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Heparan sulfate proteoglycans (HSPGs) are a major constituent of the extracellular matrix (ECM) and are found to be implicated in viral infections, where they play a role in both cell entry and release for many viruses. The enzyme heparanase-1 is the only known endo-beta-D-glucuronidase capable of degrading heparan sulphate (HS) chains of HSPGs and is thus important for regulating ECM homeostasis. Heparanase-1 expression is tightly regulated as the uncontrolled cleavage of HS may result in abnormal cell activation and significant tissue damage. The overexpression of heparanase-1 correlates with pathological scenarios and is observed in different human malignancies, such as lymphoma, breast, colon, lung, and hepatocellular carcinomas. Interestingly, heparanase-1 has also been documented to be involved in numerous viral infections, e.g., HSV-1, HPV, DENV. Moreover, very recent reports have demonstrated a role of heparanase-1 in HCV and SARS-CoV-2 infections. Due to the undenied pro-carcinogenic role of heparanase-1, multiple inhibitors have been developed, some reaching phase II and III in clinical studies. However, the use of heparanase inhibitors as antivirals has not yet been proposed. If it can be assumed that heparanase-1 is implicated in numerous viral life cycles, its inhibition by specific heparanase-acting compounds should result in a blockage of viral infection. This review addresses the perspectives of using heparanase inhibitors, not only for cancer treatment, but also as antivirals. Eventually, the development of a novel class antivirals targeting a cellular protein could help to alleviate the resistance problems seen with some current antiretroviral therapies. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed circular DNA (cccDNA). The HBV community is investing large human and financial resources to develop new therapeutic strategies that either silence or ideally degrade cccDNA, to cure HBV completely or functionally. cccDNA transcription is considered to be the key step for HBV replication. Transcription not only influences the levels of viral RNA produced, but also directly impacts their quality, generating multiple variants. Growing evidence advocates for the role of the co-transcriptional regulation of HBV RNAs during CHB and viral replication, paving the way for the development of novel therapies targeting these processes. This review focuses on the mechanisms controlling the different co-transcriptional processes that HBV RNAs undergo, and their contribution to both viral replication and HBV-induced liver pathogenesis. [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]

Background: Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union. Methods: This 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24 weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered. Results: Overall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8 months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9 weeks [41.3 months]). Conclusion: This 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients. [ABSTRACT FROM AUTHOR]

Background: HCV treatment uptake has drastically increased in HIV-HCV coinfected patients in France since direct-acting antiviral (DAA) treatment approval, resulting in HCV cure in 63% of all HIV-HCV patients by the end of 2015. We investigated the impact of scaling-up DAA on HCV prevalence in the whole HIV population and in various risk groups over the next 10 years in France using a transmission dynamic compartmental model.Methods: The model was based on epidemiological data from the French Dat'AIDS cohort. Eight risk groups were considered, including high-risk (HR) and low-risk (LR) men who have sex with men (MSM) and male/female heterosexuals, intra-venous drug users, or patients from other risk groups. The model was calibrated on prevalence and incidence data observed in the cohort between 2012 and 2015.Results: On January 1, 2016, 156,811 patients were registered as infected with HIV in France (24,900 undiagnosed patients) of whom 7938 (5.1%) had detectable HCV-RNA (722 undiagnosed patients). Assuming a treatment coverage (TC) rate of 30%/year (i.e., the observed rate in 2015), model projections showed that HCV prevalence among HIV patients is expected to drop to 0.81% in 2026. Sub-analyses showed a similar decrease of HIV-HCV prevalence in most risk groups, including LR MSM. Due to higher infection and reinfection rates, predicted prevalence in HR MSM remained stable from 6.96% in 2016 to 6.34% in 2026. Increasing annual TC rate in HR MSM to 50/70% would decrease HCV prevalence in this group to 2.35/1.25% in 2026. With a 30% TC rate, undiagnosed patients would account for 34% of HCV infections in 2026.Conclusions: Our model suggests that DAA could nearly eliminate coinfection in France within 10 years for most risk groups, including LR MSM. Elimination in HR MSM will require increased TC. [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]

Background and Aims: Tenofovir disoproxil fumarate (TDF) demonstrated potent and sustainable antiviral efficacy and a good safety profile in patients with chronic hepatitis B (CHB) in controlled clinical trials. Real-world data are important to confirm effectiveness and safety data in patient populations encountered in routine clinical practice.Methods: This non-interventional, prospective, 36-month study included treatment-naïve and treatment-experienced patients with CHB initiating their first TDF regimen (monotherapy or combination therapy) in routine clinical practice in France. Clinical, virologic, biochemical, compliance, and safety data were collected.Results: Data from 440 consecutive patients from 58 centers were analyzed. The majority of the cohort was male (71 %), hepatitis B "e" antigen-negative (HBeAg-) (74 %), and treatment-experienced (56 %); 11 % were aged ≥65 years; and comorbidities were reported in 39 %. After 12 months, 92 % of the overall cohort achieved virologic response (HBV DNA <69 IU/mL) which was maintained to 36 months (96 %); virologic response was achieved by >90 % of patients irrespective of HBeAg status, age, or prior treatment history. At 36 months, 77 % of patients had normal alanine aminotransferase levels. Fourteen patients lost hepatis B surface (HBs) antigen, and seven seroconverted to anti-HBs. TDF was well tolerated over the 36-month study, including in 14 women who became pregnant during the study. Median estimated glomerular filtration rate did not change markedly from baseline irrespective of prior treatment history.Conclusions: TDF demonstrated potent virologic and biochemical responses across a broad range of patients reflective of routine clinical practice. The safety profile was consistent with results from pivotal trials. [ABSTRACT FROM AUTHOR]

Chronic HCV infections represent a major worldwide public health problem and are responsible for a large proportion of liver related deaths, mostly because of HCV-associated hepatocellular carcinoma and cirrhosis. The treatment of HCV has undergone a rapid and spectacular revolution. In the past 5 years, the launch of direct acting antiviral drugs has seen sustained virological response rates reach 90% and above for many patient groups. The new treatments are effective, well tolerated, allow for shorter treatment regimens and offer new opportunities for previously excluded groups. This therapeutic revolution has changed the rules for treatment of HCV, moving the field towards an interferon-free era and raising the prospect of HCV eradication. This manuscript addresses the new challenges regarding treatment optimisation in the real world, improvement of antiviral efficacy in 'hard-to-treat' groups, the management of patients whose direct acting antiviral drug treatment was unsuccessful, and access to diagnosis and treatment in different parts of the world. [ABSTRACT FROM AUTHOR]

The article discusses a study published within the issue on the discovery of a novel orally bioavailable small molecule inhibitor of hepatitis B virus (HBV) gene expression. Topics include key obstacles that should be dealt with to attain HVC cure, the key challenge for HBV drug development and HBV cure, and definitions of cure that have been agreed upon by the community about the degree of viral depletion that can be achieved.

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]

The management of treatment failure in patients with chronic hepatitis B, remains a clinical concern. Incomplete viral suppression and the emergence of drug resistance are key determinants of treatment failure. The correct choice of a potent first-line 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 have significantly lower rates of resistance compared with those with a low barrier to resistance. Management of treatment failure requires precise clinical and virological monitoring as well as early treatment intervention with appropriate noncross-resistant antivirals. Long-term surveillance of treatment efficacy and possible emergence of drug resistance is necessary in patients who have been sequentially treated with multiple antivirals. The identification of novel treatment targets remains a major research goal to improve the efficacy of current antiviral therapy through combination therapy regimens. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of chronic hepatitis B remains limited to monotherapy with pegInterferon-alpha or one of 5 different nucleoside analogues (NUC). While viral suppression can be achieved in approximately 95% of patients with new-generation NUCs, the rate of HBeAg seroconversion ranges from only 20% with NUCs to 30% with pegInterferon-alpha. HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5years. Attempts to improve the response by administering two different NUCs or a combination of NUC and pegInterferon-alpha have been unsuccessful. This situation has led researchers to investigate a number of steps in the HBV replication cycle as potential targets for new antiviral drugs. Novel targets and compounds could readily be evaluated in in vitro and in vivo models of HBV infection. The addition of one or more new drugs to the current regimen should offer the prospect of markedly improving the response to therapy, reducing the future burden of drug resistance, cirrhosis and hepatocellular carcinoma. [Copyright &y& Elsevier]

Over the past few decades there has been remarkable progress in viral hepatitis. Beginning with discovery of the viral agents, we now have reliable methods to diagnose and monitor all hepatitis virus infections, as well significant advances in treatment and prevention. Nonetheless, important challenges remain. This supplement to Gut looks forward to the next generation of challenges in the field of viral hepatitis, and this introductory article highlights several key issues. [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]

Background/Aims: Data on the efficacy of adefovir dipivoxil (ADV) in elderly and cirrhotic patients with lamivudine-resistant (LAM-R) chronic hepatitis B are scarce. This retrospective cohort study evaluated the safety and efficacy of ADV in this specific patient population. Methods: Sixty-eight cirrhotic LAM-R patients, of whom 19 (27.9%) were elderly (≥65 years of age) and nine had severe disease (two post-orthotopic liver transplantation, four pre-orthotopic liver transplantation and three decompensated), with hepatitis B virus (HBV) infection received ADV. Virological and biochemical responses to the addition of ADV were analysed. Results: At inclusion, all patients were receiving LAM; ADV was added. 75.4% of patients received a combination of LAM and ADV throughout this study for a median treatment duration of 12.6 months; the remainder received ADV with an overlap with LAM treatment for a median duration of 7.9 months. At the end of follow-up, 41.2% of patients had undetectable HBV DNA (≤2000 copies/ml) with a median reduction of 3.4 log10 copies/ml. Time to reach undetectable HBV DNA was dependent on baseline alanine aminotransferase (ALT) levels and HBeAg status. Normalization of serum ALT levels was observed in 55.2% (32/58) of patients. In patients who were HBeAg positive at baseline, HBeAg loss and seroconversion occurred in 23% (9/39) and 10% (4/39) respectively. No resistance mutations and no significant side effects were observed during the study period. Conclusion: Adefovir dipivoxil provides effective and safe treatment in cirrhotic and elderly patients who failed LAM therapy. [ABSTRACT FROM AUTHOR]

The management of hepatitis B virus resistance to antivirals has evolved rapidly in recent years. The definition of resistance is now well established, with the importance of partial response and the improvement of assays to detect genotypic resistance and virological breakthrough. Data on phenotypic resistance have allowed to define the cross-resistance profile for the main resistant mutants, providing a rationale for treatment adaptation. Clinical studies have shown that an early treatment intervention in case of a virological breakthrough or a partial response with the addition of a second drug having a complementary cross-resistance profile allows one to maintain the majority of patients in clinical remission. The prevention of resistance should rely on the use of the most potent antivirals with a high genetic barrier to resistance as a first-line therapy. The future perspectives are to design strategies to hasten the HBsAg clearance, which should become a new treatment endpoint, to prevent drug resistance and to decrease the incidence of complications of chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis B virus has been evolving gradually over a long period of time, resulting in a large amount of genetic diversity, despite the constraints imposed by the complex genetic organization of the viral genome. This diversity is partly due to virus/host interactions and partly due to parallel evolution in geographically distinct areas. Recombination also appears to be an important element in HBV evolution. Also, human intervention in the form of mass vaccination and antiviral treatment will reduce the burden of HBV-related liver disease but may also be accelerating evolution of the virus. [Copyright &y& Elsevier]

Abstract: Treatment of chronic hepatitis B remains a clinical challenge. Long-term viral suppression is a major goal of antiviral therapy to improve the clinical outcome of the patients. Antiviral treatment of chronic hepatitis B relies currently on immune modulators such as interferon alpha and its pegylated form, and viral polymerase inhibitors. Because of the slow kinetics of viral clearance and the spontaneous viral genome variability, viral mutants resistant to nucleoside analogs may be selected. However, the development of new antiviral agents is rapidly improving the offing of therapy of chronic hepatitis B. These new therapeutic advances are reviewed in this manuscript. [Copyright &y& Elsevier]

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]

OBJECTIVES: The noninvasive serum markers, FibroTest–ActiTest (FT–AT), are an alternative to liver biopsy in patients with chronic hepatitis C and B. The aim was to use these markers in a prospective study of patients treated with lamivudine in order to assess the impact of treatment, as well as the factors associated with fibrosis progression. METHODS: Two hundred and ninety-eight patients were included in a prospective longitudinal study in 50 hospitals across France. FT–AT were measured at baseline, and then after 6, 12, and 24 months of lamivudine 100-mg treatment. Epidemiological, clinical, and virologic characteristics were analyzed by univariate and multivariate analysis. RESULTS: Two hundred and eighty-three patients were included for analysis. The accuracy of FT–AT versus biopsy was validated with the area under the ROC curve, 0.77 (SE = 0.03) for bridging fibrosis and 0.75 (SE = 0.06) for severe activity (A3). At baseline, bridging fibrosis (METAVIR stages F2–F3–F4) was highly associated ( p < 0.001) in multivariate analysis with male gender and age and marginally associated with anti-HBe presence ( p= 0.05) and non-Asian ethnic origin ( p= 0.046). Lamivudine treatment had a very significant impact overall. FT decreased significantly from 0.51 at baseline to 0.37 at 24 months ( p < 0.001), and 85% of patients had improvement at 24 months. AT also decreased significantly from 0.56 to 0.13 ( p < 0.0001), and 91% of patients had improvement at 24 months. A three-phase kinetics was observed for both fibrosis and activity; there was a marked improvement during the first 6 months, followed by a plateau between 6 and 12 months, and another improvement between 12 and 24 months. The occurrence of a YMDD variant does not entirely explain these three-phase variations. The first phase impact on fibrosis rates was higher in Asian patients ( p= 0.01) and in patients younger than 40 yr ( p < 0.001). CONCLUSIONS: In patients with chronic hepatitis B, a 24-month course of lamivudine treatment leads to a significant decrease in necroinflammatory grades and fibrosis stages as assessed by noninvasive markers, with the occurrence of a three-phase kinetics. FT–AT should be useful in the noninvasive follow-up of lamivudine treatment. (Am J Gastroenterol 2005;100:1970–1980) [ABSTRACT FROM AUTHOR]

Chronic Hepatitis B virus (HBV) infections remain a major problem public health problem worldwide, as well as a therapeutic challenge for clinicians. This review focuses on the main viral and host determinants involved in HBV persistence in infected cells. The mechanism of HBV resistance to nucleoside analogs are described as well as the concept for multiple drug therapy and combination with immunostimulatory approaches. [Copyright &y& Elsevier]

The core promoter mutants of hepatitis B virus (HBV) emerge as the dominant viral population at the late HBeAg and the anti-HBe stages of HBV infection, with the A1762T/G1764A substitutions as the hotspot mutations. The double core promoter mutations were found by many investigators to moderately enhance viral genome replication and reduce hepatitis B e antigen (HBeAg) expression. A much higher replication capacity was reported for a naturally occurring core promoter mutant implicated in the outbreak of fulminant hepatitis, which was caused by the neighboring C1766T/T1768A mutations instead. To systemically study the biological properties of naturally occurring core promoter mutants, we amplified full-length HBV genomes by PCR from sera of HBeAg[sup +] individuals infected with genotype A. All 12 HBV genomes derived from highly viremic sera (5 × 10[sup 9] to 5.7 × 10[sup 9] copies of viral genome/ml) harbored wild-type core promoter sequence, whereas 37 of 43 clones from low-viremia samples (0.2 × 10[sup 7] to 4.6 × 1[sup 0]7 copies/ml) were core promoter mutants. Of the 11 wild-type genomes and 14 core promoter mutants analyzed by transfection experiments in human hepatoma cell lines, 6 core promoter mutants but none of the wild-type genomes replicated at high levels. All had 1762/ 1764 mutations and an additional substitution at position 1753 (T to C), at position 1766 (C to T), or both. Moreover, these HBV clones varied greatly in their ability to secrete enveloped viral particles irrespective of the presence of core promoter mutations. High-replication clones with 1762/1764/1766 or 1753/1762/1764/1766 mutations expressed very low levels of HBeAg, whereas high-replication clones with 1753/1762/1764 triple mutations expressed high levels of HBeAg. Experiments with site-directed mutants revealed that both 1762/ 1764/1766 and 1753/1762/1764/1766 mutations conferred significantly higher viral replication and lower HBeAg expression than... [ABSTRACT FROM AUTHOR]

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]

Résumé: Selon les estimations au niveau mondial, 5 % des patients porteurs d'une infection chronique virale B (VHB) sont co-infectés par le virus de l'hépatite Delta (VHD) qui est considéré comme l'hépatite virale la plus sévère. Cette co-infection augmente le risque de mortalité hépatique et globale ainsi que le risque de développer un carcinome hépatocellulaire (CHC). Le VHD est un virus défectif qui nécessite l'antigène HBs (AgHBs) pour entrer et sortir des hépatocytes, mais sa réplication et son cycle viral sont indépendants du VHB. Le VHD diminue la réplication du VHB chez la majorité des patients. La connaissance des mécanismes virologiques du VHD permet de comprendre l'histoire naturelle de cette co-infection ainsi que les stratégies de dépistage et de diagnostic. Il existe deux modes de présentation du VHD : soit une infection aiguë VHB/VHD caractérisée par une cytolyse biphasique ; soit une super-infection par le VHD d'un patient porteur d'une infection chronique VHB (traité ou non). Le dépistage de l'ensemble des porteurs d'un AgHBs positif reste primordial et surtout si les patients présentent des facteurs de risque de co-infection : population issue de l'immigration, usagers de drogues intraveineuses, pratiques sexuelles à risque ou co-infection avec le VIH et/ou le VHC. Tout patient porteur d'un AgHBs positif doit avoir une sérologie VHD qui doit être répétée en cas de facteur de risque. En cas de cytolyse aiguë chez un porteur d'une infection chronique VHB, une sérologie VHD doit être réalisée. Toute sérologie positive doit être complétée par une charge virale sérique VHD pour identifier les porteurs d'une infection chronique et discuter un éventuel traitement. Des stratégies de dépistage doivent être mise en place pour dépister l'ensemble des porteurs d'une co-infection. It is estimated that 5% of patients with chronic viral B infection (HBV) are co-infected with hepatitis Delta virus (HDV) worldwide. HDV is considered as the most severe viral hepatitis. This co-infection increases the risk of liver and overall mortality as well as the risk of hepatocellular carcinoma (HCC). HDV is a defective virus that requires HBsAg to enter and exit hepatocytes, but its replication and viral cycle are independent of HBV. HDV decreases HBV replication in most patients. Understanding the virological mechanisms of HDV provides insight into the natural history of this co-infection as well as screening and diagnostic strategies. There are two modes of presentation of HDV infection: either an acute HBV/HDV infection characterized by biphasic cytolysis; or an HDV superinfection of a patient with chronic HBV infection (treated or not). Screening of all HBsAg-positive patients remains essential, especially those with risk factors for co-infection: migrants, intravenous drug users, risky sexual practices, or co-infection with HIV and/or HCV. All patients with positive HBsAg should have an HDV serology test, which should be repeated in case of risk factors. In case of acute cytolysis in a patient with positive HBsAg, an HDV serology must be performed. Any positive serology should be completed by a serum HDV viral load to identify chronically infected patients and discuss possible treatment. Screening strategies should be implemented to identify all co-infected individuals. [ABSTRACT FROM AUTHOR]

Introduction: The risk of mortality in people with a history of injection drug use (PHID) is high, as is the prevalence of hepatitis C virus (HCV) infection. Although direct‐acting antivirals (DAA) are effective in this population in terms of sustained virological response, it is not known whether PHID benefit as much as people with no history of injection drug use from DAA‐related HCV cure in terms of reduced all‐cause mortality. Methods: Using Cox proportional hazards models based on the ANRS CO22 Hepather cohort data (n = 9735), we identified factors associated with all‐cause mortality among HCV‐infected people. We tested for interaction effects between drug injection status, HCV cure and other explanatory variables. Results: DAA‐related HCV cure was associated with a 66% (adjusted hazard ratio [95% confidence interval]: 0.34 [0.29–0.39]) lower risk of all‐cause mortality, irrespective of drug injection status. Detrimental effects of unhealthy alcohol use on mortality were identified in PHID only. Discussion and Conclusions.: DAA‐related HCV cure led to comparable benefits in terms of reduced mortality in PHID and people with no history of injection drug use. Policies and strategies to enhance DAA uptake among PHID are needed to lower mortality in this population. Clinical trial registration details: ClinicalTrials.gov: NCT01953458. [ABSTRACT FROM AUTHOR]

Objectives: Improving the understanding of the patterns of quantitative hepatitis B surface antigen (qHBsAg) trajectories associated with HBsAg loss is important in light of novel anti‐hepatitis B virus agents being developed. We evaluated long‐term qHBsAg trajectories in persons with HIV and HBV during tenofovir‐containing antiretroviral therapy in the Swiss HIV Cohort Study. Methods: We included 29 participants with and 29 without HBsAg loss, defined as qHBsAg <0.05 IU/mL. We assessed qHBsAg decline during therapy in both groups and used agglomerative hierarchical clustering to identify different qHBsAg trajectory profiles in persons with HBsAg loss. Results: The median follow‐up time was 11.9 years (IQR 8.4–14.1), and the median time to HBsAg loss was 48 months (IQR 12–96). Among participants with HBsAg loss, 79% had a qHBsAg decline ≥1 log10 IU/mL 2 years after starting tenofovir. The trajectories in qHBsAg levels during tenofovir therapy were heterogeneous, characterized by five distinct profiles. Among participants without HBsAg loss, only 7% had a qHBsAg decline ≥1 log10 IU/ml after 2 years. Conclusions: Most persons with HIV who experienced HBsAg loss had an early decline in qHBsAg levels, with diverse trajectories during long‐term tenofovir therapy. In persons without HBsAg loss, qHBsAg levels remained remarkably stable over time. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) affects more than 250 million people worldwide, and is one of the major aetiologies for the development of cirrhosis and hepatocellular carcinoma (HCC). In spite of universal vaccination programs, HBV infection is still a public health problem, and the limited number of available therapeutic approaches complicates the clinical management of these patients. Thus, HBV infection remains an unmet medical need that requires a continuous effort to develop new individual molecules, treatment combinations and even completely novel therapeutic strategies to achieve the goal of HBV elimination. The following review provides an overview of the current situation in chronic HBV infection, with an analysis of the scientific rationale of certain clinical interventions and, more importantly, explores the most recent developments in the field of HBV drug discovery. [ABSTRACT FROM AUTHOR]

Immunoblotting normalization issues have been recently overcome by whole lane staining. Herein, we are taking advantage of these recent advances and of the fluorophore status of the Ponceau S stain in order to combine the advantages of whole lane staining and fluorescence. By Ponceau S excitation at 488 nm, we identify the so-called 'fluorescent Ponceau' method as more linear, more sensitive and more repeatable than the others in protein lysates of distant biochemical profiles (cells, human and mouse tissues). This essentially cost-free method at the single experiment level provides accessible and robust means for post-blot normalization of many types of analytes. [Display omitted] • 'Housekeeping protein' signals robustness is much problematic in western blotting. • Ponceau Red is a fluorescent dye, amenable to fluorescence-based quantification. • Herein, a novel fluorescent Ponceau-based normalization technique is detailed. • It outcompetes regular Ponceau and pertinent commercial products. • Criteria used were sensitivity, linearity, and repeatability. [ABSTRACT FROM AUTHOR]

Purpose: Hepatitis C virus (HCV) cure after treatment with direct-acting antivirals (DAAs) can improve health-related quality of life (HRQoL). However, specific groups with chronic HCV may still exhibit worse post-cure HRQoL because of persisting severe liver fibrosis or social vulnerability factors (e.g. unhealthy alcohol use, living in poverty). We assessed the effect of such factors on longitudinal measures of HRQoL in chronic HCV patients. Methods: ANRS CO22 HEPATHER is a prospective cohort of chronic HCV patients receiving DAAs, which included notably patients with social vulnerability factors, a population usually under-represented in clinical trials. Multivariable mixed-effects linear regression models helped identify factors associated with longitudinal measures of HRQoL (PROQOL-HCV scores). Results: At enrolment, 52.4% of the 2740 participants were men, median age was 56 years [interquartile range 50–64], and 21.5% had severe liver fibrosis (FIB-4 > 3.25). Twenty-eight per cent reported current or past unhealthy alcohol use [> 2(3) alcohol units per day for women (men)], and 28.1% were living in poverty (standard of living under 1015€/month per household consumption unit). At first PROQOL-HCV completion, 54.0% of patients were HCV-cured. After multivariable adjustment, people with current or past unhealthy alcohol use, individuals living in poverty, those with severe liver fibrosis, and women had worse HRQoL in the dimensions explored. Conversely, HCV cure was associated with better HRQoL. Conclusions: Specific socially vulnerable groups of patients with chronic HCV infection still experience impaired HRQoL, independently of HCV cure. Patient-centred interventions, including social support and referral for comorbidities, should be prioritized for them. Trial registration with ClinicalTrials.gov NCT01953458. [ABSTRACT FROM AUTHOR]

Summary: Chronic hepatitis B (CHB) infection affects over 250 millon people worldwide and 800000 are expected to die yearly due to the development of hepatocellular carcinoma (HCC). Current antiviral therapies include nucleoside analogs (NAs) that target the viral retrotranscriptase inhibiting de novo viral production. Pegylated interferon (Peg‐IFN) is also effective in reducing the viral DNA load in serum. However, both treatments remain limited to control the infection, aiming for viral suppression and improving the quality of life of the infected patients. Complete cure is not possible due to the presence of the stable DNA intermediate covalently closed circular DNA (cccDNA). Attempts to achieve a functional cure are thus ongoing and novel targets and molecules, together with different combination therapies are currently in the pipeline for early clinical trials. In this review we discuss novel treatments both targeting directly and indirectly cccDNA. As we gain knowledge in the Hepatitis B virus (HBV) transcriptional control, and newer technologies emerge that could potentially allow the destruction of cccDNA, exciting new possibilities for curative therapies are discussed. [ABSTRACT FROM AUTHOR]

Background and Aims: The liver is an innervated organ that develops a variety of chronic liver disease (CLD). Axon guidance cues (AGCs), of which ephrins, netrins, semaphorins and slits are the main representative, are secreted or membrane‐bound proteins that can attract or repel axons through interactions with their growth cones that contain receptors recognizing these messengers. While fundamentally implicated in the physiological development of the nervous system, the expression of AGCs can also be reinduced under acute or chronic conditions, such as CLD, that necessitate redeployment of neural networks. Methods: This review considers the ad hoc literature through the neglected canonical neural function of these proteins that is also applicable to the diseased liver (and not solely their observed parenchymal impact). Results: AGCs impact fibrosis regulation, immune functions, viral/host interactions, angiogenesis, and cell growth, both at the CLD and HCC levels. Special attention has been paid to distinguishing correlative and causal data in such datasets in order to streamline data interpretation. While hepatic mechanistic insights are to date limited, bioinformatic evidence for the identification of AGCs mRNAs positive cells, protein expression, quantitative regulation, and prognostic data have been provided. Liver‐pertinent clinical studies based on the US Clinical Trials database are listed. Future research directions derived from AGC targeting are proposed. Conclusion: This review highlights frequent implication of AGCs in CLD, linking traits of liver disorders and the local autonomic nervous system. Such data should contribute to diversifying current parameters of patient stratification and our understanding of CLD. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) is a satellite RNA virus that requires the presence of hepatitis B virus (HBV) for its replication. HDV/HBV co‐infection is often associated with a faster disease progression of chronic hepatitis in comparison to HBV mono‐infection. Therefore, the development of novel antiviral therapies targeting HDV represents a high priority and an urgent medical need. In this review, we summarize the ongoing efforts to evaluate promising HDV‐specific drugs, such as lonafarnib (LNF), pegylated interferon lambda (PEG‐IFN‐λ) and their use as a combination therapy. Furthermore, we review the most recent developments in the area of anti‐HBV drugs with potential effects against HDV, including therapeutic agents targeting hepatitis B surface antigen (HBsAg) expression, secretion and function. Finally, we consider the important insights that have emerged from the development of these potential antiviral strategies, as well as the intriguing questions that remain to be elucidated in this rapidly changing field. [ABSTRACT FROM AUTHOR]

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]

Clinical manifestations of hepatitis B virus (HBV) infection are ranged from fulminant hepatitis to decompensated cirrhosis or hepatocellular carcinoma. Liver transplantation (LT) is one therapeutic option of these HBV infection complications. Intrahepatic viral persistence and low levels of circulating viral particles despite treatment optimization may lead to HBV recurrence after LT, which jeopardizes graft and patients survival after LT. HBV recurrence prophylactic strategies are based on nucleos(t)ides analogues (NUCs) treatment to block viral replication and anti-HBs immunoglobulin administration to neutralize circulating viral particles. The risk of HBV recurrence is also important in case of transplantation with a graft from a donor with a history of HBV infection (HBc+) to a "HBV naive" recipient or in case of immunosuppressive therapy after solid organ or hematopoietic stem cell transplantation for a HBc+ recipient. Prophylactic strategies are mainly focused on biological monitoring and NUCs therapy for high-risk situations. [ABSTRACT FROM AUTHOR]

Summary Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (PegIFN-α) or any of the five approved nucleos(t)ide analogues (NUC) treatments. While viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NUC, i.e. entecavir and tenofovir, HBsAg loss is achieved by PegIFN-α and/or NUC in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NUC or a combination of NUC and PegIFN-α have not provided a dramatic increase in the rate of functional cure . Because of this and the need of long-term NUC administration, there is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, in order to define new targets and develop new antiviral drugs. This includes a direct inhibition of viral replication with entry inhibitors, drugs targeting cccDNA, siRNA targeting viral transcripts, capsid assembly modulators, and approaches targeting the secretion of viral envelope proteins. Restoration of immune responses is a complementary approach. The restoration of innate immunity against HBV can be achieved, with TLR agonists or specific antiviral cytokine delivery. Restoration of adaptive immunity may be achieved with inhibitors of negative checkpoint regulators, therapeutic vaccines, or autologous transfer of engineered HBV-specific T cells. Novel targets and compounds will readily be evaluated using both relevant and novel in vitro and in vivo models of HBV infection. The addition of one or several new drugs to current therapies should offer the prospect of a markedly improved response to treatments and an increased rate of functional cure . This should lead to a reduced risk of antiviral drug resistance, and to a decreased incidence of cirrhosis and hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Bulevirtide recently received conditional approval from the EMA for the treatment of chronic hepatitis delta, but the ideal duration of therapy is unknown. Herein, we describe the first case of hepatitis delta cure following 3 years of bulevirtide monotherapy in a patient with compensated cirrhosis and esophageal varices. During the 72-week off-bulevirtide follow-up, virological and biochemical responses were maintained. In the off-therapy liver biopsy, intrahepatic HDV RNA and hepatitis D antigen were undetectable, <1% of hepatocytes were hepatitis B surface antigen positive and all were negative for hepatitis B core antigen. Ishak grading and staging were improved following treatment. [ABSTRACT FROM AUTHOR]