Investigarea unor markeri virali si de gazda corelati cu lipsa de raspuns la tratamentul anti-viral în hepatita cronica cu virus C (HepGen)

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1 Investigarea unor markeri virali si de gazda corelati cu lipsa de raspuns la tratamentul anti-viral în hepatita cronica cu virus C (HepGen) Gabriela Oprisan INCDMI Cantacuzino si consortiul proiectului HepGen

2 INFORMATII PRIVIND PROIECTUL HepGen Proiect PCCA tip 2 nr 88/2012 (HepGen): Titlu: Investigarea unor markeri virali si de gazdã corelati cu lipsa de rãspuns la tratamentul anti-viral în hepatita cronicã cu virus C Coordonator: Gabriela Oprisan- INCDMI Cantacuzino Consortiul: 4 parteneri dintre care unul este IMM (P4 =laborator clinic de genetica): P1 SVB - Spitalul Clinic de Boli Infectioase si Tropicale Dr Victor Babes P2 ICF Institutul Clinic Fundeni P3 IVN - Institutul de Virusologie Ştefan S. Nicolau P4 - PG - Personal Genetics PERIOADA de derulare Finantare: Total de la bugetul de stat: lei Total cofinatare (P4) = lei

3 Consortiul HepGen Coordonator: Institutul National de Cercetare-Dezvoltare pentru Microbiologie si Imunologie Cantacuzino Gabriela Oprisan; Sorin Dinu; Maria Condei; Monica Straut; Codruta Usein; Mihaela Oprea; Monica Delia Teleman By iayork P1: Spitalul Clinic de Boli Infectioase si Tropicale Dr. Victor Babes: Prof. Petre Iacob Calistru; Prof. Emanoil Ceausu; Alma Kosa; Gratiela Tardei; Simin Florescu; Cristiana Oprea; Claudia Leulescu; Angelica Nour; George Gherlan; Gh. Voiculescu; Simona Cazacu P2: Institutul Clinic Fundeni Prof. Mihai Voiculescu; Elena Rusu; Monica Ecobici; Laurentiu Micu; Diana Zilisteanu; Camelia Achim; Andreea Radasan; Mirela Miu; Emilia Grigore; Georgia Micu; Laura Panaiteanu; Paula Dragoescu P3: Institutul de Virusologie Stefan S. Nicolau Prof. Simona Ruta; Camelia Sultana; Carmen Diaconu; Camelia Grancea; Aura Temereanca; Petruta Mihaila P4: SC Personal Genetics Georgeta Cardos; Bogdanka Militescu; Petruta Gurban; Antonie Edu; Gabriela Bucur; Cristina Ionescu; Pompilia Apostol; Vladimir Celmare; Sonia Spandole; Eugen Radu

4 HEPATITA C * Infectia produsa de HCV, virus ARN, de polaritatea + * Genul: Hepacivirus; Familie: Flaviviridae * Transmitere : parenterala, verticala, sexuala * Necultivabil (identificat prin clonare) * Poate produce infectii persistente * > 170 mil. de purtatori (3% din populatia globului) * Prevalenta in Romania: 4.56% * Patologie: hepatita acuta, cronica, ciroza hepatica, carcinom hepatocelular *Tratamentul clasic PEG-interferon + ribavirin -Tratamentele bazate pe antivirale = DAAs (inhibitori de proteaza virala: Telaprevir, Boceprevir) - Inhibitori de polimeraza virala (Sofobuvir) etc.

5 Premizele proiectului - Raspunsul viral sustinut (SVR) se obtine numai la 40 50% dintre pacientii naivi pentru tratamentul cu interferon, infectati cu HCV genotip 1, datorită selectării mutaţiilor de rezistenţă şi a unei sensibilităţi mai scăzute la IFN/RBV a acestui genotip - Tratamentul cu PEG-IFN si ribavirina produce efecte adverse si este costisitor - Virusul: Genotipul HCV, cinetica virala si mutatiile in capsida virala (gena core) in pozitiile 70 si 91 sunt asociate cu raspunsul la tratamentul cu PEG-IFN /Ribavirina - Gazda: polimorfismul in regiunea genei IL28B ca predictor major; polimorfismul genei HLA-B27 asociat cu eliminarea virala (clearance), concentratia serologica a proteinei IP-10 cu val. predictiva negativa etc.

6 Obiective - Proiectul îsi propune să definească factorii de predictie a răspunsului la terapia PEG-IFN/RBV prin analiza integrată a factorilor virali si de gazdă - Investigarea factorilor virali asociati cu lipsa raspunsului la tratament (genotip, variabilitate, cinetica incarcaturii virale) - Analiza unor factori de gazda (genetici, serologici) corelati cu raspunsul la tratament - Evaluarea mutatiilor de rezistenta la noile antivirale (DAAs) si a factorilor predictivi - Studii epidemiologice si corelarea factorilor virali cu factorii genetici si non-genetici umani - Transferul rezultatelor proiectului la autoritatile decidente din domeniul politicii sanitare Deliverabile: - Dezvoltarea unui algoritm bazat pe factori virali si markeri genetici si serologici umani, utilizabil in predictia raspunsului la tratamentul cu antivirale - Dezvoltare si transfer de tehnologie

7 Variabilitatea genetica a HCV Niveluri la care se manifesta variabilitatea genetica: * Sase genotipuri majore cu > 30 % divergenta * Subtipuri (>80) cu 20-25% divergenta Tulpini (variante individuale) izolate in contexte epidemiologice diferite cu 5-8% divergenta * Cvasispecii heterogenitate genetica HCV la acelasi individ infectat - < 5% diferente nucleotidice Raspunsul la terapia antivirala este mai scazut pentru pacientii infectati cu subtipurile 1a, 1b si 4a si mai important pentru cei infectati genotipurile 2 si 3

8 RASPUNSUL LA TRATAMENT GHANY ET ALHEPATOLOGY, Vol. 49, No. 4, 2009 Rapid virological response (RVR) HCV - ARN negativ dupa 4 sapt. de tratament Early virological response (EVR) reducere ARN HCV de >2 log 10 fata de momentul initial (EVR partial ) sau ARN HCV negativ dupa 12 sapt. de treatment (EVR complet) End-of-treatment response (ETR) ARN HCV negativ la sfarsitul tratamentului Sustained virological response (SVR) ARN HCV negativ la 24 sapt. dupa incheierea treatmentului predictor major al raspunsului pe termen lung Nonresponder esec terapeutic dupa 24 sapt de la incheierea trat. - virologic breakthrough (negativare si reaparitie a ARN in timpul trat.) - virologic relapse (recadere) - null response (scădere < 2 log 10 a viremiei în săpt. 12, fără negativare) partial response (scădere > 2 log 10 a viremiei în săpt. 12, fără negativare)

9 FACTORII ASOCIATI CU ESECUL LA TRATAMENTUL CU IFN/RBV Tarik Asselah et. al. 2010

10 Genomul HCV

11 Genomul HCV Core R 70 > Q sau H Core L 91 > M In poziţia 70, arginina (R) este înlocuită cu glutamină (Q) sau cu histidină (H) In poziţia 91 leucina (L) este substituită cu metionină (M) Akuta N, 2005; 2006

12 MODELUL EXPERIMENTAL (I) - Studiu prospectiv cu un lot de min. 150 de pacienti naivi, recrutati de SVB si ICF - loturi retrospective cu pacienti care au incheiat tratamentul (SVB si IVN) sau pacienti care nu au raspuns la tratament (ICF) Toti pacientii semneaza un formular de consimtamant informat - Criteriile de includere/ excludere au la baza protocoalele CNAS in vigoare - Crearea unei baze de date (anonimizata) privind caracteristici socio-demografice, biologice, epidemiologice, clinice, gestionata de SVB - Analiza statistica a datelor la IC

13 MODELUL EXPERIMENTAL (II) - Evaluarea raspunsului la tratament (Viral Load) la SVB - Evaluarea fibrozei la SVB si ICF - Analiza virala/genotipare prin PCR, qpcr si secventiere la IC - Selectarea unor probe virale de catre SVB pentru secventiere nextgen la Personal Genetics (FLX 454/Roche) - Analiza informatica si design de primeri/pcr la IC, PG si IVN pentru analiza markerilor de rezistenta virala - Evaluarea unor markeri genetici umani la PG si IVN - Analiza unor markeri serologici umani la IVN - Analiza integrată a factorilor virali si de gazdă si dezvoltarea unui algoritm de predictie (consortiul HepGen)

14 METODE - Baza de date SVB In perioada noiembrie iunie 2014 au fost recrutate160 de cazuri - pacienti cu hepatita cronica C, fara coinfectii cu HBV, HIV Media de varsta este de 49 de ani (22-68 ani), 46.9% barbati. Majoritatera pacientilor din lot provin din mediul urban (73,8%), si au pregatire scolara medie sau superioara (80%). 10 dintre pacienti (6,3%) se afla la al doilea tratament antiviral Cei mai multi pacienti au declarat unul sau mai multi factori de risc pentru contactarea infectiei virale HCV: % tratamente stomatologice % transfuzii de sange % agregare familiala - 5.6% risc profesional

15 METODE - Baza de date SVB La momentul actual, dintre cei 160 de pacienti recrutati, un numar de 60 au terminat tratamentul de 48 de saptamani Dintre pacientii chestionati pentru reactii adverse (n=84),52 (61.9%) au prezentat cel putin o reactia adversa Cele mai frecvente reactii adverse evidentiate in timpul tratamentului sunt, in ordinea aparitiei: - modificarea apetitului alimentar, cu scadere ponderala - reactii adverse hematologice (anemie, neutropenie, trombopenie) - alterarea starii generale +/ - sindrom anxios depresiv

16 METODE - Baza de date SVB Analiza raspunsului virusologic pt. pacientii SVB RVR = 12% RVR partial =19% EVR = 39.8% EVR partial= 80.8% SVR = 36.4%

17 METODE - Studiu prospectiv analiza statistica realizata pe un lot de 87 de pacienti cu hepatita cronica, infectati cu HCV genotip 1b, fara coinfectii cu HBV sau HIV, au inceput trat. cu IFN/RBV - Evaluare VL (viral load) pt. RVR (4 sapt.) si EVR (12 sapt.) comparativ cu VL la initierea tratament Analiza virus: - PCR si secventiere in gena core - PCR si secventire in gena NS3 - PCR si secventiere genom HCV prin tehnica Next-generation (FLX 454/Roche) - dezvoltarea unor sisteme Real-Time PCR de tip ARMS pentru detectia mutatiilor de rezistenta virala Core 70 si 91

18 METODE Analiza genetica umana: - polimorfism in gena IL28B (SNP rs ) - polimorfisme in gena ITPA (anemie) - genotipare HLA-B27 Analiza serologica: - nivelului plasmatic al proteinei IP10 - nivelului plasmatic al proteinei scd26 Analiza statistica a fost realizata cu programul SPSS versiunea 16.0 (dr. Monica Delia Teleman, IC)

19 REZULTATE ANALIZA VIRUS Genotiparea HCV prin secventiere in gena core N = 140 (la IC) 1a 9,8% *3% 4a-2,8% *1.5% 3a-2,8% *0.5% 1b - 84,6% *92,6% *Sultana C, Oprisan G, Szmal C, Vagu C, Temereanca A, Dinu S, Teleman MD, Ruta S. Molecular epidemiology of hepatitis C virus strains from Romania. J Gastrointestin Liver Dis Sep;20(3):261-6.

20 Amino Acid Substitutions in the Hepatitis C Virus Core Region are the Important Predictor of Hepatocarcinogenesis Norio Akuta et al. HEPATOLOGY, Vol. 46, No. 5, Mutatii in core: 70 R > Q/H si 91 L > M ca predictori pentru rezistenta la tratament (PEG-IFN + ribavirin) si carcinogeneza hepatica - Proteina core are potential oncogenic la soarecii transgenici - Importanta in clinica: la pacientii din Japonia, de genotip 1b si cu mutatii de rezistenta in core, tratati in mod repetat numai cu IFN, s-a constatat reducerea riscului de carcinogeneza hepatica si cresterea ratei de supravietuire - Carcinogeneza hepatica este influentata de interactia dinamica dintre Virus Gazda si Tratament

21 Genotiparea HCV prin secventiere in gena core Alinierea secventelor aac pt vizualizarea mutatiilor Core 70 si Core 91

22 Antiviral therapy Standard of Care Yee et al - The American Journal of GASTROENTEROLOGY Pegylated interferon alfa (PegIFN) and ribavirin (RBV) for weeks,depending on the viral genotype : the advent of direct-acting-antivirals (DAAs) - the standard of care for many patients with HCV genotype 1 infection became a combination of an oral NS3 protease inhibitor boceprevir or telaprevir along with pegylated IFN (PegIFN) and ribavirin (RBV). In Romania: PegIFN + RBV DAAs in teste clinice

23 NS3 Protease (180 aa) Nina Mani, 2012 Mutatii de rezistenta la DAAs: V36, T54, T55, R155, A156, V170 etc.

24 REZULTATE ANALIZA VIRUS PCR si secventiere in gena NS3 I132 V Aliniament al secventelor proteinei NS3 (181 aac) prin programul BioEdit Mutatia de rezistenta la telaprevir I132 V preexista la pacientii naivi pentru tramentul cu antiproteaza

25 PCR si secventiere genom HCV prin tehnica Next-generation - Metode Secvențierea de mare randament (next-generation sequencing) a genomului HCV 1b (dr. Eugen Radu si drd. Sonia Spandole, PG) 11 pacienți recrutati la SVB (4 din lot retrospectiv, cu status de raspuns cunoscut 2 responderi si 2 non-responderi) Inclusa o tulpina de referinta HCV 1b, clonata intr-un plasmid - secvență de control pt NGS (pfk-con1 obtinut prin amabilitatea prof. Ralf Bartenschlager, Univ. Heidelberg) Platforma de pirosecvențiere de mare randament Genome Sequencer 454 FLX/ Roche de la Personal Genetics Număr foarte mare de fragmente de ADN relativ scurte ( baze) - într-un singur experiment pot fi citite 0,4-30 miliarde de baze (cvasispecii si variante virale rare)

26 Yao E et al, Virol J 2:88, 2005 PCR si secventiere genom HCV prin tehnica Next-generation- Metode Reverstranscriere ARN viral cu primeri specifici Nested-PCR: 3 ampliconi de aproximativ 2500 pb ( ) (drd. Sorin Dinu, IC)

27 PCR si secventiere genom HCV prin tehnica Next-generation - Metode Fragmentarea ampliconilor prin nebulizare (shotgun) Ligarea de adaptori ce includ secvențe unice, necesare multiplexării (MID) Amplificare în emulsie si pirosecvențiere

28 PCR si secventiere genom HCV prin tehnica Next-generation - Metode PROCESAREA SI ANALIZA DATELOR Achiziția de imagine, analiza primară, identificarea bazelor individuale și a calității acestora software 454 Roche Filtrarea secvențelor, asamblarea de contigi pentru fiecare pacient Vicuna Finalizarea, adnotarea secvențelor consens V-FAT Corecția erorilor de pirosecvențiere RC454 Analiza variației intrahost V-Phaser 2 Toate programele de la The Broad Institute Viral Genomics Group

29 PCR si secventiere genom HCV prin tehnica Next-generation - Rezultate - Peste 1 milion de fragmente citite totalizand 400 Mbaze - Fragmente de aprox. 450 baze Acoperirea (redundanța) citirilor pentru cazuri și control între 1410 și 5040 x Secventa control: tulpina HCV 1b con-1, clonată în plasmidul pfk, identică cu cea publicata Acoperirea pentru HCV 1b con-1

30 PCR si secventiere genom HCV prin tehnica Next-generation - Rezultate Frecvența mutațiilor non-sinonime pentru cazurile R04 și R06 (SVR)

31 PCR si secventiere genom HCV prin tehnica Next-generation - Rezultate Frecvența mutațiilor non-sinonime pentru cazurile R14 și R16 (esec terapeutic)

32 PCR si secventiere genom HCV prin tehnica Next-generation - Rezultate Frecvența mutațiilor non-sinonime pentru cazurile SVB003 și SVB011 (SVR)

33 3 kb 60 Mb A Polymorphism on Chromosome 19 Predicts SVR IL28B SNP rs SNP rs Chromosome 19 Ge D, et al. Nature. 2009;461:

34 Importance of IL28B Polymorphisms (SNP rs ) * C/C genotype is associated with a higher SVR compared with T/C or T/T Treatment-naïve, genotype 1-infected patients with IL28B genotype CT or TT have a higher SVR when treated with DAA-PegIFN and RBV as compared with PegIFN and RBV treatment alone Ge D, et al. Nature. 2009;461:

35 Markerul genetic uman IL28B SNP rs : CC asociat cu SVR TT and CT asociate cu esecul terapeutic rs Rezultate IL28B : 17.8% genotip CC 64.4% genotip CT 17.8% genotip TT Testat prin reactia de discriminare alelica - Custom TaqMan Single Nucleotide Polymorhism Genotyping Assays (Applied Biosystem) la IVN, PG

36 Studiul markerilor genetici umani ITPA si HLA-B27 Personal Genetics Asocierea dintre prezenta unei alele HLA-B27 si clearance-ul spontan al HCV (metoda PCR + hibridizarea inversa - kit IVD GenoQuick HLA-B27, HAIN) Studiul markerilor 94C>A (rs ) și IVS A>C (rs ) din gena ITPA pentru evaluarea riscului de anemie medicamentoasa severa sub trat. cu IFN/RBV prin metoda PCR-RFLP (cu enzima de restrictie XmnI) Reducerea activitatii enzimei ITPA poate reduce severitatea anemiei in grade diferite, in functie de polimorfismele existente in gena ITPA

37 Studiul markerilor genetici umani ITPA si HLA-B27 Personal Genetics Rezultate HLA-B27 Alela HLA-B27 prezenta la 6% dintre pacienti (N= 100), frecventa similara de pina la 8%, raportata in literatura pt. populatia de origine caucaziana (Neumann-Haefelin 2007) Studiul markerilor ITPA Au fost identificate genotipuri homozigote de tip sălbatic (wt), precum și genotipuri heterozigote pentru polimorfismele testate Genotipuri homozigote mutante au fost obținute numai pentru markerul ITPA IVS A>C Datele obtinute sunt comparabile cu datele raportate în literatura (polimorfismul ITPA 94C>A (rs ): alela minora A=0,081; polimorfismul IVS A>C (rs ), alela C=0,074; SNP Database, National Center for Biotechnology) dar inca nu au putut fi corelate cu anemia indusa de IFN/RBV

38 Studiul markerilor serologici umani IP10 si scd26 Institutul de Virusologie Stefan S. Nicolau Analiza serologica: Nivelul plasmatic al IP-10 (Interferon-gamma inducible protein 10) testat cu Quantikine Human CXCL10/IP-10, R&DSystems - IP10 - chemokina cu activitate chemotactica pentru limfocite, celule NK si monocite corelata cu inflamatia hepatica Nivelul plasmatic al scd26 (Human scd26 ELISA, ALPCO) Proteina CD26 este o glicoproteina de membrana dipeptidilpeptidaza (DPPIV) care cliveaza peptide - IP-10 Forma solubila scd26 descris ca un marker serologic fiabil si ieftin in evaluarea severitatii bolii hepatice la pacientii HCV (marker de inflamatie hepatica)

39 Rezultate Studiul markerilor serologici umani IP10 si scd26 Institutul de Virusologie Stefan S. Nicolau - Concentratiile scazute baseline ale IP10 si scd26 sunt direct corelate cu valori reduse baseline ale ARN HCV si cu grad mic de fibroza hepatica (p=0.04 si p=0.05) - Valori scazute baseline ale IP10 (330.2 vs pg/ml; p= 0.05) si scd26 (786.1 vs ng/ml; p= 0.03) anticipeaza RVR si a EVR complet IP10 se coreleaza negativ cu diferenta de viremie HCV dintre T0 si T12 (p=0.0017)

40 % of Total cases ANALIZA STATISTICA A DATELOR Dr. Monica Delia Teleman (UMF, IC), HepGen REZULTATE (N = 87) Interferon and Ribavirin Treatment Outcome for HCV, at 4 and 12 weeks RVR Total EVR Total EVR Total+Partial 10 0 RVR Total EVR Total EVR Total+Partial Treatment Outcome RVR, EVR 13 (14.9%) RVR total 39 (44.8%) EVR total 69 (79.3%) EVR Total + Partial

41 ANALIZA STATISTICA A DATELOR Dr. Monica Delia Teleman (UMF, IC), HepGen REZULTATE (N = 87) HCV cases by Gender % Female Male Media de varsta de 50 de ani 57 % gen feminin, mai in varsta decat cazurile de gen masculin (p in T test pentru grupe independente = 0.004)

42 Caracteristici socio-demografice vs. gen Variable/ Gender Male (No.) Female (No.) P-value* Age (yrs.) < Occupation Yes No Education < (classes) Residence Rural Urban BMI < % varsta = sau > 40 de ani * Pearson Chi2 or Fischer s Exact Test

43 RVR/EVR vs. gen Gender RVR EVR No % OR *Pvalue No % OR *Pvalue Male Female Pacientii de gen Masculin au obtinut RVR in procent mai mare (24.3.%) comparativ cu cazurile de gen Feminin (8%) (p = 0.06) * Pearson Chi2 or Fischer s Exact Test

44 RVR total vs. caract. virus/gazda Host caracteristics (baseline) (Media aritmetica +/- sd) RVR No RVR *P- Value Age (yrs.) 39.8 (13.1) 51.9 (9.9) BMI 25.2 (3.8) 25.9 (4.3) 0.6 ALT (IU/ml) (54.0) 87.5 (53.8) 0.4 Glucose (mg/dl) 91.5 (14.5) (38.3) 0.3 scd (270.6) (246.5) IP (161.6) (288.1) HCV RNA log10 (IU/ml) 4.6 (1.3) 6.1 (0.6) < * Pearson Chi2 or Fischer s Exact Test

45 EVR total vs. caract. virus/gazda Host caracteristics (baseline) (Mean +/- sd) EVR No EVR 95%CI *P- Value Age (yrs.) 46.4 (11.9) 54.3 (8.9) 3.3, BMI 25.9 (3.6) 25.7 (4.7) -2.04, ALT (IU/ml) 92.5 (62.5) 83.5 (45.0) -33.2, Glucose (mg/dl) 92.6 (14.5) (46.8) 0.5, scd (236.3) (260.8) -10.1, IP (177.2) (320.6) 95.7,326.7 <0.001 HCV RNA log10 (IU/ml) 4.6 (1.3) 6.1 (0.6) 1.04, EVR au fost mai tineri si au prezentat valori semnificativ mai mici pentru IP10, Glicemie si ARN HCV la initierea trat. (T0)

46 IL28B Characteristics(baseline) Mean (+/- sd) Genotipurile IL28 B CC CT+TT *P-value Age (yrs.) 47.0 (12.8) 51.0 (11.2) 0.18 ALT (IU/ml) (77.6) 84.7 (43.4) 0.04 Hb (dl/mg) 14.9 (1.2) 14.1 (1.1) 0.01 IP (210.5) (279.2) 0.03 CD (191.6) (257.0) 0.06 HCV RNA Log10 (IU/ml) 5.8 (1.2) 6.0 (0.7) 0.3 Pacientii cu genotip CC versus genotipurile CT/TT - mai tineri, valori ALT si Hb (T0) mai mari - valori semnificativ mai mici pentru IP10 si CD26 * T test for Means, Independent Samples.

47 RVR, EVR vs. IL28B % of Total HCV cases RVR EVR CC CT TT Il28B genotype Pacientii cu genotip IL28 B tip CC au o sansa mai mare de a obtine RVR (p= 0.01) si/sau EVR (p<0.001), comparativ cu pacientii care prezinta celelalte genotipuri. * T test for Means, Independent Samples.

48 RVR, EVR vs. gradul de fibroza % of Total HCV cases RVR EVR 10 0 F0+F1+F2 F3+F4 Fibrosis Score Exista diferente pt. obtinerea RVR si/sau EVR, bazate pe scorurile de fibroza, dar diferentele nu sunt semnificativ statistice (RVR, p value = 0.3; EVR, p-value = 0.05)

49 RVR si EVR vs. mutatiile 70, 91 in gena virala core Mutatia core 70 prefigureaza o sansa mai mica pt. obtinerea RVR (Fisher s Exact Test: p-value 0.016) Nu sunt diferente semnificative pt. obtinerea RVR pt. pacienti cu mutatia virala core 91 (OR = 2.5, Pearson Chi2 Test: p- value = 0.1) Capacitatea de a atinge EVR nu pare a fi afectata de mutatiile core 70 sau 91

50 CONCLUZII Prin analiza univariata a lotului de pacienti HepGen caracteristicile urmatoare: - varsta, genul - polimorfismul in gena IL28B - valorile baseline: Hb (mg/dl); IP10; ARN HCV (IU/ml) mutatiile in gena virala core 70 si 91 par sa fie predictori pentru evolutia buna la 4 saptamani (RVR) sau 12 saptamani (EVR) de la debutul tratamentului cu IFN/RBV

51 COMUNICARI/ PUBLICATII

52 COMUNICARI/ PUBLICATII 9-11 octombrie 2013, la Hotelul Pullman Bucuresti, ICF a organizat Al XXIII lea Congres National de Hepatologie, Al III-lea Congres dehepatologie Romano-francez si al IV Curs Balcanic de Hepatologie Prof. Dr Mihai Voiculescu Improving patient outcome using predictors of response and management of adverse events Gabriela Oprisan Viral mutations correlated with treatment response in chronic hepatitis C

53 COMUNICARI/ PUBLICATII Poster la congresul ECCMID Barcelona, 2014

54 COMUNICARI/ PUBLICATII

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