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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]

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]

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Background and Aim The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB). Methods CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA). Results Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg ( n = 3) and hepatitis B surface antigen ( n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance ( n = 2) and non-compliance ( n = 1). Conclusion The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares. [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]

The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α) therapy in chronic hepatitis B (CHB) infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(t)ide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB. [ABSTRACT FROM AUTHOR]

Objectives Caveats in the understanding of ribavirin (RBV) mechanisms of action has somehow prevented the development of better analogues able to further improve its therapeutic contribution in interferon (IFN)-based and direct antiviral agent-based regimens for chronic HCV or other indications. Here, we describe a new mechanism by which RBV modulates IFN-stimulated genes (ISGs) and contributes to restore hepatic immune responsiveness. Design RBV effect on ISG expression was monitored in vitro and in vivo, that is, in non-transformed hepatocytes and in the liver of RBV mono-treated patients, respectively. Modulation of histone modifications and recruitment of histone-modifying enzymes at target promoters was analysed by chromatin immunoprecipitation in RBV-treated primary human hepatocytes and in patients' liver biopsies. Results RBV decreases the mRNA levels of several abnormally preactivated ISGs in patients with HCV, who are non-responders to IFN therapy. RBV increases G9a histone methyltransferase recruitment and histone-H3 lysine-9 dimethylation/trimethylation at selected ISG promoters in vitro and in vivo. G9a pharmacological blockade abolishes RBV-induced ISG downregulation and severely impairs RBV ability to potentiate IFN antiviral action and induction of ISGs following HCV infection of primary human hepatocytes. Conclusions RBV-induced epigenetic changes, leading to decreased ISG expression, restore an IFN-responsive hepatic environment in patients with HCV, which may also prove useful in IFN-free regimens. [ABSTRACT FROM AUTHOR]

Background and Aim In Sub-Saharan Africa, seroclearance of hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg), including their quantifiable markers, have rarely been evaluated during long-term antiviral treatment among patients coinfected with HIV and hepatitis B virus (HBV). Methods In this prospective cohort study from two randomized-control trials in Côte d'Ivoire, 161 antiretroviral-naïve HIV-HBV coinfected patients starting lamivudine ( n = 76) or tenofovir/emtricitabine ( n = 85) containing antiretroviral therapy were included. HBV DNA was quantified using an in-house assay (detection limit = 12 copies/mL) and HBsAg quantification (qHBsAg) using the Elecsys assay. Results Overall, 33 (20.5%) patients were HBeAg positive, 121 (75.2%) had detectable HBV DNA, and 92/93 (98.9%) harbored HBV genotype E. Median treatment duration was 35.5 months (interquartile range: 24.3-36.4). Among HBeAg-positive patients, cumulative proportion with HBeAg seroclearance was 46.3% ( n = 14). Overall, cumulative proportion of HBsAg seroclearance was 6.6% ( n = 10). Lower baseline qHBsAg levels and strong 12-month declines in qHBsAg were significantly associated with HBsAg seroclearance for both HBeAg-negative and HBeAg-positive patients. When taken at certain levels, these determinants provided moderate sensitivity (Se) and specificity (Sp) in predicting HBsAg seroclearance at month 36 (≤ 1000 IU/mL at baseline, Se = 0.80, Sp = 0.80; ≥ 1.0 log10 IU/mL drop at month 12, Se = 0.57, Sp = 1.00). Instead, qHBsAg levels ≤ 100 or ≤ 10 IU/mL at month 12 were optimal (both Se = 0.90 and Sp = 1.00). Detectable HBV-DNA provided fairly high Se and Sp when evaluated at baseline (Se = 1.00, Sp = 0.80), but not at month 12 (Se = 0.80, Sp = 0.40). Conclusions HBsAg seroclearance rates are not common in patients from Sub-Saharan Africa treated with anti-HBV containing antiretroviral therapy. qHBsAg levels at 12 months of treatment may accurately predict HBsAg seroclearance. [ABSTRACT FROM AUTHOR]

Background: Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. Patients and Methods: A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. Results: None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50–3.70], P = 2x10-4). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82–8.92], P = 8x10-4). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10-5). Conclusion: Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy. [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]

Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy. [ABSTRACT FROM AUTHOR]

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]

The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed. [ABSTRACT FROM AUTHOR]

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: Because of the overlapping of polymerase and envelope genes in the hepatitis B virus (HBV) genome, nucleoside analog therapy can lead to the emergence of complex HBV variants that harbor mutations in both the reverse transcriptase and the envelope proteins. To understand the selection process of HBV variants during antiviral therapy, we analyzed the in vitro fitness (the ability to produce infectious progeny) of 4 mutant viral genomes isolated from one patient who developed resistance to a triple therapy (lamivudine, adefovir, and anti-HBV immunoglobulins). Methods: The 4 mutant and the wild-type forms of HBV were expressed from vectors in hepatoma cell lines; replication and viral particle secretion capacities then were analyzed. The impact of envelope gene mutations on infectivity was tested in HepaRG cells using the hepatitis delta virus (HDV) model as a reporter for infection. Results: The dominant HBV variant characterized from the therapy-resistant patient was found to have the best replicative capacity in vitro in the presence of high concentrations of lamivudine and adefovir. The expression of envelope proteins and secretion of subviral and Dane particles by this mutant was comparable with that of wild-type HBV. HDV particles enveloped by surface proteins from the selected mutant had the highest rates of infection in HepaRG cells compared with other mutants. Conclusions: These results illustrate the importance of viral fitness and infectivity as a major determinant of antiviral therapy resistance in patients. Understanding HBV mutant selection in vivo will help to optimize new anti-HBV therapeutic strategies. [Copyright &y& Elsevier]

A correction to the article "The way forward in HCV treatment - finding the right path," published on the December 2007 issue is presented.

In patients co-infected with HIV and HBV viral load monitoring allows comparison of the efficacy of different antiviral drugs and determination of the initial response to therapy. Usually, the decline in viral load is associated with an improvement in ALT levels and liver histology scores, but some patients show transient elevations in ALT levels due to the restoration of the specific anti-HBV immune response. Analysis of liver histology is useful to determine the improvement of the inflammatory activity of the disease and liver fibrosis, and to make an accurate diagnosis when drug hepatotoxicity is suspected. HBe seroconversion and HBs loss have been described in some patients during anti-HBV therapy with lamivudine, adefovir or tenofovir, indicating that the control of viral replication by these agents may lead to a dramatic suppression of viral load. HBV drug resistant mutants can be diagnosed at an early stage with the monitoring of viral load. Future research directions include the determination of predictive factors of response, the effect of anti-HBV therapy on liver disease severity, the impact of long-term treatment on HBsAg clearance and intrahepatic cccDNA, the impact of HBV drug resistance on the liver disease, the role of cross-resistance testing of HBV strains in patients with HBV treatment failure. [Copyright &y& Elsevier]

Examines the evolution of hepatitis B virus polymerase gene sequence during Famciclovir Therapy for chronic hepatitis B. Determination of the amino acid sequences and reverse transcriptase (RT) domains of the viral polymerase; Association of the non-response to famciclovir to the complex variability of the RT domain.

Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir…). The first are used as finite-duration treatments of around 48–52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B”. [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]

Abstract: Background and aims: The combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus (HBV) infection. The aim of this study was to assess the efficacy and tolerance of TDF+FTC in patients with chronic hepatitis B (CHB). Methods: Seventy eight consecutive CHB patients from five European centers were included. All started a TDF+FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF+FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. Results: TDF+FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4log10 IU/mL, and median alanine-transaminase (ALT) was 1.10×ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (⩾F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76weeks (interquartile range 60–116). Kaplan–Meier analysis showed that, 48weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1log10 IU/mL, median ALT 0.79×ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. Conclusions: After a median follow-up of >76weeks, the TDF+FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF+FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term. [Copyright &y& Elsevier]

The synthesis of carbocyclic and phosphonocarbocyclic analogues of ribavirin, an anti-HCV inhibitor, are described. Those compounds were evaluated against HCV but also against other important viruses in order to determine their spectrum of antiviral activity. Compounds 6 and 13 displayed a moderate IC50 against HIV-1 of 43.8 and 37 μM, respectively. [Copyright &y& Elsevier]

We describe the case of a patient with chronic hepatitis B who became resistant to lamivudine and was treated successfully with adefovir dipivoxil in addition to lamivudine. Lamivudine resistance was associated with the selection of a L180M+M204V polymerase mutant. After the addition of adefovir dipivoxil, serum HBV DNA levels dropped by more than 4log10, which was followed by HBsAg clearance after 22 months of combination therapy. Moreover, anti-HBs antibody titers rose above 1000mIU/mL after 32 months of the new treatment regimen. In parallel, HBV DNA declined below 100copies/mL by a quantitative real time PCR assay. Analysis of intrahepatic viral DNA showed a significant decline of total HBV DNA and cccDNA which was accompanied by a decrease of the number of infected cells expressing viral antigens below the detection limit of immunostaining. In parallel, liver histology analysis showed an improvement in both the activity index and fibrosis score. This report suggests that in patients who previously failed lamivudine therapy, proactive antiviral treatment may lead to a beneficial virological and clinical effect. [Copyright &y& Elsevier]