Showing papers by "Fabien Zoulim published in 2011"
TL;DR: It is demonstrated that HBx is required to initiate and maintain HBV replication and highlight HBx as the key regulator during the natural infection process.
371 citations
TL;DR: This study identifies aberrant DNA methylation of specific cellular genes in HCC and the major risk factors associated with these changes, providing information that could be exploited for biomarker discovery in clinics and molecular epidemiology.
161 citations
TL;DR: ETV monotherapy can be continued in NA‐naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long‐term ETV leads to a virological response in the vast majority of patients.
158 citations
TL;DR: HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection.
Abstract: Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection.
142 citations
TL;DR: The combination of the protease inhibitor BI 201335, the polymerase inhibitors BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.
133 citations
TL;DR: 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: 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.
123 citations
TL;DR: HBsAg-negative/anti-HBc-positive HSCT recipients with chronic onco-hematological disease carry a significant risk of HBsAg seroreversion and HBeAg-positive chronic hepatitis B, independently of serum levels of HBV DNA at transplantation.
Abstract: Allogeneic hematopoietic SCT (HSCT) increases the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) carriers but the incidence, risk factors and course of HBV reactivation after HSCT in HBsAg-negative/anti-hepatitis B core antigen (anti-HBc)-positive recipients are not well known. A total of 50 HBsAg-negative/anti-HBc-positive HSCT recipients with onco-hematological diseases, underwent sequential clinical and laboratory examinations, including serum HBsAg, during follow-up. Serum HBV DNA collected at HSCT was retrospectively amplified by a sensitive PCR assay. During 17 months of follow-up, six (12%) patients had seroreverted to HBsAg, 7-32 months after HSCT, with 1- and 5-year cumulative rates of 13 and 22%. HBsAg seroreversion was associated with serum HBeAg higher than 8 log₁₀ copies per ml HBV DNA and a 1.5 to 36 fold increase of serum alanine aminotransferase leading to HBeAg-positive chronic hepatitis B in all patients. Patients with chronic onco-hematological disease and long-lasting immunosuppression following HSCT had a higher risk of HBsAg seroreversion independently of serum HBV DNA levels at HSCT. HBsAg-negative/anti-HBc-positive HSCT recipients with chronic onco-hematological disease carry a significant risk of HBsAg seroreversion and HBeAg-positive chronic hepatitis B, independently of serum levels of HBV DNA at transplantation.
82 citations
TL;DR: Small interfering peptides that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells.
81 citations
TL;DR: In vitro studies suggest that targeting nucleocapsid functions may represent an interesting approach to the development of novel HBV inhibitors to prevent and combat drug resistance.
75 citations
TL;DR: The findings suggest that CHB patients infected with BCP/PC mutant viruses are more susceptible to severe hepatitis and ACLF than those with the B CP/PC wild-type virus and that ACLF patients with PC mutant viruses have an increased risk of death.
Abstract: Objective
To investigate the features of hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutations and genotypes in a large number of mild/severe chronic hepatitis B (CHB-M/CHB-S), and acute-on-chronic liver failure (ACLF) patients and analyze the clinical implications of the virologic features.
63 citations
TL;DR: The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.
Abstract: The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)-experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a high-sensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drug-resistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADV-resistant mutations were detected in 36 of 381 patients who received LAM and then switched-to ADV in contrast to one of 82 patients who received ADV add-on LAM. Entecavir (ETV)-resistant mutations were detected not only in LAM- and ETV-treated patients but also in LAM-treated ETV-naive patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrug-resistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.
TL;DR: In HIV/HBV‐coinfected patients, most of them with normal ALT under antiretroviral treatment including HBV active drugs, TE was proficient in discriminating moderate to severe fibrosis from minimal liver disease.
Abstract: Transient elastography (TE) is a noninvasive technique to evaluate liver fibrosis. We compared the performance of TE with liver biopsy (LB) in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection. Patients prospectively underwent TE and LB. The diagnosis accuracy of TE was calculated using receiver operating characteristic (ROC) curves for different stages of fibrosis, and optimal cut-off values were defined. A sequential algorithm combining TE with biochemical score (Fibrotest) is proposed. Fifty-seven patients had both TE and LB (median time: 3 days) and two with proven cirrhosis, only TE. Forty-six (78%) were under antiretroviral therapy with anti-HBV drugs in 98%, and 19 (32%) had elevated alanine aminotransferase (ALT). A significant correlation was observed between liver stiffness measurement (LSM) and METAVIR fibrosis stages (P < 0.0001). Patients with elevated ALT tended to have higher LSM than those with normal ALT. The areas under the ROC curves were 0.85 for significant fibrosis (≥ F2), 0.92 for advanced fibrosis (≥ F3) and 0.96 for cirrhosis. Using a cut-off of 5.9 kPa for F ≥ 2 and 7.6 kPa for F ≥ 3, the diagnosis accuracy was 83% and 86%, respectively. With an algorithm combining TE and Fibrotest, 97% of patients were well classified for significant fibrosis. Using this algorithm, the need for LB can be reduced by 67%. In HIV/HBV-coinfected patients, most of them with normal ALT under antiretroviral treatment including HBV active drugs, TE was proficient in discriminating moderate to severe fibrosis from minimal liver disease.
TL;DR: This study provides the first description of predominance of HBV subgenotype D7/subtype ayw2 among Moroccan HBV chronic carriers and showed a significant prevalence of naturally occurring MHR variants in Morocco.
TL;DR: Nodular regenerative hyperplasia in HIV-infected patients seems strongly related to age and the cumulative exposure to didanosine+stavudine,didanosine, and stavuda, and to tenofovir.
TL;DR: Evidence is presented that the NF-κB signaling activator, tumor necrosis factor (TNF)-α, induces the accumulation of HBx in cells by increasing protein stability due to reduced proteasomal degradation, and it is shown that the increased level of HBX in cells cooperates with TNF-α toward activation of NF-σB and expression of NF -κB-regulated genes, indicating a positive feedback loop between HBx and NF-γB signaling.
Abstract: Hepatitis B virus (HBV) X protein (HBx) is a key player in HBV-induced hepatocellular carcinoma (HCC). HBx interacts with several cell signaling molecules, leading to activation of various transcription factors including nuclear factor-kappaB (NF-κB). Activated NF-κB signaling is implicated in many human cancers including HCC. Here, we present evidence that the NF-κB signaling activator, tumor necrosis factor (TNF)-α, induces the accumulation of HBx in cells by increasing protein stability due to reduced proteasomal degradation. The effects of TNF-α on HBx protein stability are mediated via activated NF-κB effector kinases IKKα and IKKβ and p65. The non-IKK-phosphorylable p65-S534A mutant did not induce HBx protein stability; hence, phosphorylation of p65 by IKK is a key step in TNF-α-induced stabilization of HBx. Phospho-p65 showed higher affinity to HBx compared with the non-phosphorylable p65 mutant, suggesting that the interaction of phospho-p65 with HBx might be important for HBx stabilization. We also show that the increased level of HBx in cells cooperates with TNF-α toward activation of NF-κB and expression of NF-κB-regulated genes, indicating a positive feedback loop between HBx and NF-κB signaling. Overall, our study provides evidence for interplay between HBx and NF-κB signaling, which may account for HBV-mediated liver carcinogenesis.
TL;DR: After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB.
TL;DR: Semi-synthetic derivatives of teicoplanin aglycone constitute a novel class of HCV replication inhibitors that are not cross-resistant with various HCV protease and polymerase inhibitors and in particular are potent in clearing hepatoma cells of their replicons.
Abstract: Objectives: Some semi-synthetic derivatives of glycopeptide antibiotics have been shown to exert in vitro antiviral activity against HIV and coronaviruses. Here we report and characterize the in vitro anti-hepatitis C virus (HCV) activity of several semi-synthetic derivatives of teicoplanin aglycone. Methods: Anti-HCV activity was analysed in: (i) three different subgenomic HCV replicon systems using a luciferase or quantitative RT-PCR (qRT-PCR) assay; and (ii) an infectious HCV cell culture system by means of qRT-PCR and immunofluorescence assays. Results: Several teicoplanin aglycone derivatives elicited selective anti-HCV activity in replicons as well as infectious cell culture systems, with LCTA-949 being the most potent derivative. LCTA-949 proved, in contrast to several directly acting antivirals for HCV, efficient in clearing cells of their replicons. When LCTA-949 was combined with HCV protease or polymerase inhibitors an overall additive effect was observed. Likewise, LCTA-949 was equipotent against wild-type replicons as well as against replicons resistant to polymerase and protease inhibitors. Following up to 4 months of selective pressure, no drug-resistant replicons were selected. When combined with the HCV NS3 protease inhibitor VX-950, LCTA-949 prevented the development of VX-950-resistant variants. Conclusions: Semi-synthetic derivatives of teicoplanin aglycone constitute a novel class of HCV replication inhibitors that are not cross-resistant with various HCV protease and polymerase inhibitors and in particular are potent in clearing hepatoma cells of their replicons. This class of molecules also provides a good tool to obtain novel insights into the replication cycle of HCV and into cellular factors/processes that are crucial for viral replication.
TL;DR: In this article, a mass influenza A/H1N1 vaccination campaign took place in France during the 2009 winter and 7.9% of the general population was vaccinated, however, vaccine coverage data are missing for at-risk groups.
TL;DR: A study of the failure of nucleoside analogue therapy suggests that drug-resistant mutants are not solely responsible for treatment failure, and that suboptimal treatment adherence might also have an important role.
Abstract: The failure of antiviral therapy for chronic hepatitis B can involve both virological breakthrough and genotypic resistance. A study of the failure of nucleoside analogue therapy suggests that drug-resistant mutants are not solely responsible for treatment failure. Suboptimal treatment adherence might also have an important role.
TL;DR: Current targets that are currently under investigation to develop inhibitors are viral entry, circular covalently closed DNA formation and its regulation, nucleocapsid assembly and viral morphogenesis, as well as the innate response of infected cells against HBV infection.
Abstract: Hepatitis B virus (HBV) remains a major public health issue with more than 350 million people chronically infected worldwide. Therapies using IFN-α or nucleos(†)ide analogs, which are currently approved for the treatment of chronic HBV infection, have failed to completely eliminate the virus. By describing the HBV life cycle, this article focuses on potential HBV targets and recent advances in the development of alternative antiviral strategies to fight chronic HBV infection. The targets that are currently under investigation to develop inhibitors are viral entry, circular covalently closed DNA formation and its regulation, nucleocapsid assembly and viral morphogenesis, as well as the innate response of infected cells against HBV infection. Other steps in the viral life cycle are potential targets; however, the development of novel antivirals remains challenging. The development of new HBV inhibitors represents a major advance in the field of antiviral therapy, to prevent antiviral drug resistance and to ...
TL;DR: Thiophosphonates S-PMEA 3 and S- PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity, and it was shown that their diphosphate forms S-PMApp 6 are readily incorporated by wild-type HIV- 1 RT into DNA and act as DNA chain terminators.
TL;DR: Neither Cmax levels nor the time to maximal drug levels differed between patients showing a complete virological response to adefovir, so adefavir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.
Abstract: Summary. Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well-defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14–59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2–8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus-DNA >10 000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.
TL;DR: Treatment of multiple HBV PATIENTS with ENTECAVIR PLUS TENOFOVIR and 2 years safety and EFFICACY ANALYSIS.