates hepatic fibrosis via YAP/TAZ signaling.

The Yiqi Huoxue (YQHX) recipe has been shown to attenuate liver fibrosis, but precise mechanisms have not yet been elucidated. Recently, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling has been implicated in liver fibrogenesis. This study investigated whether the YAP/TAZ signaling is involved in the therapeutic effect of YQHX on hepatic fibrosis. Wistar rats were used to generate a model of carbon tetrachloride (CCl₄)-induced liver fibrosis. Chronic hepatitis B (CHB) patients with liver fibrosis were enrolled and assigned to receive either nucleoside/nucleotide analogues (NAs) or NAs plus YQHX. Histology, immunohistochemistry, qRT-PCR, and western blotting were conducted to mechanistically assess the therapeutic effects of YQHX on liver fibrosis. YQHX markedly alleviated morphological alterations in CCl₄-induced liver fibrosis and decreased markers of hepatic fibrosis in rats. Furthermore, YQHX significantly suppressed CCl₄-meidated activation of the transforming growth factor-beta (TGF-β)/Smad signaling pathway. Notably, CCl₄ induced up-regulation of YAP, TAZ, and connective tissue growth factor (CTGF), which were significantly abrogated by YQHX. Consistent with the above major findings in rats, CHB patients treated with NAs plus YQHX had greater improvement in liver fibrosis than those given NAs alone (71.4% vs. 28.6%; P = 0.057). In addition, hepatic and plasma levels of YAP were significantly decreased after YQHX treatment in CHB patients with liver fibrosis. YAP/TAZ signaling plays a role, at least in part, in the anti-fibrotic activity of YQHX. The findings may help to better understand the mechanisms of YQHX in the treatment of liver fibrosis.

A simple-to-use tool for predicting response to peginterferon in HBV DNA suppressed chronic hepatitis B patients in China

BackgroundRational administration of peginterferon can remarkably reduce serum HBsAg level and improve the rate of HBsAg loss. Considering the high cost and adverse drug reaction of peginterferon, we aimed to develop a simple-to-use scoring system at early stage of treatment to predict low HBsAg level or HBsAg clearance at the end of treatment in virological suppression chronic hepatitis B (CHB) patients. MethodsNon-cirrhotic CHB patients with NA (nucleoside/nucleotide analogues)-induced virological suppression initiated either by add-on or switch-to peginterferon for ≥ 48 weeks were enrolled from January 2012 to June 2017 in these two tertiary centers. The retrospective experiment identified 320 suitable patients, including 192 in training and 128 in validation cohorts. ResultsUsing logistic regression, a simple-to-use scoring system integrating baseline HBsAg level <1000 IU/mL, HBsAg decline >0.5 log at week 12 and ALT flare at week 12 was developed in the training cohort and good for predicting HBsAg <100 IU/mL, HBsAg <10 IU/mL and HBsAg loss at the end of 48-week treatment. The area under receiver operating characteristics curve was 0.84, 0.86 or 0.78 in the training cohort and 0.88, 0.79 or 0.81 in the validation cohort, respectively. ConclusionsOur simple-to-use scoring system may guide for clinicians to decide whether to continue peginterferon in CHB patients to achieve low HBsAg levels or HBsAg clearance at the end of treatment, which might lead more cost-effective decision and get more patients to reach functional cures in Chinese population.

Hepatitis B core-related antigen predicts disease progression and hepatocellular carcinoma in hepatitis B e antigen-negative chronic hepatitis B patients.

The serum hepatitis B core-related antigen (HBcrAg) is considered a surrogate marker of the amount and activity of intrahepatic covalently closed circular DNA. This study aims to investigate the virological characteristics of HBcrAg in chronic hepatitis B (CHB) patients and to reveal the hepatocellular carcinoma (HCC) risk factors of hepatitis B e antigen (HBeAg)-negative patients. Hepatitis B core-related antigen was measured in 245 naive CHB patients before receiving nucleoside/nucleotide analog (NA) therapy. All patients were receiving NA (entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide) continuously for more than 1year until the end of follow-up, and they did not have a history of HCC. Hepatitis B viral status was compared between 106 HBeAg-positive and 139 HBeAg-negative patients. Median HBcrAg levels were significantly higher in HBeAg-positive patients than in HBeAg-negative patients (>6.8 vs 3.7log U/mL, P<0.01). In HBeAg-negative patients, higher HBcrAg levels were associated with cirrhosis (119 chronic hepatitis/20 cirrhosis=3.5/4.7log U/mL, P=0.03) and higher serum hepatitis B virus DNA. During a median follow-up of 5.28 (1.03-12.0) years, the 5-year cumulative HCC incidence rate was 5.4% in the HBeAg-negative cohort. In the multivariate Cox regression analysis, higher HBcrAg levels at 1year were independent predictive factors for HCC development in HBeAg-negative patients who received NA therapy (cutoff value, 4.1log U/mL; hazard ratio, 6.749; 95% confidence interval, 1.334-34.15, P<0.01) and even in non-cirrhosis patients. Hepatitis B core-related antigen was useful for understanding disease progression in CHB patients and for stratifying the risk for carcinogenesis in HBeAg-negative patients receiving NA therapy.

Nucleoside/nucleotide analog consolidation therapy in hepatitis B e-antigen positive chronic hepatitis B patients: Three years should be preferred.

To assess the role of consolidation therapy after cessation of nucleoside/nucleotide analogs (NAs) for off-treatment outcome and to explore the optimal consolidation period in hepatitis B e-antigen (HBeAg) positive chronic hepatitis B (CHB) patients. We undertook a prospective, observational cohort study including HBeAg positive CHB patients discontinuing NAs. Virological relapse was the primary endpoint of the current study and was defined as a serum hepatitis B virus DNA more than 104 copies/ml (another assay was carried out for confirmation at least 2weeks later). Propensity score matching analysis was used to balance the baseline characteristics between HBeAg positive CHB patients with different consolidation periods. A total of 190 HBeAg positive CHB patients were included. Fifty-four patients relapsed during follow-up and the cumulative relapse rates at years 1, 3, 5, and 10 were 19.5%, 24.1%, 27.2%, and 32.1%, respectively. Most patients (61.1%) relapsed in the first 6months. After propensity score matching, significantly lower cumulative relapse rates were observed in patients with consolidation period ≥36months compared with patients with consolidation period more than 36months (29.3% vs. 52.8% at year 10; p=0.012). Cessation of NAs after HBeAg seroconversion and long-term consolidation is generally safe and feasible in HBeAg positive CHB patients. Three years of consolidation should be preferred in clinical practice.

Dynamic evaluation of hepatocellular carcinoma prediction models in patients with chronic hepatitis B receiving nucleotide/nucleoside analogue treatment.

Carcinogenesis risk scores for chronic hepatitis B have been proposed, but it remains unclear whether these scores during nucleoside/nucleotide analogue (NA) therapy are useful for risk assessment. In this study, we examined changes of these scores and the predictability during NA treatment. 432 patients with no history of hepatocellular carcinoma (HCC) treated with NA were enrolled. PAGE-B, modified PAGE-B (mPAGE-B), and REACH-B scores were calculated at NA administration, 1 and 2years after administration. The median follow-up duration was 5.1years, during which 37 patients (8.6%) developed HCC. Cumulative incidence HCC development in patients with high risk of PAGE at NA administration, and 1 and 2years after NA administration was significantly higher than those with intermediate and low-risk groups (p<.05 for all time points), whereas HCC incidence in patients with high risk of mPAGE-B and REACH-B at 2years after NA administration were equivalent to those with intermediate and low-risk groups (p = .2 for mPAGE-B, and p = .1 for REACH-B). The area under the receiver operating characteristic (AUROC) for HCC development of PAGE-B at NA administration, and 1 and 2years after administration were 0.773, 0.803 and 0.737, respectively. The AUROCs of PAGE-B at each point were continuously higher than those of REACH-B (0.646, 0.725, and 0.653, respectively) and mPAGE-B (0.754, 0.734, and 0.678, respectively).PAGE-B score has a high diagnostic accuracy for HCC development at any time point during NA treatment, indicating its potential use as a real-time monitor of HCC development.

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

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

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”.

HBV-RNA Co-amplification May Influence HBV DNA Viral Load Determination.

Despite effective hepatitis B virus (HBV)‐DNA suppression, HBV RNA can circulate in patients receiving nucleoside/nucleotide analogues (NAs). Current assays quantify HBV DNA by either real‐time polymerase chain reaction (PCR), which uses DNA polymerase, or transcription‐mediated amplification, which uses reverse‐transcriptase (RT) and RNA polymerase. We assessed the effect of RT capability on HBV‐DNA quantification in samples from three cohorts, including patients with quantified HBV RNA. We compared the HBV‐DNA levels by real‐time PCR (cobas HBV, Roche 6800/8800; Xpert HBV, Cepheid), transcription‐mediated amplification (Aptima HBV, Hologic), and real‐time PCR with added RT capability (cobas HBV+RT). In the first cohort (n = 45) followed over 192 weeks of NA therapy, on‐treatment HBV‐DNA levels were higher with cobas HBV+RT than cobas HBV (mean difference: 0.14 log10 IU/mL). In a second cohort (n = 50) followed over 96 weeks of NA therapy, HBV‐DNA viral load was significantly higher with the cobas HBV+RT and Aptima HBV compared with the cobas HBV test at all time points after initiation of NA therapy (mean difference: 0.65‐1.16 log10 IU/mL). A clinically significant difference was not detected between the assays at baseline. In a third cohort (n = 53), after a median of 2.2 years of NA therapy, we detected HBV RNA (median 5.6 log10 copies/mL) in 23 patients (43.4%). Median HBV‐DNA levels by Aptima HBV were 2.4 versus less than 1 log10 IU/mL in samples with HBV RNA and without HBV RNA, respectively (P = 0.0006). In treated patients with HBV RNA, Aptima HBV measured higher HBV‐DNA levels than Xpert HBV and cobas HBV. Conclusion: Tests including an RT step may overestimate HBV DNA, particularly in samples with low viral loads as a result of NA therapy. This overestimation is likely due to amplification of HBV RNA and may have an impact on clinical decisions.

PIN5 PREVALENCE OF DRUG RESISTANCE IN NUCLEOSIDE/NUCLEOTIDE ANALOGUE-TREATED EGYPTIAN PATIENTS WITH CHRONIC HEPATITIS B VIRUS

Nucleoside/Nucleotide analogues (NAs) are used for the treatment of chronic hepatitis B virus infection (CHB), but the treatment may fail due to several factors, including viral resistance. Resistance pattern in Egyptian patients is still unknown; hence, the aim of the current study was to evaluate the prevalence of NAs resistance and its potential predictors in Egyptian patients with CHB.

Retrospective Analysis of HBV Pre-Existing Mutations and Drug-induced Resistance Mutations in Patients with Hepatitis B Virus-Related Cirrhosis

Background: The reported prevalence and necessity of detection of HBV reverse transcriptase (RT) mutation prior to treatment is varied and remains controversial. This study aimed to identify the prevalence of HBV pre-existing gene resistance mutations and compare the difference between pre-existing mutations and drug-induced resistance mutations in patients with hepatitis B virus-related cirrhosis.Methods: 180 patients with hepatitis B virus-related cirrhosis which included 68 patients with virological breakthrough and 112 treatment-naive cirrhosis patients were retrospectively enrolled. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. One-way ANOVA analysis was performed in the comparison among different groups. Ratios difference was compared with the chi-square test.Results: There were 48 patients (48/112, 42.86%) with drug resistance mutations in nucleoside/nucleotide analogues (NAs) treatment-naive group, 59 patients (59/68, 86.76%) showed drug-resistant mutations in the NAs treatment group. The gene resistance mutation patterns in treatment-naive group were mainly rtS213T, rtV214A, 191V/I and rtN/H238T/D, and the types of resistance mutations in the treated group were different. The adefovir (ADV) group: mainly rtA181T/V and rtS213T; lamivudine/ telbivudine (LAM/LDT) group: rtL180M+ rtM204I/V/S and rtM204I/V/S or a complex mutation pattern containing 204 site; entecavir (ETV) group: The drug resistance pattern is the simultaneous presence of multiple site mutations. LAM/LDT sequential ADV group: The variant type was multi-site and resistant to both ADV and LAM.Conclusion: There was a prevalence of pre-existing mutations in RT region of HBV polymerase in patients with hepatitis B virus-related cirrhosis, The mutation pattern is mainly related to LAM and ADV-related compensatory mutations, while the drug-induced mutation pattern is more complicated, mainly related to the antiviral drugs used and there are mainly primary mutations. Patients with cirrhosis should be tested genetic resistance mutation before using antiviral drugs.