Nouveau traitement de l'hépatite C chronique, l'Alisporivir, inhibiteur de la cyclophiline A : stratégie de développement et d'enregistrement

Le virus de l hépatite C (VHC) infecte 170 millions de personnes à travers le monde. Dans 50 à 85 % des cas, l hépatite C évolue vers une hépatique chronique. A cause de leur mode de contamination commun, par le sang, la prévalence dans le monde de la co-infection VIH-VHC est de 30% des infections à VIH. Par son évolution lente et silencieuse l hépatite C représente un coût pour les systèmes de soins et les traitements de références actuels présentent de nombreux effets indésirables. Un nouvel antiviral, l alisporivir, est en cours de développement. Cet analogue non immunosuppresseur de la ciclosporine inhibe l activité enzymatique de la cyclophiline A de l hôte ainsi l isomérisation de la NS5A n a pas lieu ce qui empêche la réplication du VHC. Cette thèse propose une stratégie globale de développement clinique et d enregistrement de ce nouvel antiviral. Le but poursuivi est de comprendre comment le développement peut répondre aux contraintes de l enregistrement dans certaines parties du monde et partant de l anticiper dans la stratégie globale du laboratoire.The hepatitis C virus infects 170 million people worldwide. In 50 to 85% of cases, the hepatitis C evolves into a chronic hepatic disease. Due to their common way of contamination, by infected blood, prevalence in the world of the co-infection HIV-HCV is 30 % of the infection with HIV. By its slow and silent evolution hepatitis C represents a cost for the healthcare systems and the standard treatments have many adverse effects. A new antiviral, the alisporivir, is currently in development. This cyclosporine analogue no immunosuppressive which inhibits the enzymatic activity of the cyclophilin, so the NS5A s isomerisation doesn t take place thus inhibits the VHC replication. The objective is to propose a global strategy of clinical development and registration of this new antiviral. The pursued purpose is to understand how the development can answer of the constraints of registration in certain continents and thus to anticipate it in the global strategy of a laboratory.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

International audienc