Orientador: Rejane Maria Tommasini Grotto / Banca: Dennis Armando Bertolini / Banca: Giovanni Faria Silva / Resumo: O vírus da Hepatite C (VHC) é um importante patógeno associado com doença hepática crônica sendo que alguns infectados podem desenvolver cirrose e carcinoma hepatocelular. O tratamento da hepatite C crônica visa a resposta virológica sustentada (RVS), definida como níveis de RNA viral indetectáveis no soro por seis meses depois do término do tratamento. Atualmente, a terapia padrão ouro é a combinação de interferon α peguilado e ribavirina, porém esse esquema terapêutico vem se mostrando eficaz em, apenas, 50% dos pacientes infectados com o genótipo 1, o mais prevalente no Brasil. Portanto, novas drogas mais eficazes e menos tóxicas estão sendo desenvolvidas para melhorar a assistência aos pacientes infectados pelo VHC, entre as quais merecem destaque os inibidores da serina protease NS3, a qual é uma enzima essencial para a replicação do VHC e assim um potencial alvo para novas terapias antivirais. Entretanto, a emergência de variantes resistentes é o maior obstáculo para o sucesso da terapêutica. Variantes resistentes já foram isoladas em pacientes tratados com os inibidores de protease e, estão associadas com a falência terapêutica. Porém o impacto dessas variantes resistentes em pacientes virgens de tratamento ainda não foi esclarecido e, esse tipo de informação pode avaliar o impacto dos inibidores de protease na terapia antiviral. O objetivo deste estudo foi avaliar a presença de mutações de resistência e polimorfismos genéticos na região genômica NS3 do VHC em 37 pacientes virgens de tratamento com inibidores de protease infectados com genótipo 1. RNA viral sérico foi utilizado como fonte para amplificação e seqüenciamento da região NS3 do VHC e, avaliar a presença de mutações de... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Hepatitis C Virus (HCV) is an important pathogen associated with chronic hepatic disease and some infected patients can develop cirrhosis and hepatocellular carcinoma. The treatment of chronic hepatitis C aimed the sustained virological response (SVR), defined as having undetectable serum HCV RNA at the end of therapy for at least 6 months. Currently, the gold standard therapy is a combination of pegylated interferon-α and the ribavirin, however this treatment present efficacy in only 50% of patients infected with genotypes 1, the most prevalent in Brazil. Then, new drugs more effective and less toxic have been developed to improve the attendance of the HCV infected patients as the serine protease NS3 inhibitors, which is an enzyme essential to HCV replication and main target of new antiviral therapies. However, the emergence of drug resistant variants has been the major obstacle to therapeutic successful. Resistant variants have already been isolated in patients treated with protease inhibitors and, these resistant variants are associated with non response to treatment. But the impact of the resistant variants in naïve protease inhibitors patients is unclear yet and, this information can evaluate the impact of protease inhibitors in antiviral therapeutic. The goal of this study was evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV in 37 protease inhibitors-naive genotype 1 HCV infected patients. Serum viral RNA was used as source to amplification and sequencing of NS3 region of HCV and, evaluates the presence of resistance mutations and polymorphisms in this region. The results showed that only 07 (18.9%) samples presented resistant variants, the mutations... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:23:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-15Bitstream added on 2014-06-13T19:28:48Z : No. of bitstreams: 1 zeminian_lb_me_botfm.pdf: 506409 bytes, checksum: 08bea6131bbfbe54e0327803c5f6bb14 (MD5) / Ministério da Saúde / O vírus da Hepatite C (VHC) é um importante patógeno associado com doença hepática crônica sendo que alguns infectados podem desenvolver cirrose e carcinoma hepatocelular. O tratamento da hepatite C crônica visa a resposta virológica sustentada (RVS), definida como níveis de RNA viral indetectáveis no soro por seis meses depois do término do tratamento. Atualmente, a terapia padrão ouro é a combinação de interferon α peguilado e ribavirina, porém esse esquema terapêutico vem se mostrando eficaz em, apenas, 50% dos pacientes infectados com o genótipo 1, o mais prevalente no Brasil. Portanto, novas drogas mais eficazes e menos tóxicas estão sendo desenvolvidas para melhorar a assistência aos pacientes infectados pelo VHC, entre as quais merecem destaque os inibidores da serina protease NS3, a qual é uma enzima essencial para a replicação do VHC e assim um potencial alvo para novas terapias antivirais. Entretanto, a emergência de variantes resistentes é o maior obstáculo para o sucesso da terapêutica. Variantes resistentes já foram isoladas em pacientes tratados com os inibidores de protease e, estão associadas com a falência terapêutica. Porém o impacto dessas variantes resistentes em pacientes virgens de tratamento ainda não foi esclarecido e, esse tipo de informação pode avaliar o impacto dos inibidores de protease na terapia antiviral. O objetivo deste estudo foi avaliar a presença de mutações de resistência e polimorfismos genéticos na região genômica NS3 do VHC em 37 pacientes virgens de tratamento com inibidores de protease infectados com genótipo 1. RNA viral sérico foi utilizado como fonte para amplificação e seqüenciamento da região NS3 do VHC e, avaliar a presença de mutações de... / The Hepatitis C Virus (HCV) is an important pathogen associated with chronic hepatic disease and some infected patients can develop cirrhosis and hepatocellular carcinoma. The treatment of chronic hepatitis C aimed the sustained virological response (SVR), defined as having undetectable serum HCV RNA at the end of therapy for at least 6 months. Currently, the gold standard therapy is a combination of pegylated interferon-α and the ribavirin, however this treatment present efficacy in only 50% of patients infected with genotypes 1, the most prevalent in Brazil. Then, new drugs more effective and less toxic have been developed to improve the attendance of the HCV infected patients as the serine protease NS3 inhibitors, which is an enzyme essential to HCV replication and main target of new antiviral therapies. However, the emergence of drug resistant variants has been the major obstacle to therapeutic successful. Resistant variants have already been isolated in patients treated with protease inhibitors and, these resistant variants are associated with non response to treatment. But the impact of the resistant variants in naïve protease inhibitors patients is unclear yet and, this information can evaluate the impact of protease inhibitors in antiviral therapeutic. The goal of this study was evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV in 37 protease inhibitors-naive genotype 1 HCV infected patients. Serum viral RNA was used as source to amplification and sequencing of NS3 region of HCV and, evaluates the presence of resistance mutations and polymorphisms in this region. The results showed that only 07 (18.9%) samples presented resistant variants, the mutations... (Complete abstract click electronic access below)

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Submitted by FERNANDA CRISTINA WINCKLER null (fwinckler@fmb.unesp.br) on 2016-11-30T19:00:44Z No. of bitstreams: 1 DISSERTAÇÃO FINAL 30.11.16.pdf: 468887 bytes, checksum: 372ef2c27b73313e5608616205ed1d2e (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-12-02T16:28:26Z (GMT) No. of bitstreams: 1 winckler_fc_me_bot.pdf: 468887 bytes, checksum: 372ef2c27b73313e5608616205ed1d2e (MD5) / Made available in DSpace on 2016-12-02T16:28:26Z (GMT). No. of bitstreams: 1 winckler_fc_me_bot.pdf: 468887 bytes, checksum: 372ef2c27b73313e5608616205ed1d2e (MD5) Previous issue date: 2016-10-19 / A hepatite C é uma doença infecciosa que torna-se crônica em cerca de 85% dos infectados que poderão desenvolver cirrose e carcinoma hepato celular. O tratamento antiviral em muitos dos pacientes não é eficaz, principalmente quando estes portam o genótipo 1 e fibrose avançada, a resposta inflamatória também desempenha seu papel sobre a resposta virológica sustentada (RVS) durante o tratamento com Interferon Peguilado (PegIFN) associado a Ribavirina (RBV). Nesse estudo nosso objetivo principal foi avaliar a influência da resposta inflamatória através de células e citocinas/quimiocinas sobre a resposta virológica do paciente em tratamento antiviral com terapia tripla. Incluimos pacientes com RNA VHC+, nunca tratados (naive), portadores do genótipo 1, ambos os sexos e com fibrose avançada F3 (n=6); F4 (n=21) candidatos ao tratamento em regime triplo. Os pacientes tiveram suas amostras coletadas e analizadas nas semanas 0 e 12 do tratamento e os seguintes parâmetros foram analisados: IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, TNF-α, IFN-γ, RANTES, MCP-1, MIG, IP- 10, através de citometria de fluxo (método CBA). Foram incluídos 15 voluntários saudáveis (grupo controle) e 27 pacientes que foram separados em G1(RVS) e G2 (não RVS), a taxa de RVS foi de 63%. Os pacientes com hepatite C crônica tiveram os níveis circulantes de IP10, MCP-1, MIG, RANTES, IL-8 e IL-6 mais elevados quando comparados com voluntários saudáveis, quando comparados G1xG2 os níveis de RANTES (p=0,04) e IL-6 (p=0,02) foram associadas com a RVS na semana 0, seus níveis eram mais baixos em G1, na semana 12 os níveis de RANTES (p=0,04) e IL-8 (n=0,01) foram associados com a RVS, seus níveis são mais elevados em G2, a comparação entre as semanas 0 e 12 mostrou que em G1 os níveis de IL6 (p= 0,02) e MCP-1 (p=0,001) apresentam associação com o tratamento e em G2 os parâmetros associados ao tratamento foram RANTES (p=0,05) e MCP-1 (p=0,01). Os resultados sugerem que, a citocina IL-6 e a quimiocina RANTES estão associadas com a RVS na semana 0. Na semana 12, RANTES assim como IL-8 influenciam na RVS durante terapia antiviral em regime triplo. Quando comparado semana 0 e 12 em pacientes RVS, a citocina IL-6 está associada ao tratamento. Em pacientes não RVS, RANTES esta associada ao tratamento e MCP-1 está associada ao tratamento independente da resposta obtida. / Hepatitis C is an infectious disease which becomes chronic in about 85% of infected people who can develop cirrhosis and hepatocellular carcinoma. Antiviral therapy isn’t effective in many patients, especially when these patients are genotype 1 and have advanced fibrosis, the inflammatory response also plays a role on sustained virological response (SVR) during treatment with Pegylated (PegIFN) plus Ribavirin (RBV). The aim of this study was evaluate the influence of the inflammatory response by cells and cytocines/chemokines on the virologic response of the patients under antiviral treatment with triple therapy. We included patients with HCV RNA+, naive, genotype 1, both male and female and with advanced fibrosis F3 (n=6); F4 (n=21) for triple treatment regimen. Patients had their samples collected and analyzed at weeks 0 and 12 of treatment and the following parameters were analyzed: IL- 2, IL-4, IL-6, IL-8, IL-10, IL-17A, TNF-α, IFN-γ RANTES, MCP-1, MIG, IP-10 by flow cytometry (CBA method). Control group of 15 healthy volunteers and 27 patients, who were separated into GI (SVR) and G2 (not SRV), were included, the SVR rate was 63%. Patients with chronic hepatitis C had higher circulating levels of IP10, MCP-1, MIG, RANTES, IL-8 and IL-6 compared with healthy volunteers, when G1xG2 were compared, levels of RANTES (p=0,040 and IL-6 (n=0,02) were associated with a SVR at week 0 and its levels were lower in G1; at week 12, levels of RANTES (p=0,04) and IL-8 (p=0,01) were associated with a SVR and its levels were higher in G2. The comparison between weeks 0 and 12 showed that, in G1, the IL6 levels (p = 0.02) and MCP-1 (p = 0.001) were associated with the treatment and in G2, the parameters associated with the treatment were RANTES (p = 0.05) and MCP-1 (p = 0.01). The results suggest that the cytocine IL-6 and chemokine RANTES are associated with SVR at week 0. At week 12, RANTES as well as IL-8 influence in SVR during antiviral therapy in triple regimen. When weeks 0 and 12 in patients SVR are compared, the cytocine IL-6 is associated with treatment. In non-SVR patients, RANTES is associated with treatment and MCP-1 is associated with independent treatment of the patient's response.

H θεραπεία της χρόνιας ηπατίτιδας C παραμένει πρόκληση ,ιδιαίτερα για κάποιους ασθενείς ,μια και ποικίλοι παράγοντες που αφορούν τόσο τον ιό όσο και τον ξενιστή σχετίζονται με χαμηλότερη ιολογική απάντηση στη θεραπεία .Ο γονότυπος τύπου 1 και το υψηλό ιϊκό φορτίο έναρξης είναι οι κύριοι ιϊκοί παράγοντες που σχετίζονται με χαμηλότερη ιολογική απάντηση στη θεραπεία ,ενώ για τον ασθενή οι παράγοντες που σχετίζονται με χαμηλότερη ιολογική απάντηση στη θεραπεία είναι η μη ανταπόκριση ή η υποτροπή σε προηγούμενη θεραπεία ,η παρουσία κίρρωσης ,η Αφροαμερικανική καταγωγή, η μεγαλύτερη των 40 ετών ηλικία, η μη συμμόρφωση στη θεραπεία και η παχυσαρκία. Τα οβάλ ηπατοκύτταρα είναι πρόδρομα ηπατικά κύτταρα που έχουν συσχετισθεί με την εξέλιξη της ηπατικής νόσου και την ανάπτυξη ηπατοκυτταρικού καρκινώματος σε πειραματικά μοντέλα .Πρόσφατα έχουμε αποδείξει ότι σε περιπτώσεις χρόνιας ηπατίτιδας τύπου Β ή C η παρουσία πρόδρομων ηπατικών κυττάρων σχετίζεται με τη σοβαρότητα της νόσου το βαθμό ίνωσης και το σχετιζόμενο κίνδυνο ανάπτυξης ηπατοκυτταρικού καρκινώματος Αυτή η μελέτη προσπάθησε να εντοπίσει τους παράγοντες που παίζουν καθοριστικό ρόλο στην μακροχρόνια ανταπόκριση στη θεραπεία ασθενών με χρόνια ηπατίτιδα C καθώς και τον ρόλο που μπορεί να έχει σε αυτή τη διαδικασία η ύπαρξη πρόγονων ηπατικών κυττάρων . Στόχος του έργου είναι η διερεύνηση ποικίλων κλινικών γενετικών εργαστηριακών και ιστολογικών παραμέτρων οι οποίες σχετίζονται με τη θεραπεία σε ασθενείς με χρόνια HCV λοίμωξη. Δευτερογενής στόχος της μελέτης είναι ο καθορισμός ομάδων υψηλού κινδύνου για την ανάπτυξη κίρρωσης και ηπατοκυτταρικού καρκίνου. ΣΧΕΔΙΑΣΜΟΣ 135 ενήλικες ασθενείς με θετική PCR και με βιοψία ήπατος που πιστοποιούσε χρόνια ηπατίτιδα εισήχθησαν στη μελέτη και τυχαιοποιήθηκαν να λάβουν είτε μονοθεραπεία με 3 MU ιντερφερόνης a2b τρεις φορές την εβδομάδα για 24 εβδομάδες ή συνδιασμό με ιντερφερόνη ή ή πεγκυλιωμένη ιντερφερόνη a2a (40 KD) μία φορά την εβδομάδα και προσθήκη 1000ή1200 mg ριμπαβιρίνης για 24 ή 48 εβδομάδες ανάλογα τον γονότυπο .Όλοι οι ασθενείς παρακολουθούνταν για την ασφάλεια την αντοχή και την αποτελεσματικότητα στο τέλος της εβδομάδας 2, 4, 8 και κάθε 4 εβδομάδες κατά τη διάρκεια της θεραπείας . Μετά την ολοκλήρωση της θεραπείας οι ασθενείς παρακολουθούνταν στις εβδομάδες 4, 12, 24 . Το πρώιμο τελικό σημείο ήταν η απώλεια του μετρήσιμου RNA του ιού της ηπατίτιδας C (HCV- RNA < 100c/ml) την εβδομάδα 24 μετά το τέλος της θεραπείας . Για να μελετήσουμε τη συσχέτιση των πρόγονων ηπατικών κυττάρων με την ανταπόκριση στη θεραπεία μελετήθηκαν 77 ηπατικές βιοψίες από ισάριθμους ασθενείς με χρόνια ηπατίτιδα C. Σαν μάρτυρες χρησιμοποιήθηκαν 10 φυσιολογικές ηπατικές βιοψίες .29 ασθενείς που ανταποκρίθηκαν στη θεραπεία και είχαν αρνητική PCR στο τέλος της προκαθορισμένης περιόδου αποτέλεσαν την ομάδα (Α) .29 ασθενείς που δεν ανταποκρίθηκαν στη θεραπεία και είχαν θετική PCR στο τέλος της προκαθορισμένης περιόδου αποτέλεσαν την ομάδα (Β) και τέλος 19 ασθενείς που υποτροπίασαν μετά αρχική ανταπόκριση στη θεραπεία αποτέλεσαν την ομάδα (Γ).Εξετάσθηκαν τομές παραφίνης πάχους 4 μm και καταμετρήθηκαν τα κύτταρα με μορφολογία οβάλ ηπατοκυττάρων δηλαδή AFPmRNA(+) και πρωτεΐνες CK19 (+) CK7(+) LCA(-) KAI CD34(-) Τα αποτελέσματα εκφράστηκαν σε ποσοστό επί τις %για τα κύτταρα με τα αντίστοιχα μορφολογικά χαρακτηριστικά και συσχετίστηκαν με τις αντίστοιχες κλινικές παραμέτρους. Ηπατικά προγονικά κύτταρα παρουσιάστηκαν και στις 87 βιοψίες αν και ήταν σημαντικά λιγότερα στις βιοψίες ελέγχου. Σύμφωνα με την έκφραση AFPmRNA η επί της % έκφραση ήταν :Ομάδα Β 53.4+ 1.3 > Ομάδα Γ 49+1.8 > Ομάδα Α 30.7 + 1.9 Οι ασθενείς που έλαβαν ιντερφερόνη ανταποκρίθηκαν καλύτερα στη θεραπεία αν ήταν < 40 είχαν γονότυπος 3,ιστορικό IV Χρήσης ουσιών αρνητική PCR-HCV (-) στην εβδομάδα 24 μετά θεραπεία &είχαν απουσία κίρρωσης ενώ είχαν μικρότερη πιθανότητα ανταπόκρισης αν είχαν ηλικία >40 έτη γονότυπο 1 ιστορικό μετάγγισης, αυξημένη ALT ή παρουσία κίρρωσης. Οι ασθενείς που έλαβαν θεραπεία συνδιασμού είχαν ευνοϊκή πρόγνωση αν εμφάνιζαν γονότυπο 2 ή 3 και μη ευνοϊκή αν είχαν γονότυπο 1,4 παρουσία κίρρωσης& αυξημένη γGt . Οι αυξημένες τρανσαμινάσες δεν αποτελούσαν προγνωστικό δείκτη. Στους ασθενείς που έλαβαν θεραπεία με πεγκυλιωμενη ιντερφερονη η ηλικία ή η απουσία κίρρωσης δεν αποτελούσε ανεξάρτητο προγνωστικό παράγοντα αντίθετα με την παραμονή αυξημένης ALT & γGt στον 6ο μήνα θεραπείας Ανεξάρτητοι προγνωστικοί παράγοντες για οποιαδήποτε θεραπευτικό σχήμα ήταν η Ηλικία (< 40 ετών )και η απουσία κίρρωσης .Οι ασθενείς με Φυσιολογικές τρανσαμινάσες αποτελούσαν το 40% των ασθενών μας στη δική μας μελέτη φάνηκε ότι ανταποκρίνονται καλύτερα στη θεραπεία και Σε μικρότερο ποσοστό εμφανίζουν κίρρωση ( 7% ) ενώ οι ασθενείς με κίρρωση Ανταποκρίνονται λιγότερο καλά σε όλες τις θεραπείες εμφανίζουν μεγαλύτερη διάρκεια λοίμωξης,λιπώδες ήπαρ σε μεγαλύτερο ποσοστό (64%) Έχουν αυξημένα ποσοστά ALT-γGt. Ενώ η παρουσία κίρρωσης είναι ανεξάρτητη από τον γονότυπο Τα ΠΗΚ υπάρχουν συχνά σε βιοψίες ήπατος ασθενών με ΧΗC και εκφράζουν AFPmRNA Υπάρχει σημαντική συσχέτιση με τη σοβαρότητα της νόσου και την ανταπόκριση στη θεραπεία Τα ΠΗΚ μπορεί να αποτελέσουν ανεξάρτητο προγνωστικό παράγοντα για την ανταπόκριση στη θεραπεία σε ασθενείς με χρόνια ηπατίτιδα C. / The treatment of chronic hepatitis C remains a challenge, particularly for certain patients as several virus related and patient related factors are associated with a lower virologic response to therapy. Hepatitis C virus genotype 1and a high baseline viral load are the major viral factors associated with a lower virologic response to therapy .Patient –related factors include previous relapse or non response to treatment, the presence of cirrhosis, the African America ethnicity, older age, contraindications to treatment and obesity. Oval hepatocytes (HK) are liver stem cells which are involved in the progress of liver disease and hepatocellular carcinoma development in experimental models. We have previously shown that in case of chronic hepatitis type B or C the presence of OH is related to the severity of the disease, the grade of fibrosis and the relative risk for HCG development. This study try to determine the factors effect the long term suppression of hepatitis C virus and also investigate the correlation of OH expression with treatment response in patients with chronic hepatitis C. Design 135 patients aged 18 years or more with positive HCV RNA and liver biopsy, were enrolled and randomly allocated to one of three regimens: 3mega units (MU) interferon a2btree times a week for 24 weeks, 3mega units (MU) interferon a2b tree times a week, plus 1000-12000 mg ribavirine per day for 24 weeks or 48 weeks or peg interferon alfa-2a (40KD) plus ribavirine 1000 or 1200 per day for 24 or 48 weeks because of different genotype. All patients were assessed for safety, tolerance and efficacy and the end of weeks 2, 4, 8and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 12 and 24.The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/ml) at week 24 after treatment. The study comprised 77 liver biopsies obtained to an equal number of patients with chronic hepatitis C virus infection. To investigate the correlation of OH expression with treatment response ten normal liver biopsy were used as control. Twenty nine patients were assigned as responders (group A) 29 as non responders (group B) and 19 as releasers (group C). Paraffin sections (4μm thick) were subjected. To OH expretion . Cells with morphologic features of OH that were AFPmRNA or protein +/CK19+/CK7+ and LCA (-) /CD 34(-) were scored. Results were expressed as% of positive cells following morphometric analysis and correlated with the clinical parameters. Findings Sustained virological response at 24 weeks after treatment was found in 18( 22% ) of the 88 patient treated for 24 weeks with 3mega units (MU) interferon a2b three times a week ,35 ( 47%) of the 74 patient treated with the combination regiment, and 28 (60% ) of the 47 treated with peg interferon alfa-2a (40KD) plus ribavirine. Logistic recreation identified five independent factors significantly associated with response to treatment with interferon: genotype 2 or 3 , age forty years or less, minimal fibrosis stage, Ivd users , PCR negative at 6 months. Tree factors associated with the response to combination therapy: genotype 2 or 3, no cirrhosis, and high γgt the only factors significantly associated with response with the pegylated interferon treatment is high levels of γgt and alt to the sixth month of treatment. Oval hepatocyte expression was present in all 87 specimens, being significantly lower in controls compared with cases of chronic hepatitis C. According to the AFPmRNA expression, the grade for % OH expression was: (group B) non responders: 53.4+- 1.3> (Group C ) relapses :49+_1.8>(group A) responders30.7 +_1.9The difference was recorded as follows>(group A) vs. Bp<0.01, group A vs. C p<0.01, group B vs. C p<0.05. Conclusions This study demonstrates that OH are frequently present and expresses AFPmRNA in liver biopsies of patients with chronic hepatitis C. There is a significant association with the severity of disease and with response to treatment and may provide additional prognostic information and predict prognosis in cases of chronic hepatitis c. Age forty years or less and the presence of cirrhosis or no, they are independent factors significantly associated with response to any treatment. Patient with persistently normal or almost normal transaminase levels have higher virological response to therapy and less frequently cirrhosis Patient with cirrhosis exhibit lower response rates to therapy. The presents of cirrhosis is not related to genotype . Patients have frequently high levels of alt and γgt before and six months after therapy and have a worse virological response to any therapy.

Le traitement du virus de l'hépatite C (VHC) a connu une révolution récente, rapide et exemplaire grâce à l'arrivée des agents antiviraux directs (AAD) en plusieurs vagues depuis 2011, détrônant ainsi la bithérapie interféron-pégylé/ribavirine. Ces nouveaux traitements ont été rapidement confrontés à des limites concernant leur efficacité et leur tolérance notamment à leurs débuts avec les inhibiteurs de la protéase NS3/4A de première génération. L'arrivée de nouveaux AAD sur le marché lors d'une 2ème vague en 2014 a permis toutefois de surpasser celles-ci et de devenir le traitement de référence du VHC.Leur efficacité remarquable a laissé naître l'idée d'une potentielle élimination du VHC grâce à l'utilisation universelle de ces traitements. Cependant, leur coût élevé et les comportements à risque observés dans des sous-groupes de population (utilisateurs de drogues intraveineuses et homosexuels) restent encore des problématiques cruciales à surmonter pour espérer atteindre les objectifs fixés par l'Organisation Mondiale de la Santé en 2030 concernant l'élimination du VHC. De plus ces traitements, permettant l'élimination virale quasi-systématique et donc consécutivement une diminution du risque de complications hépatiques, ont été récemment confrontés à une polémique concernant un potentiel risque de récidive précoce de carcinome hépatocellulaire (CHC) suite à une exposition à ces derniers.Le travail présenté dans cette thèse s'articule autour de trois problématiques ayant toutes pour objectif principal d'optimiser l'utilisation de ces traitements dans l'optique de contrôler l'histoire naturelle de la maladie à l'échelle individuelle et à l'échelle populationnelle par l'intermédiaire de diverses méthodes statistiques.Nos résultats ont permis de montrer au sein d’une première problématique ayant exploré l'efficacité et la tolérance de ces traitements antiviraux à l’échelle individuelle: (i) une efficacité antivirale moindre que celle annoncée dans les essais de phase III des inhibiteurs de protéase de première génération(télaprévir et bocéprévir), (ii) un effet indésirable significatif des inhibiteurs de protéase de première génération sur la fonction rénale, (iii) une tolérance moins bonne de ces premières molécules que lors du traitement par bithérapie avec une incidence accrue d'anémie probablement liée à un surdosage en ribavirine induit par les inhibiteurs de protéase et (iv) une efficacité antivirale remarquable des AAD arrivés depuis 2014 sans impact des caractéristiques du patient ni des dosages pharmacologiques sur la réponse virologique. Dans un second temps, la problématique d'un risque de récidive de CHC accru après un traitement par AAD a également été explorée par l'analyse d'une cohorte locale, celle-ci ayant conclu à l'absence de risque accru comparé à un groupe de patients non exposés. Enfin, nos travaux basés sur la modélisation de la transmission du VHC en France dans la population coinfectée VIH-VHCont montré qu'un taux annuel de traitement par AAD de 50% était nécessaire dans la population homosexuelle ayant des pratiques à haut-risque de transmission pour contrer l'épidémie actuellement observée.Nos travaux ont donc permis d'apporter des données pour optimiser l'utilisation des nouveaux traitements anti-VHC par l'intermédiaire de diverses approches statistiques et ont apporté des éléments de réponse aux grandes problématiques actuelles. L'efficacité exemplaire et la tolérance quasi-parfaite des dernières molécules antivirales permettent une utilisation universelle de ces traitements dans toutes les populations de patients. Des études complémentaires robustes sont cependant nécessaires pour apporter des arguments à la question de la récidive du CHC. Des efforts sont également attendus concernant l'accès au traitement, la diminution des coûts associés et un dépistage renforcé du VHC pour espérer pouvoir éradiquer un jour cette maladie. / The arrival of direct-acting antivirals agents (DAAs) has spurred a rapid revolution in the treatment of hepatitis C virus (HCV), supplanting the previous standard of care, i.e. pegylated interferon and ribavirin. These new treatments are associated with an increased rate of virological response however they rapidly faced some limits more particularly at the beginning with the first generation NS3/4A protease inhibitors. From 2014 on the second wave of DAA was available for treatment of chronic HCV infection and surpassed previous encountered limits. These treatments are nowadays the gold standard for HCV treatment in high-income countries.The idea of HCV eradication recently emerged since DAA treatment are highly effective. However, their associated high cost and recent high-risk behaviors associated with an increased risk of HCV transmission (among intravenous drug users and homosexuals) have been reported. These issues need therefore to be addressed in order to achieve the objectives of the World Health Organization for 2030 of an HCV eradication. Moreover, these treatments allow a sustained virological response in almost all patients and consequently reduce the risk of liver-related complications, but a recent controversy regarding a potential increased risk of hepatocellular carcinoma after DAA treatment has been raised.Three issues will be extensively discussed in this manuscript regarding how these treatments can be used to optimize their effect on HCV natural history at the individual and population level through different statistical approaches.As regards the first issue, this project allowed us to demonstrate regarding the tolerance and efficacy of DAA treatment: (i) a lower antiviral efficacy than previously reported in the phase III trials for first generationprotease inhibitor regimen (telaprevir and boceprevir), (ii) impairment of renal function during first generation protease inhibitor treatment, (iii) an increased rate of reported side effects during first-generation protease inhibitor treatment and more particularly anemia, potentially related to an increased ribavirin biodisponibility induced by protease inhibitor intake and (iv) a remarkable antiviral efficacy of second generation DAAs without impact of patients' characteristics norpharmacology on virological response rate. The recent issue regarding a higher risk of HCC recurrence after DAA treatment was also explored through a local cohort study and no impact of DAA treatment was observed when comparing DAA-exposed vs non DAA-exposed patients. Finally, we conducted amodelling study on HCV transmission in the coinfected HIV-HCV French population and our results suggested that an annual DAA treatment coverage rate of 50% was required in the homosexual population with high-risk behaviors to counter the recent observed epidemic in this population.Our different works provide new insights on how to optimize the use of DAA treatment through several statistical approaches and bring new elements for discussion on the recent controversy. The new DAA have an excellent efficacy and tolerance profile and should be universally used in all populations without restriction. However, further studies are required to explore on a deeper level the question regarding HCC recurrence after DAA treatment. Efforts are also still needed regarding DAA treatment access, associated costs and HCV screening to reach the objective of HCV eradication