Il management del paziente difficile nelle infezioni virali croniche Definire e trattare il paziente “difficile” HCV monoinfetto Carlo Cammà Cattedra di Gastroenterologia Università di Palermo carlo.camma@unipa.it Roma 25 Novembre 2010

HCV Difficult to Treat Patients HCV-infected Patient Virological Factors Genetic factors Severity of fibrosis Metabolic Factors

HCV Difficult to Treat Patients HCV-infected Patient Virological Factors Genetic factors Severity of Fibrosis Metabolic Factors

HCV Difficult to Treat Patients The promise of personalized medicine Effetto medio Mega-trial The promise of personalized medicine

Genetics Predict Response: IL28B Genotype C/C Confers Higher SVR Rates D. Ge, Nature , 2009

Rate of SVR and rs12979860 C-allele frequency in diverse ethnic groups. DL Ge et al. Nature 461, 399-401 (2009) doi:10.1038/nature08309

Genetics Predict Response: IL28B Genotype C/C Confers Higher SVR Rates 29 114 79 10 51 47 4 22 8 T/T T/C C/C T/T T/C C/C T/T T/C C/C T/T* T/C* C/C* Gt 1 Gt 2/3 Gt 4 *Genotype of rs12979860 on chromosome 19 (Ge D et al. Nature. 2009;461:399-401). Strättermayer A et al. EASL 2010. 7 7

HCV Difficult to Treat Patients E’ la risposta all’interferone interamente correlata al polimorfismo genetico ? NO

IL28b and outcome of combination antiviral therapy with PEG-IFN + Riba SNP Study Overall SVR SVR in persons with indicated genotype (%) % of SVR explained by the favorable genotype   Homozygous favorable allele Heterozygous or homozygous unfavorable allele Rs12979860 Ge et al. 56 82 40 Rs8099917 Suppiah et al. 46 36 63 Rauch et al. 64 74 50 68 Balagopal et al. Gastroenterology 2010

HCV Difficult to Treat Patients HCV-infected Patient Virological Factors Genetic factors Severity of fibrosis Metabolic Factors

233 Cirrhotic pts (ITT analysis) HCV Difficult to Treat Patients 233 Cirrhotic pts (ITT analysis) Patients with virological response (%) Di Marco V et al, personal data

HCV Difficult to Treat Patients E’ la risposta all’interferone interamente correlata al polimorfismo genetico e alla fibrosi ? NO

HCV Difficult to Treat Patients IDEAL study SVR rates IL28b Genotype CC CT TT Overall 69% 33% 27% HCV RNA ≤600,000 / METAVIR F0-2 86% 63% 52% HCV RNA ≤600,000 / METAVIR F3-4 25% 0% HCV RNA >600,000 / METAVIR F0-2 70% 29% 23% HCV RNA >600,000 / METAVIR F3-4 37% 21% 12% Come si può tradurre tutto ciò in qualcosa di clinicamente utile è evidenziato in questa tabella, con dati tratti da pazienti inclusi nel famoso studio IDEAL. La probabilità di guarire dall’epatite C con terapia antivirale (pur in presenza di un genotipo sfavorevole) varia tra 70-86% e lo 0-12% in funzione della combinazione di tre parametri: polimorfismo IL28b, presenza e severità di fibrosi e carica virale. Gastroenterology 2010;139:120-9 13

HCV Difficult to Treat Patients HCV-infected Patient Virological Factors Genetic factors Severity of fibrosis Metabolic Factors

HCV Difficult to Treat Patients (HEPATOLOGY 2006) Steatosis (± visceral obesity) and IR hyporesponsiveness to antiviral therapy.

IR and SVR in G1 Chronic Hepatitis C HCV Difficult to Treat Patients IR and SVR in G1 Chronic Hepatitis C ROMERO-GOMEZ et al, Gastroenterology 2005 16

HCV Difficult to Treat Patients LowVit D SVR Hepatology, 2010

HCV Difficult to Treat Patients Factors Associated with SVR Menopause and SVR Factors Associated with SVR MV analysis in 442 Female Patients with CHC Villa et al., submitted

HCV Difficult to Treat Patients HCV-infected Patient Virological Factors Genetic factors Severity of fibrosis Metabolic Factors Rapid Virological Response as Strongest Predictor of SVR

HCV Difficult to Treat Patients RVR Range RVR in G1 10% - 50%

HCV Difficult to Treat Patients RVR 24 wks PR

RVR Baseline Predictors of RVR in Naive Patients with G1 CHC Low Baseline HCV-RNA IL28B Gene RVR Vitamin D Levels Absence of Severe Fibrosis Lower BMI LDL-COL Insulin Resistance Steatosis

IL-28B and RVR

IL 28 RVR LowVit D

HCV Difficult to Treat Patients IDEAL study

Differences between Peg 2-a and 2-b Pharmacodinamic profile Peg 2-a Peg 2-b RVR 4 wk Triple therapy

DAA

DAA TELAPREVIR (T)

DAA BOCEPREVIR (BOC)

DAA LEAD-IN

HCV Difficult to Treat Patients 3 scenari clinici IL-28B LEAD IN RVR TRIPLICE

PR 24 wks LEAD-IN RVR

Naive IL28 TT 40% NR TRIPLICE

???? Naive IL28 TC LEAD-IN: ??? TRIPLICE

HCV Difficult to Treat Patients TRASFERIBILITA’ RISULTATI MEGA-TRIAL

Non tutto ciò che può essere misurato conta, e non tutto ciò che conta può essere misurato. Albert Einstein

Disclaimer Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l. Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l. Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice. 01-13-RTG-2010-IT-4769-AV