Traitement des hépatites B, C, D

Les hépatites virales sont un problème majeur de santé publique au niveau international. Environ 2 milliards de sujets dans le monde ont été en contact avec le VHB, soit qu\u27ils aient une infection, soit qu\u27ils aient éliminé partiellement le virus [1]. Quatre cents millions d\u27individus sont porteurs chroniques d\u27une infection par le virus de l\u27hépatite B (VHB) et parmi ceux-ci, environ à 15 millions sont co-infectés par un virus satellite du virus de l\u27hépatite B appelé le virus de l\u27hépatite Delta (VHD).Dans le monde, près de 200 millions de sujets sont également infectés par le virus de l\u27hépatite C [2]. Les chiffres concernant la mortalité et la morbidité globale de ces infections sont partiellement connus. L\u27OMS estime qu\u27environ 2 millions de décès par an sont dus aux infections par les virus des hépatites C (http://www.who.int/fr/). On sait également que les patients porteurs d\u27une infection chronique ont un risque majeur d\u27évoluer vers la cirrhose du foie et le carcinome hépato-cellulaire (le risque serait de 200 par rapport à un sujet non infecté [3, 4] ). Dans les pays développés, les hépatites B et C sont également responsables d\u27une grande partie des transplantations hépatiques [1] . L\u27objectif de cette revue est de faire le point sur le traitement des hépatites B, C et Delta en envisageant les schémas thérapeutiques les plus adaptés à l\u27Afrique. Nous aborderons d\u27abord le traitement des hépatites B, le traitement des co-infections B-Delta, le traitement des hépatites B chez les patients VIH puis le traitement des hépatites C et celui des hépatites C chez les patients vivant avec le VIH

Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis

Spermatogenesis is a highly regulated process that involves both mitotic and meiotic divisions, as well as cellular differentiation to yield mature spermatozoa from undifferentiated germinal stem cells. Although Gpat2 was originally annotated as a glycerol-3-phospate acyltransferase by sequence homology to Gpat1 , GPAT2 is highly expressed in testis but not in lipogenic tissues and is not up-regulated during adipocyte differentiation. New data show that GPAT2 is required for the synthesis of piRNAs, a group of small RNAs that protect the germ cell genome from retrotransposable elements. In order to understand the relationship between GPAT2 and its role in the testis, we focused on Gpat2 expression during the first wave of mouse spermatogenesis. Gpat2 expression was analyzed by qPCR, in situ hybridization, immunohistochemistry and Western blot. Gpat2 mRNA content and protein expression were maximal at 15 dpp and restricted to pachytene spermatocytes. To achieve this transient expression, both epigenetic mechanisms and trans-acting factors are involved. In vitro assays showed that Gpat2 expression correlates with DNA demethylation and histone acetylation and that it is up-regulated by retinoic acid. Epigenetic regulation by DNA methylation was confirmed in vivo in germ cells by bisulfite sequencing of the Gpat2 promoter. Consistent with the initiation of meiosis at 11 dpp, methylation decreased dramatically. Thus, Gpat2 is expressed at a specific stage of spermatogenesis, consistent with piRNA synthesis and meiosis I prophase, and its on-off expression pattern responds predominantly to epigenetic modifications.Fil: Garcia Fabiani, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Montanaro, Mauro Aldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Lacunza, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; ArgentinaFil: Cattaneo, Elizabeth Renee. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Coleman, Rosalind A.. University of North Carolina; Estados UnidosFil: Pellon Maison, Magali. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Gonzalez-Baró; MR. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; Argentin

Les mutants précore et du promoteur basal du core du virus de l’hépatite B

Le virus de l’hépatite B (VHB) est le seul virus à ADN qui possède une étape de reverse transcription au cours de son cycle de réplication. L’absence d’activité 3’-5’ exonucléasique de la fonction reversetranscriptase de l’ADN polymérase du virus génère une accumulation de mutations sur l’ensemble du génome viral. Ainsi, chez un même individu vont coexister des populations virales sauvages et mutées qui pourront évoluer tout au long de l’histoire naturelle de l’infection. La variabilité génétique du VHB s’observe dans toutes les régions du génome viral. La mutation la plus fréquemment décrite dans la région précore (PC) du VHB est la mutation G1896A qui induit la formation d’un codon stop dans l’ARN précore et abolit la synthèse de l’antigène HBe. Dans la région du promoteur basal du core (PBC), la double mutation (A1762T-G1764A) est associée à une baisse de la synthèse de l’antigène HBe. L’impact des mutants PC et du PBC dans l’histoire naturelle de l’hépatite B et dans la sévérité des lésions hépatiques n’est pas clairement établi

The Pricing Behaviour of Firms in the Euro Area: New Survey Evidence

This study investigates the pricing behaviour of firms in the euro area on the basis of surveys conducted by nine Eurosystem national central banks. Overall, more than 11,000 firms participated in the survey. The results are very robust across countries. Firms operate in monopolistically competitive markets, where prices are mostly set following mark-up rules and where price discrimination is a common practice. Our evidence suggests that both time- and state-dependent pricing strategies are applied by firms in the euro area: around one-third of the companies follow mainly time-dependent pricing rules while two-thirds use pricing rules with some element of state-dependence. Although the majority of firms take into account a wide range of information, including past and expected economic developments, about one-third adopts a purely backward-looking behaviour. The pattern of results lends support to the recent wave of estimations of hybrid versions of the New Keynesian Phillips Curve. Price stickiness arises both at the stage when firms review their prices and again when they actually change prices. The most relevant factors underlying price rigidity are customer relationships – as expressed in the theories about explicit and implicit contracts – and thus, are mainly found at the price changing (second) stage of the price adjustment process. Finally, we provide evidence that firms adjust prices asymmetrically in response to shocks, depending on the direction of the adjustment and the source of the shock: while cost shocks have a greater impact when prices have to be raised than when they have to be reduced, reductions in demand are more likely to induce a price change than increases in demand.

Systemic diseases and biotherapies: Understanding, evaluating, and preventing the risk of hepatitis B reactivation

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs

Quantification de l’antigène HBs : intérêts et limites dans le suivi des patients infectés par le virus de l’hépatite B

Hepatitis B surface antigen (HBsAg) is usually used as a qualitative marker for the diagnosis of hepatitis B virus (HBV) infection, ant its persistence for more 6 months defines chronic hepatitis B (CHB) infection. HBsAg quantification was introduced several years ago. Commercial quantitative assays are now available and studies have suggested its interest for the monitoring patients with chronic hepatitis B. Indeed, HBsAg titers can correlate with intrahepatic cccDNA levels. Several studies have shown that HBsAg titers vary in the different phases of the natural history of the CHB infection. The kinetic of serum HBsAg seems to have a predictive value of HBsAg clearance after treatment or of reactivation, in the case of lack of response to treatment. However, interpretation has to take into account the phase of CHB infection, the HBV genotype, HBeAg status and serum HBV DNA

Correlation between the promoter basal core and precore mutations and HBsAg quantification in French blood donors infected with hepatitis B virus

International audienceHepatitis B virus (HBV) basal core promoter (BCP) and precore (PC) mutations, HBV viral load and HBV surface antigen (HBsAg) quantitation were screened to assess correlations between these HBV markers in asymptomatic chronic hepatitis B carriers in France. From January 2006 to July 2007, 200 sera were collected from patients who were discovered to be HBsAg-positive when they volunteered to give blood. Direct sequencing of precore/core gene was used to detect A1762T/G1764A mutations in the BCP and G1896A in the PC region. HBV viral load and HBsAg were quantified with two commercials assays. The prevalence of the BCP and PC mixed/mutants were 37% and 60% respectively (P = 0.0001). HBV DNA level and HBsAg titer were significantly lower in subjects harboring the mixed/mutant PC virus compared to those infected by the wild phenotype. No significant difference was observed in HBV viral loads of blood donors infected by wild or mixed/mutant BCP viruses. Mutant or mixed PC virus was associated with male gender, HBeAb-positive status and HBV/D and HBV/E genotypes. BCP mutations were associated with age, and both HBV/A-HBV/E genotypes.The genetic properties of HBV in this cohort showed that most of the blood donors had a negative HBeAg serological status and harbored the PC mutant phenotype in combination with low levels of both HBV DNA and HBsAg. As the study was conducted in healthy subjects who could be considered as asmptomatic carriers, these results suggest a possible protective effect of the G1896A mutation against severe liver lesions. J. Med. Virol. 87:529–535, 2015. © 2014 Wiley Periodicals, Inc

Epidemiology of intensive care unit-acquired sepsis in Italy: results of the SPIN-UTI network

BACKGROUND: Sepsis is the major cause of mortality from any infectious disease worldwide. Sepsis may be the result of a healthcare associated infection (HAI): the most frequent adverse events during care delivery especially in Intensive Care Units (ICUs). The main aim of the present study was to describe the epidemiology of ICU-acquired sepsis and related outcomes among patients enrolled in the framework of the Italian Nosocomial Infections Surveillance in ICUs - SPIN-UTI project. STUDY DESIGN: Prospective multicenter study. METHODS: The SPIN-UTI network adopted the European protocols for patient-based HAI surveillance. RESULTS: During the five editions of the SPIN-UTI project, from 2008 to 2017, 47.0% of HAIs has led to sepsis in 832 patients. Overall, 57.0% episodes were classified as sepsis, 20.5% as severe sepsis and 22.5% as septic shock. The most common isolated microorganisms from sepsis episodes were Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The case fatality rate increased with the severity of sepsis and the mean length of ICU-stay was significantly higher in patients with ICU-acquired sepsis than in patients without. CONCLUSION: Our study provides evidence that ICU-acquired sepsis occurs frequently in Italian ICU patients and is associated with a high case fatality rate and increased length of stay. However, in order to explain these findings further analyses are needed in this population of ICU patient

Résultats de trois méthodes pour la détection de la mutation précore G1896A du virus de l’hépatite B chez les donneurs de sang français : PCR temps réel, séquençage et test Inno-LIPA

AIM: To screen hepatitis B virus (HBV) genotypes and associated basal core promoter (BCP; T1762A/A1764) and precore (PC; A1896) mutations among the 100 HBV surface antigen (HBsAg) positive voluntary blood donors in France. METHODS: HBV genotypes were determined by using direct sequence analysis. Three methods were used to detect G1896A mutation: non-commercial real-time PCR (PCRTR°, line probe assay (InnoLiPA HBV PreCore, INNOGENETICS(®)) and direct sequencing of precore gene. HBV viral load was quantified with two commercial real-time PCR (COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HBV Test/Roche and Real Time HBV/M2000/Abbott). RESULTS: The mean age of donors was 30 (18-64). Patients were from Africa (42%), Europa (50%), and Asia (8%). HBV/D was the most predominant (37%) genotype followed by HBV/A (31%) and HBV/E (22%). PC and BCP mutants were found in 57% with Inno-LIPA HBV test and 59% with both PCRTR and sequencing methods. A significant difference in the viral load of blood donors with wild and PC mutants was observed with the Taqman Cobas real time PCR (3,19 Log(10) UI/ml versus 4,93 Log(10) UI/ml, p < 0.05). Precore phenotype determination was in agreement with the three PC mutation detection methods in 56% of cases. CONCLUSIONS: Non-Caucasian genotype E was present in the French blood donors. PC mutation was more common than BCP mutations in this study. As HBV infected blood donors were more often asymptomatic carriers, we could speculate that the G1896A mutation may favour the asymptomatic state, supporting previous observations