Showing papers by "Fabien Zoulim published in 2017"

Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study.

Abstract: Summary Background Listeriosis is a severe foodborne infection and a notifiable disease in France. We did a nationwide prospective study to characterise its clinical features and prognostic factors. Methods MONALISA was a national prospective observational cohort study. We enrolled eligible cases declared to the National Reference Center for Listeria (all microbiologically proven) between Nov 3, 2009, and July 31, 2013, in the context of mandatory reporting. The outcomes were analysis of clinical features, characterisation of Listeria isolates, and determination of predictors of 3-month mortality or persisting impairment using logistic regression. A hierarchical clustering on principal components was also done for neurological and bacteraemic cases. The study is registered at ClinicalTrials.gov, number NCT01520597. Findings We enrolled 818 cases from 372 centres, including 107 maternal–neonatal infections, 427 cases of bacteraemia, and 252 cases of neurolisteriosis. Only five (5%) of 107 pregnant women had an uneventful outcome. 26 (24%) of 107 mothers experienced fetal loss, but never after 29 weeks of gestation or beyond 2 days of admission to hospital. Neurolisteriosis presented as meningoencephalitis in 212 (84%) of 252 patients; brainstem involvement was only reported in 42 (17%) of 252 patients. 3-month mortality was higher for bacteraemia than neurolisteriosis (hazard ratio [HR] 0·54 [95% CI 0·41–0·69], p Interpretation The severity of listeriosis is higher than reported elsewhere. We found evidence of a significantly reduced survival in patients with neurolisteriosis treated with adjunctive dexamethasone, and also determined the time window for fetal losses. MONALISA provides important new data to improve management and predict outcome in listeriosis. Funding Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme

Abstract: BACKGROUND & AIMS: Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real-world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization. METHODS: Patients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post-liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6-92.5%), 98% (43/44) without cirrhosis (95% CI 88.2-99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5-90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5-89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died. CONCLUSIONS: Daclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

The negative impact of HBV/HCV coinfection on cirrhosis and its consequences.

Abstract: SummaryBackground Hepatitis B virus (HBV)/hepatitis C virus (HCV) confection has been rarely studied in nonasian series. Aim To compare the characteristics of HBV/HCV coinfected patients to those of HBV- or HCV-monoinfected patients in the ANRS CO22 HEPATHER cohort study. Patients and Methods Of the 20 936 included patients, 95 had HBV/HCV coinfection (hepatitis B surface antigen, anti-HCV antibody and HCV RNA positive) and were matched with 375 HBV- and 380 HCV-monoinfected patients on age, gender and time since HBV or HCV diagnosis. Results F3-F4 fibrosis was more frequent in coinfected patients (58%) than in HBV- (32%, P < .0001), but similar in HCV-monoinfected patients (52%, P = .3142). Decompensated cirrhosis was more frequent in coinfected patients (11%) than in HBV- (2%, P = .0002) or HCV- (4%, P = .0275) monoinfected patients. Past excessive alcohol use was more frequent in coinfected patients (26%) than in HBV (12%, P = .0011), but similar in HCV monoinfected patients (32%, P = .2868). Coinfected patients had a higher proportion with arterial hypertension (42%) than HBV- (26%) or HCV-monoinfected patients (25%) (P < .003). Multivariable analysis confirmed the association between F3-F4 fibrosis and HCV infection in HBV-infected patients (OR = 3.84, 95% CI 1.99-7.43) and the association between decompensated cirrhosis and coinfection in HBV infected (OR = 5.58, 95% CI 1.42-22.0) or HCV infected patients (OR = 3.02, 95% CI 1.22-7.44). Conclusions HCV coinfection harmfully affects liver fibrosis in HBV patients, while decompensated cirrhosis is increased in coinfected patients compared with HBV- or HCV-monoinfected patients. HCV treatment is as safe and effective in coinfected as monoinfected patients and should be considered following the same rules as HCV monoinfected patients.

Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.

Abstract: Background and Aims Arrival of direct-acting antiviral agents against hepatitis C virus with high-sustained virological response rates and very few side effects has drastically changed the management of hepatitis C virus infection. The impact of direct-acting antiviral exposure on hepatocellular carcinoma recurrence after a first remission in patients with advanced fibrosis remains to be clarified. Methods 68 consecutive hepatitis C virus patients with a first hepatocellular carcinoma diagnosis and under remission, subsequently treated or not with a direct-acting antiviral combination, were included. Clinical, biological and virological data were collected at first hepatocellular carcinoma diagnosis, at remission and during the surveillance period. Results All patients were cirrhotic. Median age was 62 years and 76% of patients were male. Twenty-three patients (34%) were treated with direct-acting antivirals and 96% of them achieved sustained virological response. Median time between hepatocellular carcinoma remission and direct-acting antivirals initiation was 7.2 months (IQR: 3.6-13.5; range: 0.3-71.4) and median time between direct-acting antivirals start and hepatocellular carcinoma recurrence was 13.0 months (IQR: 9.2-19.6; range: 3.0-24.7). Recurrence rate was 1.7/100 person-months among treated patients vs 4.2/100 person-months among untreated patients (P=.008). In multivariate survival analysis, the hazard ratio for hepatocellular carcinoma recurrence after direct-acting antivirals exposure was 0.24 (95% confidence interval: 0.10–0.55; P<.001). Conclusions Hepatocellular carcinoma recurrence rate was significantly lower among patients treated with direct-acting antivirals compared with untreated patients. Given the potential impact of our observation, large-scale prospective cohort studies are needed to confirm these results.

Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort)

Abstract: OBJECTIVE: To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis. DESIGN: This prospective study involved 35 French centres. Inclusion criteria were biopsy-proven HCV or HBV cirrhosis, Child-Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework. RESULTS: 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p\textless0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p\textless0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control. CONCLUSION: BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted

Novel targets for hepatitis B virus therapy.

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

Genome-wide identification of direct HBx genomic targets.

Abstract: The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication.

Hepatitis A outbreak in HIV-infected MSM and in PrEP-using MSM despite a high level of immunity, Lyon, France, January to June 2017.

Abstract: Since 2016, an increase in the number of hepatitis A cases affecting mainly men who have sex with men (MSM) has been reported in low endemic countries in Europe. We calculated the attack rate in Lyon, France, in populations considered at high-risk: HIV-infected MSM and HIV-negative MSM receiving HIV pre-exposure prophylaxis (PrEP). In these populations, high level of immunity did not prevent the outbreak, indicating that vaccination should be reinforced, particularly in younger individuals.

Modeling HIV-HCV coinfection epidemiology in the direct-acting antiviral era: the road to elimination

Abstract: 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.

Challenges to a Cure for HBV Infection

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

Hepatitis C virus infection propagates through interactions between Syndecan-1 and CD81 and impacts the hepatocyte glycocalyx.

Abstract: The hepatitis C virus (HCV) infects hepatocytes after binding to heparan sulfate proteoglycans, in particular Syndecan-1, followed by recognition of the tetraspanin CD81 and other receptors. Heparan sulfate proteoglycans are found in a specific microenvironment coating the hepatocyte surface called the glycocalyx and are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins, and infectious agents. We investigated the mutual influence of HCV infection on the glycocalyx and revealed new links between Syndecan-1 and CD81. Hepatocyte infection by HCV was inhibited after knocking down Syndecan-1 or Xylosyltransferase 2, a key enzyme of Syndecan-1 biosynthesis. Simultaneous knockdown of Syndecan-1 and CD81 strongly inhibited infection, suggesting their cooperative action. At early infection stages, Syndecan-1 and virions colocalized at the plasma membrane and were internalized in endosomes. Direct interactions between Syndecan-1 and CD81 were revealed in primary and transformed hepatocytes by immunoprecipitation and proximity ligation assays. Expression of Syndecan-1 and Xylosyltransferase 2 was altered within days post-infection, and the remaining Syndecan-1 pool colocalized poorly with CD81. The data indicate a profound reshuffling of the hepatocyte glycocalyx during HCV infection, possibly required for establishing optimal conditions of viral propagation.

Ethics and hepatitis B cure research

Abstract: Recent scientific advances, including the development of curative therapies for HCV and the establishment of global cure initiatives for HIV, have led to international calls seeking a cure for chronic infection with HBV.1 ,2 Over 240 million people live with chronic HBV, resulting in up to 780 000 deaths annually due to hepatic fibrosis/cirrhosis and hepatocellular carcinoma (HCC).3 ,4 Persons chronically infected with HBV who do not receive treatment have a lifelong risk of developing HCC, the third most common cause of disease globally.5–7 Along with scaled-up approaches to preventing and treating chronic HBV infection, having a safe and effective cure for HBV infection promises to minimise the global burden of HBV-related morbidity and mortality and reduce the economic and other burdens of lifelong treatment. Nevertheless, as HBV cure research proceeds, it is critical to anticipate and address the associated ethical issues to best protect the rights, interests and welfare of those who participate in the research as well as those who are or will become chronically infected with HBV. In this paper, after describing briefly the rationale for work aimed at achieving HBV cure, we delineate some of the key ethical issues that are especially salient for HBV cure research: (1) risks of interventions; (2) outcome measures, monitoring and modelling; (3) selection of study population; (4) language and consent; and (5) fairness. HBV infects hepatocytes and can establish a long-lived persistent reservoir through unintegrated covalently closed circular (ccc)DNA (and to a lesser extent integrated HBV DNA) that can continually produce HBV DNA and viral proteins, particularly hepatitis B surface antigen (HBsAg).8 Following the administration of nucleos(t)ide reverse transcriptase inhibitors or interferon α, the main strategies for treating chronic HBV infection,9 ,10 HBV DNA declines to often undetectable levels and liver inflammation improves, …

Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus

Abstract: Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 dependence receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro. In patients, UNC5A mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples. UNC5A mRNA is downregulated in F2 (3-fold; P=0.009), in F3 (10-fold, P=0.0004) and more dramatically so in F4/cirrhosis (44-fold; P<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(-) tissues. UNC5A transcript was found strongly downregulated in HCC samples (33-fold; P<0.0001) as compared with non-HCC samples. In vivo, association of UNC5A transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained in vitro showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the UNC5 promoter and translation in a UNC5A 5'UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A dependence receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.

Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients.

Abstract: Background/Aims: A recent study reported that entecavir had inferior efficacy in nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients compared to NA-naive patients. We sought to compare the efficacy of tenofovir disoproxil fumarate (TDF) in NA-experienced and NA-naive CHB patients. Methods: We retrospectively enrolled 252 consecutive patients who had a serum hepatitis B virus (HBV) DNA level greater than 2,000 IU/mL at the initiation of TDF treatment and who received TDF for at least 6 months. Complete virologic suppression (CVS) was defined as undetectable serum HBV DNA. We generated a multivariate Cox proportional-hazard model to examine predictive factors that were independently associated with time to CVS. Results: The mean age of patients was 48.2 years, and the cohort included 181 NA-naive patients and 71 NA-experienced patients. The median duration of TDF treatment was 14.4 (interquartile range, 9.5-17.8) months. A total of 167 (92.3%) of 181 NA-naive patients achieved CVS, and 60 (84.5%) of 71 NA-exposed patients achieved CVS. Forty-nine (89.1%) of 55 patients who previously took an NA aside from adefovir and 11 (68.8%) of 16 adefovir-experienced patients achieved CVS. In multivariable analysis, previous adefovir exposure significantly influenced time to CVS (hazard ratio, 0.37; 95% confidence interval, 0.19-0.72; P=0.003), after adjusting for HBeAg positivity, baseline HBV DNA level and cirrhosis. Conclusions: Tenofovir had inferior efficacy in adefovir-experienced CHB patients compared to NA-naive patients. The response of patients with previous adefovir exposure to TDF monotherapy should be monitored closely. (Clin Mol Hepatol 2017;23:66-73)