Search

Summary: Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy‐proven Child‐Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2‐year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan‐Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53 years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2‐year median HBsAg levels were 810 and 463 IU/mL, respectively. After a median follow‐up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age > 50 years, platelets ≤ 150 × 103/mm3 and body mass index ≥ 30 kg/m2. Two out of five risk scores were validated, and the most accurate was PAGE‐B at 1 year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host‐related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE‐B score was the most accurate risk score. In the French prospective multicentre ANRS CO12 CirVir cohort, among 317 patients with biopsy‐proven compensated HBV‐related cirrhosis, host conditions, comorbidities and severity of liver disease were independent predictors of HCC occurrence. Only two out of five HCC risk scores were validated in those patients and the European PAGE‐B score was the most accurate. Moreover, HCC in patients without a maintained virological suppression seem more aggressive and less accessible to curative treatment. [ABSTRACT FROM AUTHOR]

Abstract: Despite the availability of a preventive vaccine and active antiviral treatments that stop disease progression and reduce the risk of hepatocellular carcinoma, hepatitis B is still a major public health problem. Only an estimated 10% of the 257 million people living with HBV have been diagnosed and as few as 1% are being adequately treated. Barriers to diagnosis and treatment include: (i) limited awareness and lack of knowledge about HBV infection and HBV‐related diseases; (ii) under‐diagnosis with insufficient screening and referral to care; (iii) limited treatment due to drug availability, costs, reimbursement policies and the need for long‐term or life‐long therapy. These barriers and the actions needed to improve access to treatment are strongly influenced by the prevalence of infection and affect middle‐high vs low‐middle income countries differently, where most HBV carriers are found. In high‐prevalence regions and low‐to middle‐income countries, the main challenges are availability and cost while in low‐prevalence regions and middle‐to high‐income countries low screening rates, public awareness, social stigma and discrimination play an important role. Overcoming these challenges on a global scale is a complex clinical and public health challenge and multilateral commitment from pharmaceutical companies, governments, funders and the research community is lacking. The new WHO 2016 Global Health Sector Strategy on viral hepatitis targets testing and treatment, suggesting that important but strong actions are needed from advocacy groups, scientific societies and funding agencies to foster awareness and access to cure. [ABSTRACT FROM AUTHOR]

Summary The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardised appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilising cure, i.e ., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterised by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardised assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. [ABSTRACT FROM AUTHOR]

Current first-choice treatments for chronic hepatitis B are able to efficiently induce viral suppression in the majority of patients, but life-long therapy is needed to maintain infection under control due to their inability to eliminate the virus from infected hepatocytes. The residual viral replication and antigen production in most patients under treatment substantially contributes to the residual risk of hepatocarcinogenesis. New therapeutic approaches are needed to overcome hepatitis B virus persistence in the infected cells, or at least to control its transcriptional and replicative activity. In this review, the authors discuss the key points of the viral life cycle and host immune responses that need to be addressed to achieve a "functional cure," or even a "complete cure," allowing a finite duration of treatment and preventing virus reactivation and liver disease progression in a significantly higher number of patients than what is currently attained. [ABSTRACT FROM AUTHOR]

Treatment with either pegylated interferon-alpha (peg IFN-α) or last generation nucleos(t)ide analogues ( NAs) successfully leads to serum viral load suppression in most chronically infected hepatitis B ( CHB) patients, but HBsAg loss is only achieved in 10% of the cases after a 5-year follow-up. Thus, therapy must be administered long-term and it will not completely eliminate infection because of the persistent hepatitis B virus ( HBV) minichromosome in infected cells, and cannot completely abolish the risk of developing severe sequelae such as cirrhosis and hepatocellular carcinoma. Recent progress in the development of in vitro and in vivo models of HBV infection have helped renew interest in the investigation of the viral life cycle, as well as specific virus-host cell interactions to identify new targets for the development of new antiviral drugs. This includes either direct inhibition of viral replication by targeting fundamental steps such as entry, ccc DNA formation/stability, viral transcripts, capsid assembly and secretion or the manipulation of the host immune system for better defence against infection. Multiple strategies are currently under investigation, including boosting endogenous innate responses and/or restoring adaptive immunity via engineering of HBV-specific T cells or via the use of inhibitors of negative regulators, as well as therapeutic vaccines. It is increasingly clear that multiple therapeutic strategies must be combined to reach a cure of HBV and that the definition of clinical, virological and immunological correlates for the management of treatment are urgently needed. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) remains a public health concern with 240 million people affected worldwide. HBV is an hepadnavirus that replicates its genome in hepatocytes. One of the key steps of the viral life cycle is the formation of ccc DNA - covalently closed circular DNA - in the nucleus, the equivalent of a viral mini-chromosome that acts as a template for subsequent virus replication. Current antiviral medications are not effective in eradicating ccc DNA, which can persist in the infected liver even in the absence of detectable HBV DNA or HBsAg in the blood. ccc DNA cannot be measured in serum, and few surrogate markers have been proposed. Persistent ccc DNA has been associated with various clinical events, including viral reactivation induced by immunosuppressive therapies, HBV recurrence after liver transplantation and hepatocellular carcinoma ( HCC). ccc DNA remains the main target to achieve a cure of HBV infection, thus extensive efforts are being made to develop new antiviral concepts to degrade or silence ccc DNA. [ABSTRACT FROM AUTHOR]

Background & Aims Few data are available on the prevalence of renal abnormalities in chronic hepatitis B virus ( HBV)-infected patients. The multicentric cross-sectional HARPE study evaluated the prevalence of kidney disease indicators, in chronic HBV surface antigen carriers patients ( HBsAg+) with active or inactive infection. Patients and methods Two hundred and sixty-eight HBsAg+ adult patients, naïve of any oral antihepatitis B virus treatment were prospectively included over 2 years. Data for renal assessment were collected once from patient files. Univariate tests and multiple linear regressions were performed with the SAS software, version 8.02 ( SAS, Inc., Cary, NC, USA). Results Among the 260 patients analysed, 58% were men, the mean age was 42 ± 14 years, 59.6% were inactive carriers whereas 47 patients, mostly active, were about to start an antiviral therapy. Prevalence of proteinuria, haematuria, glycosuria, uninfectious leukocyturia was 38.1%, 20.6%, 3.9% and 9% respectively. According to the international definition, a total of 64.6% of patients were found to have kidney disease. Diabetes, hypertension and dyslipidaemia were observed, respectively, in 4.6%, 9.2% and 38.8% patients. There were no significant differences in these results within the three subgroups. Conclusion Renal abnormalities are highly prevalent in our population and pre-exist before the initiation of any antihepatitis B virus treatment. This emphasizes the need for: (i) a baseline renal evaluation in all HBs antigen-positive patients; (ii) a regular renal monitoring before and during antihepatitis B virus treatment to diagnose and manage renal impairment and adjust antihepatitis B virus treatment doses to renal function when necessary. [ABSTRACT FROM AUTHOR]

Background & Aims: Suboptimal virologic response to nucleos(t)ide analogs may represent a significant risk factor for resistance development in patients with chronic hepatitis B virus infection; treatment options have not been well studied. We evaluated long-term efficacy and safety of tenofovir alone and in combination with emtricitabine in a prospective, placebo-controlled trial in patients who remained viremic on adefovir therapy. Methods: Hepatitis B e antigen-positive and -negative patients with hepatitis B virus DNA ⩾1000 copies/ml despite up to 96weeks of adefovir were randomized to double-blind tenofovir or emtricitabine/tenofovir for 168weeks. Patients with hepatitis B virus DNA ⩾400 copies/ml (⩾69IU/ml) at or after week 24 could switch to open-label emtricitabine/tenofovir. Results: Overall, 90/105 (86%) patients (46/53 tenofovir and 44/52 emtricitabine/tenofovir) completed the 168-week study period, including 74/105 (70%) patients (35/53 tenofovir and 39/52 emtricitabine/tenofovir) who completed the study on their initial randomized treatment. Long-term viral suppression (hepatitis B virus DNA <400 copies/ml) was maintained at week 168 in 84% and 82% of patients receiving either emtricitabine/tenofovir combination or tenofovir monotherapy, respectively (non-completer equal to failure analysis). Baseline viral load as well as the presence of lamivudine and/or adefovir resistance-associated mutations at baseline had no impact on long-term treatment response. No resistance to tenofovir was observed through 168weeks. Both treatments had a favorable safety profile. Conclusions: Tenofovir monotherapy is as effective as emtricitabine/tenofovir combination therapy in maintaining long-term viral suppression in patients with a suboptimal response to adefovir, and is well tolerated in this population. [Copyright &y& Elsevier]

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11e32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

The article discusses the reasons to consider earlier for the treatment of chronic hepatitis B virus (HBV) infections. It states that cirrhosis, liver failure and hepatocellular carcinoma (HCC) diseases are caused by the HBV infection which occur at the early stage of life. It also informs that cirrhosis is linked to the hepatocyte death and as per the guidelines of international liver associations, patients must go through the antiviral therapy after the symptoms of progressive liver disease.

Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide. According to World Health Organization estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma (HCC). Major progress in the treatment of chronic hepatitis B (CHB) has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is an important factor in determining the success of long-term therapy for CHB. The development of resistance to nucleoside analogues (NUCs) has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multidrug resistance. The selection of a potent antiviral with a high barrier to resistance as a first-line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, the drug mechanisms of action and cross resistance. Furthermore, because of specific viral kinetics, prolonged treatment with NUCs does not result in the clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as preventing drug resistance and its complications in the long term. [ABSTRACT FROM AUTHOR]

Abstract: Because of the slow kinetics of viral clearance and the spontaneous genetic variability of hepatitis B virus (HBV), antiviral therapy of chronic hepatitis B remains a clinical challenge. Despite the recent development of lamivudine, adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic HBV infection, there is still a major need for new antiviral compounds. Entecavir, a guanosine analog, has been recently approved in US for the therapy of chronic hepatitis B and its registration is expected soon in Europe. Extensive studies have been performed to characterize its antiviral activity in enzymatic and tissue culture models, as well as in animal models of HBV infection. In clinical trails, entecavir administration was associated with a significantly more potent viral suppression compared to lamivudine, and a significant advantage in terms of biochemical and histological improvement compared to lamivudine. Entecavir was tolerated as well as lamivudine in these phase III trials. No case of resistance was detected after two years of therapy in nucleoside naïve patients. Treatment of patients with lamivudine failure requires a higher dosage of entecavir and induces a significant decline in viraemia levels. However, 10% of these patients developed entecavir resistance after two years of therapy. The availability of entecavir as a new treatment option is providing clincians more choice to keep both viral replication and liver disease under control. This provides new hope for improved treatment concepts for chronic HBV infection. [Copyright &y& Elsevier]

Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide. Until recently, interferon (IFN)-α was the only approved drug for the treatment of chronic HBV infection. The recent registration of lamivudine, a dideoxycytidine analogue that inhibits both the HIV and HBV reverse transcriptases, has provided new perspectives for the treatment of chronic HBV infection. Lamivudine treatment for 12 months leads to a control of viral replication during therapy in the majority of the patients and to sustained anti-hepatitis B e (anti-HBe) seroconversion in 16 to 22% of the patients, associated with a biochemical and histological response. Further studies showed that extended lamivudine therapy increases the rate of anti-HBe seroconversion. However, long-term therapy is associated with the progressive emergence of drug resistant mutants. In most cases these mutants are not associated with a deterioration of the liver disease within the available follow-up. In the remaining patients and in particular settings such as liver transplantation, a severe exacerbation of the liver disease is observed and that requires add-on therapy. Lamivudine treatment of patients infected with a pre-core mutant also showed beneficial effect with the control of viral replication, and a biochemical and histological response in approximately 60% of the patients at 1 year. These patients face the same problem of drug resistant mutants, and the optimal duration of lamivudine treatment still needs to be determined in this clinical situation. Moreover, lamivudine therapy is the only therapeutic option in decompensated cirrhotic patients to allow liver transplantation, and in liver transplant patients with HBV recurrence following transplantation. Adverse effects of lamivudine therapy are comparable to those observed in placebo-treated patients. ALT flares have been observed mainly in relation to the re-occurrence of viral replication due to the rebound of viral replication after therapy withdrawal, or to the emergence of drug resistance mutants. Therefore, lamivudine provides a new treatment alternative for patients with chronic HBV infection. For each patient, its indication has to be weighed against the risk of developing viral resistance but also against the risk of natural history of the disease. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection. [ABSTRACT FROM AUTHOR]

Over 257 million people live with chronic hepatitis B virus (HBV) infection and there is no known cure. The effective preventative vaccine has no impact on existing infection. Despite the existence of drugs which efficiently suppress viral replication, treatment is usually life-long and finite therapies that cure HBV infection are urgently required. However, even if such therapies were available today, it is unlikely they would reach all of those who need it most, due to chronic hepatitis B (CHB) being largely undiagnosed across the globe and to the dire need for health systems promoting access to therapy. Considerable challenges to developing and implementing an effective HBV cure remain. Nonetheless, important advances towards a cure are being made, both in the development of a multitude of new therapeutic agents currently undergoing clinical trials, and through the establishment of a new global initiative dedicated to an HBV cure, ICE-HBV, that is working together with existing organisations to fast-track an HBV cure available to all. [ABSTRACT FROM AUTHOR]

Virally encoded proteins have evolved to perform multiple functions, and the core protein (HBc) of the hepatitis B virus (HBV) is a perfect example. While HBc is the structural component of the viral nucleocapsid, additional novel functions for the nucleus-localized HBc have recently been described. These results extend for HBc, beyond its structural role, a regulatory function in the viral life cycle and potentially a role in pathogenesis. In this article, we review the diverse roles of HBc in HBV replication and pathogenesis, emphasizing how the unique structure of this protein is key to its various functions. We focus in particular on recent advances in understanding the significance of HBc phosphorylations, its interaction with host proteins and the role of HBc in regulating the transcription of host genes. We also briefly allude to the emerging niche for new direct-acting antivirals targeting HBc, known as Core (protein) Allosteric Modulators (CAMs). [ABSTRACT FROM AUTHOR]

Summary Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV. [ABSTRACT FROM AUTHOR]

Summary: Antiviral therapy of chronic hepatitis B remains a clinical challenge. The primary goal of therapy is to prevent liver disease progression. Because of the mechanism of viral persistence in infected hepatocytes, long-term antiviral therapy is needed in the majority of patients. Incomplete viral suppression and emergence of drug resistance is a major concern. The correct choice of a first-line potent therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance, such as entecavir and tenofovir, have significantly lower rates of resistance when compared with those with a low barrier to resistance such as lamivudine, adefovir, or telbivudine. Management of treatment failure requires a precise clinical and accurate virologic monitoring as well as an early treatment intervention with appropriate complementary drugs with respect to their cross-resistance profile. Long-term surveillance for treatment efficacy and possible emergence of drug resistance is necessary for those patients who have been sequentially treated with multiple antivirals. Finally, the identification of novel treatment targets remains a major research challenge to improve the efficacy of current antiviral therapy. [ABSTRACT FROM AUTHOR]

Background & Aims: We compared treatments for patients with chronic hepatitis B virus (HBV) infection who had an incomplete response to adefovir dipivoxil (ADV). We evaluated a combination of fixed-dose emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) from the start (early combination) versus TDF as monotherapy. Methods: Patients (n = 105) were randomly assigned to groups given TDF (n = 53) or FTC/TDF (n = 52). End points included HBV DNA suppression, biochemical and serologic response, and response by baseline or developed resistance mutations through 48 weeks of treatment. Patients given TDF monotherapy had the option to receive FTC, as fixed-dose FTC/TDF, if viremia persisted after week 24. Results: At baseline, patients'' mean HBV DNA level was 5.97 log10 copies/mL, and 58% had received lamivudine (LAM); LAM- and ADV-associated mutations were detected in 13 and 10 patients, respectively, by population sequencing and in 14 and 18 patients, respectively, by reverse hybridization line probe assay (INNO-LiPA HBV DR). Through week 24 (direct comparison of blinded therapy), viral decay curves were identical between groups. At week 48, 81% of patients initially given TDF or TDF/FTC had HBV DNA levels below 400 copies/mL. The presence of baseline LAM- or ADV-associated mutations did not affect response. Adherence to therapy appeared to be the primary factor associated with HBV DNA levels below 400 copies/mL at week 48. Conclusions: TDF monotherapy and the combination of FTC and TDF had similar efficacy in patients with incomplete viral suppression after therapy with ADV; response was not influenced by the presence of baseline LAM- or ADV-associated mutations. Initial monotherapy followed by combination therapy was as effective as early combination therapy. [Copyright &y& Elsevier]

Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading to treatment failure and progression to liver disease. There has been much research into the mechanisms of resistance to NA and selection of these mutants. Five NA have been approved by the US Food and Drug Administration for treatment of CHB; it is unlikely that any more NA will be developed in the near future, so it is important to better understand mechanisms of cross-resistance (when a mutation that mediates resistance to one NA also confers resistance to another) and design more effective therapeutic strategies for these 5 agents. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Associations between HBV genotype and resistance phenotype have allowed cross-resistance profiles to be determined for many commonly detected mutants, so genotyping assays can be used to adapt therapy. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second NA, if this drug is given at early stages of these events. However, best strategies for preventing NA resistance include first-line use of the most potent antivirals with a high barrier to resistance. It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB. [Copyright &y& Elsevier]

The precore (pc) W28* mutation arises from immune-selective pressures during the hepatitis B “e” antigen (HBeAg)-positive phase of chronic hepatitis B virus (HBV) infection and has been linked to severe liver-related morbidity. Here, we examined the determinants of harboring this mutation and its rate of emergence in treated patients co-infected with human immunodeficiency virus (HIV) and HBV. In a three-year prospective cohort of 165 HIV-HBV co-infected patients, pcW28* mutation was determined via DNA-chip during yearly sampling. In a subgroup with liver biopsies, HBV covalently-closed circular (ccc)-DNA and total intrahepatic (IH)-DNA were quantified by real-time PCR. From respective inclusion to year-3 visits, median HBV-DNA levels decreased (5.88 log 10 IU/mL to <1.78 log 10 IU/mL, p < 0.001) and tenofovir-use increased (15.8%–71.4%, p < 0.001). At baseline, 47 of 162 (29.0%) patients had the pcW28* mutation and were more frequently HBeAg-negative (adjusted-OR = 4.37, 95%CI = 1.76–10.86) and had non-A HBV genotypes (adjusted-OR = 9.14, 95%CI = 4.05–20.66). No association with HIV-related factors was observed. In 114 patients without baseline mutation and available data, four developed incident pcW28* mutation by the end of follow-up (cumulative 3.5%, 95%CI = 1.3–9.1%). In the 32 patients with liver biopsies, 10 (31.3%) patients harboring the pcW28* mutation had significantly lower adjusted mean cccDNA (0.05 versus without = 0.43 copies/cell, p < 0.001) and total IH-DNA levels (2.31 versus without = 18.59 copies/cell, p = 0.006). In conclusion, the pcW28* mutation infrequently appeared in this co-infected study population with increased use of potent antivirals and suppressed levels of circulating virus. [ABSTRACT FROM AUTHOR]

In HBV-infected patients, therapies with nucleoside analogues or IFNα remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immune-therapeutic options. HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA. The cytokines tested were type-I IFNs, IFNγ, type-III IFNs, TNFα, IL-6, IL-1β, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFNα. The cytokine presenting the highest effect on HBV DNA was IL-1β, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBsAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1β and already used therapies, i.e. IFNα or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1β was found to have a very potent antiviral effect against HBV in vitro . HBV was previously shown to promptly inhibit IL-1β production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1β may help to further inhibit HBV replication in vivo . [ABSTRACT FROM AUTHOR]

Background and Aims HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss. Methods This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity. Results Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region. Conclusion In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements. [ABSTRACT FROM AUTHOR]

Background & Aims In hepatitis B e antigen (HBeAg) positive-HIV co-infected patients treated with combined antiretroviral therapy (cART), including tenofovir disoproxil fumarate (TDF), the rate of HBe seroconversion remains low. Whether adding pegylated interferon alfa (PegIFN) could increase the likelihood of HBeAg loss and HBe seroconversion has not been assessed. Methods A 48-week PegIFN therapy was added to HBeAg positive-HIV co-infected patients on TDF and emtricitabine, or lamivudine for at least 6 months. The primary endpoint was HBV sustained response: HBe seroconversion with undetectable HBV DNA levels 24 weeks after completing PegIFN therapy (W72). Results Fifty-one patients (49 men, median age 46 years, range: 32–65), were included. Median duration of HIV, HBV infections and TDF therapy was 10.3 (0.6–22), 9.8 (0.5–16), and 3.3 (0.5–6.8) years, respectively. Median baseline CD4 count was 506 (175–1316)/mm 3 . HIV viral load was <50 copies/ml in 49 (96%) patients. Nine (18%) patients stopped PegIFN prematurely. Ten (20%) patients experienced HBeAg loss at W72 and four (8%) patients had a HBV sustained response. No HBs seroconversion was observed. Only patients with more than 350 CD4/mm 3 at baseline achieved HBe loss. HBeAg level >10 PEI U/ml at W12 or a quantitative HBsAg decline <0.5 log IU/ml at W24 had 100% and 84% negative predictive values for response, respectively. Conclusions 48-week PegIFN additional therapy to cART including TDF did not significantly increase the HBe seroconversion rate, despite an HBeAg loss in 20% of the patients. HBe and HBs kinetics may nevertheless be of help in tailoring and optimising this strategy. [ABSTRACT FROM AUTHOR]

Summary: Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies. [Copyright &y& Elsevier]

Abstract: We explored in the duck hepatitis B virus (DHBV) model the impact of electroporation (EP)-mediated DNA vaccine delivery on the neutralizing humoral response to viral preS/S large envelope protein. EP enhanced the kinetics and magnitude of anti-preS response compared to the standard needle DNA injection (SI). Importantly, EP dramatically enhanced the neutralizing potency of the humoral response, since antibodies induced by low DNA dose (10μg) were able to highly neutralize DHBV and to recognize ten antigenic regions, including four neutralization epitopes. Whereas, SI-induced antibodies by the same low DNA dose were not neutralizing and the epitope pattern was extremely narrow, since it was limited to only one epitope. Thus, EP-based delivery was able to improve the dose efficiency of DNA vaccine and to maintain a highly neutralizing, multi-specific B-cell response, suggesting that it may be an effective approach for chronic hepatitis B therapy at clinically feasible DNA dose. [Copyright &y& Elsevier]

Background & Aims: Long-term viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this study was to investigate the efficacy and safety of entecavir plus tenofovir combination in 57 CHB partial responders or multidrug resistant patients. Methods: Investigator-initiated open-label cohort study. Quantitative HBV-DNA measurement and resistance testing (line-probe-assays and direct-sequencing) at baseline and every 3months. Results: Fifty seven patients (37 HBeAg+), median age 45years, previously treated with a median of three lines of antiviral therapy (range 1–6), 24/57 with advanced liver disease, were included. Median ALT at baseline was 1.0ULN (range 0.3–22) and HBV-DNA 1.5×104 IU/ml (range 500–1×1011 IU/ml). Median treatment duration of combination therapy was 21months. HBV-DNA level dropped 3 logs (median, range 0–8log; p <0.0001), 51/57 patients became HBV-DNA undetectable, median after 6months (95% CI, 4.6–7). The probability for HBV DNA suppression was not reduced in patients with adefovir or entecavir resistance or in patients with advanced liver disease. Viral suppression led to decline in ALT (median 0.7ULN; range 0.2–2.4; p =0.001). Five patients lost HBeAg (after 15, 18, 20, 21, and 27months, respectively), one patient showed HBs-seroconversion. Patients with advanced disease did not show clinical decompensation, two patients with cirrhosis and undetectable HBV DNA developed HCCs. No death, newly induced renal impairment or lactic acidosis were reported. Conclusions: Rescue therapy with entecavir and tenofovir in CHB patients harboring viral resistance patterns or showing only partial antiviral responses to preceding therapies was efficient, safe, and well tolerated in patients with and without advanced liver disease (249). [Copyright &y& Elsevier]

Background & Aims: Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited. Methods: In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy. Results: During a median follow-up of 11 (3–23)months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3–31)months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04–0.58; p =0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43–1.52; p =0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43–1.64; p =0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27–2.71; p =0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations. Conclusions: Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed. [Copyright &y& Elsevier]