EPATITE B, UNA EPIDEMIA SCONOCIUTA

EPATITE B, UNA EPIDEMIA SCONOCIUTA Maurizio KOCH Azienda Ospedaliera San Filippo Neri U.O.C. Gastroenterologia ed Epatologia

Hepatitis B Virus Hepadnavirus 100 volte più infettivo di HIV Si trova nel sangue e nei fluidi corporei Sopravvive più di 7 giorni nel sangue essiccato

Different virus replication strategies different treatment goals HBV HIV HCV Host cell Viral RNA cccdna Proviral DNA Host DNA Nucleus TREATMENT Long-term reduction of viral replication to lowest possible level 1 TREATMENT TREATMENT Lifelong suppression of viral replication 2,3 Definitive viral clearance 1 SVR possible for HCV 1 1. Pawlotsky JM. J Hepatol 2006;44:S10-S13; 2. Siliciano JD, Siliciano RF. J Antimicrob Chemother 2004;54:6-9; cccdna = covalently closed circular DNA 3. Lucas GM. J Antimicrob Chemother 2005;55:413-416

L impatto della epatite B nel mondo è alto Infetti presente/passato Infezioni croniche Morte Causa di morte per malattia ~ 2 miliardi 350-400 milioni 0.5-1.2 milioni/anno 10 causa nel mondo Lavanchy D, J viral Hepatol 2004 Conjeevaram HS, J Hepatol 2003

Prevalenza HBsAg 8% = alta 2% - 7% = intermedia <2% = bassa

2 miliardi di HBV infetti 25 40% (75-160 M)/die di cirrosi o HCC 6 miliardi Popolazione mondiale 350-400 milioni di Epatiti croniche HBV IMPATTO GLOBALE DELL EPATITE B WHO Fact Sheets Conjeevaram HS, J hepatol 2003 Lee WM N Engl J Med 1997 Lok AS N Engl J Med 2002

HBV genotypes G A F H A G D E A D B C C

Le dimensioni del Problema in Italia Ogni giorno in Italia muoiono 57 persone per epatocarcinoma o cirrosi 14 sono HBsAg+ 600.000-1.000.000 di portatori cronici di HBV (HBsAg+) 1034 nuove infezioni all anno anno notificate e ~ 10.000 stimate (il numero effettivo di nuove infezioni per anno stimate (il numero effettivo di nuove infezioni per anno è 5-10 volte il numero di casi denunciati) 250.000 portatori tra cittadini immigrati WHO: Department of Communicable Diseases Surveillance and response 2002; AISF: documento conclusivo commissione sull epidemiologia delle malattie epatiche

Il paziente con epatite cronica HBeAg +: il ruolo della risposta immunitaria Immune-tolerance Immune-activation Immune-control HBV-DNA ( log10 gen.eq./ml ) 9 8 7 6 5 4 3 2 HBeAg Anti- HBe IgM anti-hbc ( PEI Units ) 100 10 1 ALT ( U / L ) 400 300 200 100 0

Association of Liver Disease with Virological/Biochemical Percent of Patients with Active Liver Disease 100 90 80 70 60 50 40 30 20 10 0 Parameters p < 0.001 57.9% p = 0.073 35.5% 13.3% 9.5% Normal Elevated Normal Elevated p = 0.088 40.9% 13.6 % < 6.5 >6.5 ALT (IU/L) AST (IU/L) HBV DNA (log 10 copies/ml) p-value is based on a Fisher s exact test Hu KQ, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 653.

STORIA NATURALE Primary HBV Infection Epatite acuta Epatite cronica Cirrosi Epatocarcinoma Morte

STORIA NATURALE Primary HBV Infection Epatite acuta 70-90% 10-30% Cirrosi Epatite cronica 0.1-0.5% Subclinica Epatite acuta Epatite Fulminante Epatocarcinoma Morte

STORIA NATURALE Primary HBV Infection Epatite acuta Epatite cronica 95% neonati da madri HBsAg+/HBeAg+ 3% giovani 18 24 anni Cirrosi 23 28% bambini 1 Epatocarcinoma 5 anni 0.2% adulti immunocompetenti Morte

STORIA NATURALE Epatite cronica lieve moderata grave cirrosi Portatore inattivo 10-20 % ~1 % x anno 4-6 % per anno guarigione scompenso Epatocarcinoma morte / trapianto

Prevalenza dei diversi fattori eziologici in 9997 soggetti con epatopatia,, Italia 2001 Alcol+HCV 11,6% Alcol 9,4% Altro 12,7% HBsAg+ 10% HBsAg anche con altri fattori=13,4% HCV anche con altri fattori=69,9% Alcol anche con altri fattori=23,0% HCV+ 56,3% Sagnelli et al. J. Med. Virol. 2005

Tasso di mortalità (decessi per 100.000 abitanti) ) per Cirrosi ed HCC in Italia 1969-2001 Morti x 100.000 45 40 35 30 25 20 15 10 5 0 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000 2001 Anni Cirrosi HCC Dati ISTAT

Perchè vaccinare?

Vaccinazione Anti-HBV 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 1987 1986 14 12 10 8 6 4 2 0 Incidenza di epatite B in Italia. SEIEVA 1985-2003 Stroffoni Hepatol 2000 1985

Incidenza (per 100000) età specifica di epatite B in Italia. SEIEVA 1985-2003 45 40 35 30 25 20 15 10 5 0 1985 Vaccinazione Anti-HBV 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 15-24 > 24 0-14 1999 2000 2001 2002 2003 Stroffoni Hepatol 2000

Perchè sottoporre a screening?

Screening per epatite B: motivazioni precoce identificazione e cura dei soggettti infetti (Valla et al 2003) Prevenzione della diffusione ad altri soggetti (Valla et al. 2003) Terapie antivirali efficaci sono in grado di rallentare la progressione della malattia nei soggetti con epatite cronica B e ritardare l insorgenza della cirrosi (Liaw et al 2004) Per i pazienti con cirrosi in fase terminale l unica possibile terapia è il trapianto di fegato

Dove dovrebbe essere disponibile lo screenig per epatite B Carceri Strutture sanitarie ed in particolare: Centri per malattie sessualmente trasmissibili Centri per il trattamento della dipendenza da sostanze d abuso Centri trasfusionali Centri per la terapia dell HIV Centri per immigrati Agenzie internazionali per l adozione

Perchè trattare?

Survival in compensated cirrhosis B Reference Area Pts (n) Median age (yrs) Follow-up yrs (range) 5-year survival Liaw 1989 Asia 76 41 3 (1-7) 80 % De Jong 1992 Europe 77 46 4 (2-17) 84 % Fattovich 2002 Europe 161 48 6 (1-16) 86 % 100 % 80 survival 86 Incidence 100 person/yrs=3.5 60 68 40 30 20 0 decompensation 16 18 9 HCC 0 1 2 3 4 5 6 7 8 9 10 Fattovich, Am J Gastroenterol 2002; 97: 2886-95

Relazione tra livelli di HBV DNA e indice di attività istologica. Una review di 26 studi prospettici 12 Histology Activity Index 10 8 6 4 2 0 2 4 6 8 10 12 HBV DNA level log cp/ml From: Mommeja-Marin H, Hepatology. 2003.

Relazione tra livelli di HBV DNA e sviluppo di cirrosi Iloeje, Gastroenterology 2006

Clinical benefits of HBeAg and HBsAg clearance HBeAg clearance HBsAg clearance Disease remission HBsAg seroconversion Prevention of HCC Increased survival Hoofnagle Ann Intern Med 1981; Fattovich Hepatology 1986;Di Bisceglie Gastroenterology 1987; Niederau NEJM 1996; Chu Gastroenterology 2002; van Zonneveld Hepatology 2004

HBsAg clearance improves survival rates Probability of survival in patients with and without HBsAg clearance Retrospective study of 309 patients over mean follow-up of 5.7 years Survival (%) 100 80 60 40 20 P<0.001 With HBsAg clearance No HBsAg clearance 0 2 4 6 8 10 12 14 Years Fattovich et al. Am J Gastroenterol 1998

Cumulative probability of complications-free survival in 101 HBeAg negative patients treated with IFN for 2 years Patients alive and complications-free (%) Patients at risk 100 80 60 40 20 HCC: 7% vs 7%, NS Decompensation: 0% vs 27%, p<0.001 P<0.001 0 0 12 24 36 48 60 72 84 96 108 120 Sustained response (30 pts) Treatment failure (71 pts) 30 30 30 30 30 28 19 18 13 10 3 71 68 64 59 45 36 28 21 15 5 4 Months Lampertico, Hepatol 2003

HBsAg clearance continues to increase after therapy in HBeAg-negative patients treated with PEG-IFN 11 n=230 11% Patients with HBsAg clearance (%) 9 7 5 3 3% 6% 8% 1 Years after EOT 1 2 3 4 Marcellin et al. EASL 2008

Therapy for Chronic Hepatitis B: 2008 1992 1998 2002 2005 2006 2008 and beyond interferonalfa lamivudine The New Era ORAL Therapy adefovir entecavir pegylated IFN-α telbivudine Tenofovir* Combination Rx *FDA-approved for HIV and in review by FDA for HBV indication ** in phase III trial

Lamivudine in compensated cirrhosis Time to diagnosis of HCC Percentage with diagnosis Placebo P=0.047 Lamivudine Time to diagnosis (months) Excluding 5 cases in yr1: HR=0.47; P=0.052 Placebo (n=215) Lamivudine (n=436) Liaw et al, NEJM 2004

Resistance Rates in Naïve Patients Cumulative of resistance (%) 100 Genotypic resistance to ADV 4 80 60 40 20 0 HBeAg(-) ) patients 29 18 11 0 3 1 2 3 4 5 Year of treatment Prevalence of resistance (%) Genotypic resistance to LVD 2,3 100 80 60 40 20 0 24 2 40 3 67 57 2 3 ND 1 2 3 4 5 Year of treatment Prevalence of resistance (%) 100 80 60 40 20 0 Genotypic resistance to ETV 1 HBeAg(+) and (-)( ) patients <1% <1% 1% 1% 1 2 3 4 Year of treatment ND 5 Colonno RJ, Hepatology. 2006; Zefix (lamivudine) (August 2006). Chang TT. J Gastroenterol Hepatol 2004; Hepsera (August 2006) Standrigg DN, J Hepatol. 2006; Lai CL, Hepatology. 2006

Monotherapy exerts pressure on replicating virus Treatment start Wild-type STAT-C-resistant variant Viral load Selection of resistant variants Treatment end Time Hypothetical representation based on information from Sarrazin C, et al. Gastroenterology 2007;132:1767-1777; Hinrichsen H, et al. Gastroenterology 2004;127:1347-1355

Potent viral load suppression with entecavir even from high baseline levels Average intracellular entecavir tri-phosphate drug concentrations are approximately 50 times greater than the IC50 of wild-type HBV 1 HBV DNA reductions by baseline DNA level 2 Nucleoside naïve, HBeAg(+) and (-) patients Median HBV DNA (Copies/mL) ³ 10 10 11 10 10 10 10 9 10 8 10 7 10 6 10 5 10 4 10 3 10 2 n=87 n=40 n=151 n=144 n=97 n=82 n=27 n=13 0 24 36 48 72 < 300 copies/ml Treatment Week 1. Tenney DJ, et al. Antimicrob Agents Chemother. 2007;51:902 911. Colonno R. ISVHLD 2006; Oral presentation O200

Patients with HBV DNA <400 c/ml 100 Percentage (%) 90 80 70 60 50 40 30 98% 98% P=0.983 20 10 0 Randomized Double Blind Open Label TDF 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 Weeks on Study ADV N= 125 121 117 111 TDF N= 250 239 240 226 Observed Data Marcellin P, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 57.

Efficacy Varies among Nucleos(t)ide Analogs HBV DNA mean reduction at 1 year HBeAg-negative patients HBV DNA PCR negativity at 1 year HBeAg-negative patients HBV DNA level (log copies/ml) 10 9 8 7 6 5 4 3 2 1 6.9 3.9 log 7.4 7.6 7.7 5 log 4.4 log 5.2 log ADV 2 LAM 1 ETV 3 LdT 1 PCR negative (%) Data not from head-to-head studies. Design, inclusion and evaluation criteria may differ. HBV DNA thresholds: 1000 copies/ml (ADV); 300 copies/ml (LAM, LdT, ETV); 400 copies/ml (TDF) 100 80 60 40 20 51% 71% 90% 88% 93% ADV 4 LAM 1 ETV 5 LdT 1 TDF 6 95% LdT 7 1. Lai CL et al. N Engl J Med. 2007;357:2576 2588; 2. Chang TT et al. N Engl J Med. 2006;354:1001 1010; 3. Lai CL et al. N Engl J Med. 2006;354:1011 1020; 4. Hadziyannis SJ et al. N Engl J Med. 2003;348:800 807; 5. Lai CL et al. N Engl J Med. 2006;354:1011 1020; 6. Marcellin P et al. Hepatology. 2007;46 (S1):290-291A; 7. Globe study: data on file.

May 2003 May 2005 ALT 206 60 25 40 426 182 40 41 IgM anti-hbc 1.75 0.85 0.05 0.10 1.30-0.05 0.04 HBV-DNA (log cp/ml) 9 8 7 6 5 4 3 2 1 0 LLQ LLQ LAM 100 mg/day ADV 10 mg/day 0 2 4 6 8 10 12 14 16 18 20 22 24 Months

O.DONNELL

E.A.R.L.Y. Study: Mean HBV 12 DNA Change ETV (n=33) ADV (n=32) Mean Change in HBV DNA Mean change in HBV DNA by PCR (log 10 copies/ml) 10 8 6 4 2 0 *Primary efficacy end point: p<0.0001 4.42* 6.23* Log 10 300 copies/ml Dosing through Week 48 5.08 7.28 Extended dosing phase 0 8 16 24 32 40 48 56 64 72 80 88 96 Weeks Other Results at Week 96: Normal ALT: 97% vs. 85% HBe Seroconversion: 24% vs. 25% Discontinuation due to AE: 0% vs. 3% 5.96 7.82 Leung N, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 998.

Spontaneous HBeAg seroconversion: reduces fibrosis progression Cumulative probability of regression of fibrosis (%) 100 80 60 40 20 0 Patients with sustained disease remission Patients without sustained disease remission P<0.00005 0 20 40 60 80 100 120 Time (months) Hui et al. Hepatology 2007

Spontaneous HBeAg seroconversion: reduces incidence of cirrhosis Cumulative incidence of cirrhosis (%) 100 80 60 40 20 0 Disease progression HBeAg reversion HBeAg-negative hepatitis Sustained remission 0 2 4 6 8 10 12 14 16 18 Years after HBeAg seroconversion Hsu et al. Hepatology 2002

Histological outcome % 100 90 80 70 60 50 40 30 20 10 Fibrosis P<0.01 HBsAg persistence (n=42) HBsAg clearance (n=20) 0 Improvement Stability Deterioration Korevaar et al. AASLD 2007

Relazione tra decremento di HBV DNA terapia indotto e miglioramento dell istologia epatica Literature analysis of 26 prospective clinical studies Predominantly Caucasian patient population Median histologic activity index improvements from baseline 4 3 2 1 0 r=0.96 p<3x10-6 1 2 3 4 5-1 Median log 10 HBV DNA level decrease from baseline -2 Mommeja-Marin H, Hepatol 2003

Hepatitis B and risk of HCC Percent cumulative incidence 12 10 8 6 4 2 0 HBsAg+, HBeAg+ HBsAg+, HBeAg HBsAg, HBeAg 0 1 2 3 4 5 6 7 8 9 10 Time (years) Yang NEJM 2002

Cumulative Hazards of Progression from Asymptomatic CHB to Chronic Hepatitis Cumulative Hazard of Chronic Hepatitis 0.6 0.5 0.4 0.3 0.2 0.1 0.0 HBeAg(+) HBV DNA 10 4 HBeAg(-) HBV DNA 10 4 HBeAg(-) HBVDNA <10 4 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of follow-up Chen JD, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 644.

Cumulative Hazards of Progression from Chronic Hepatitis to Cirrhosis Cumulative Hazard of Liver Disease 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 HBeAg(+) HBV DNA 10 4 HBeAg(-) HBV DNA 10 4 HBeAg(-) HBV DNA <10 4 1 2 3 4 5 6 7 8 9 10 Year of follow-up Chen JD, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 644.

Il trattamento dell epatite cronica B Stresa 2007 Ishak: S2 S4 S6 Interferone Peghilato (6-12 mesi) Lieve Moderata Grave Cirrosi Cirrosi scompensata NUC (per 5 anni o 6 mesi success. perdita HBs) HBeAg pos HBV DNA > 20.000IU/mL > 200 IU/mL HBeAb pos HBV DNA > 2.000IU/mL > 200 IU/mL

Treatment of chronic hepatitis B Summary PegInterferon Lamivudine Adefovir Entecavir Response in Yr 1 HBe Ag+(seroconversion) 27% 16%-21% 12% 21%** HBe Ag+ (HBV DNA neg 1 ) 25% 40%-44% 40%* 67%** HBe Ag- (HBV DNA neg 1 ) 63% 60%-70% 51% 90%*** Duration of treatment HBe Ag+ 1 yr >1 yr >1 yr > 1yr HBe Ag- 1 yr >>1 yr 2 >>1 yr 2 >>1 yr 2 Durability of response 3 HBe Ag+ 4 NA 50%-80% 91% 69% HBe Ag- 5 ~20% <10% ~5% NA 1 PCR assays * AnnInternMed200 2 indefinite therapy ** NEJM 2006 3 24 weeks post-treatment *** NEJM 2006 4 HBe Ag seroconversion 5 undetectable HBV DNA

Treatment of chronic hepatitis B Summary 2-5 yr PegInterferon Lamivudine Adefovir Entecavir Response in Yr 2 HBe Ag+(seroconversion) 12-14%* 11%*** HBe Ag+ (HBV DNA neg 1 ) 81%*** HBe Ag- (HBV DNA neg 1 ) 34% 71%** Response in Yr 5 HBe Ag+(seroconversion) 50% HBe Ag+ (HBV DNA neg 1 ) HBe Ag- (HBV DNA neg 1 ) 67% 1 PCR assays Hepatol 2005 * NEJM 2003 ** NEJM 2005 *** NEJM 2006 Gastroenterol 2003 Hepatol 2005

Decline of HBV cccdna During LdT and LAM Therapy 38 patients on LdT and 32 patients on LAM 0 HBV DNA Change Intrahepatic HBV DNA ccc DNA Intrahepatic HBV DNA and cccdna were measured by a previously validated real-time PCR assay Log 10 c/ml -1-2 -3-4 -5 * Greater reduction of HBV DNA with LdT; no differences in CCC or intrahepatic DNA between groups Wong DKH, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 1002. -6-7 LdT LAM