Diagnosi e terapia delle epatiti croniche virali

Transcription

1 Diagnosi e terapia delle epatiti croniche virali Fabrizio Magnolfi Direttore della Struttura Complessa di Gastroenterologia Ospedale S. Donato - Arezzo

2 Caso clinico 1

3 Fattori eziologici delle Epatopatie Croniche Giusti, Casi* Sagnelli, Casi 10.7% Alcool 5.5% HDV 3% Altro 31.3% HBV 11% NASH Altro HBV HCV+Alcool 4% 6% 9% NANB 47.2% 3.3% Autoimm Alcool 20% 49% HCV * Epatiti croniche (diagnosi istologiche) osservate nel decennio Altro Autoimmune 1%; PBC 1%; Emocromatosi 1%; HBV+HCV 1%; HBV+Alcool 1%; HBV+HCV+Alcool 1%

4 CHRONIC HEPATITIS: DIAGNOSIS HBV Clinical HCV Symptoms +/- Laboratory test Biochemical Serological Virological (viremia / genotype) Histology Imaging US TC RM Liver biopsy HAI

5 CHRONIC HEPATITIS : DIAGNOSIS GENOTYPES BEFORE THERAPY HCV Hybridization HBV Gen. Rari F America latina Nord Europa & USA - A Bacino Mediterraneo - D Russia D Africa D, E & A India A Far East C & B Sequencing Hybridization G Francia, USA H Messico, Australia C

6 AIMS OF ANTIVIRAL THERAPY IN CHRONIC VIRAL HEPATITIS INFECTION DISEASE To inhibit viral replication To eradicate viral infection To reduce/suppress liver necroinflammation To slow/avoid progression to cirrhosis To slow/avoid cirrhosis complications (HCC)

7 La terapia personalizzata della epatite cronica da HCV HCV Geno 2 e 3 Virus molto sensibili Attività antivirale dominante HCV Geno 1 e 4 Virus resistenti Notevole importanza dei cofattori (Età,peso )

8 Factors conditioning SVR Genotype Viral load Fibrosis stage Age Duration of infection Male BMI, Steatosis, Diabetes HBV,HIV

9 Fattori che influenzano la risposta antivirale nella epatite cronica da HCV Wald Q Wald Q-quadro quadro Carica virale pre-trattamento Età Livello ALT Istologia Razza Peso corporeo 800 vs mg RBV US vs non-us Sesso Geno1 vs non-1 Lee et al. J Hepatol 37; 2002

10 PEG IFN alfa 2 b + RBV in CHC Pts Genotype 2 and 3 in relation to viral load 100% 80% 95% 91% 86% 70% 60% 40% 20% 0% GENO 2< GENO 2 > GENO 3 < GENO 3 > S.Zeuzem AASLD 2004

11 THERAPY OF CHRONIC HEPATITIS C (Tailoring of Therapy with optimized schedules) Shorter treatment for easy Geno 2/3 Dose of PEG-INF may be low in G 2 Full doses and time for genotipe 3, High viral load Shorter treatment for low viremic Geno 1 (Early response at 4 Wk) RIBAVIRIN: fix dose for genotype 2 and 3: 13.1 mg/kg or more for genotype 1 Longer treatment or High doses for slow responders New options for difficult cases and NR

12 Short treatment for 24 Wk with Peg-IFN alpha 2 b +Riba in CHC, G 1 and low viral load 235 patients: - genotype 1 - HCV viral load < IU/ml Peg-IFN a2b: 1.5 mg/kg/week+ Ribavirin mg/die for 24 weeks All patients: SR: 50% - 48-week historical control 71% (Manns et al., Lancet 2001) Patients negative at week 4: SR: 89% - 48-week historical control 85% (Manns et al., Lancet 2001) Zeuzem S, J Hepatol 2006

13 High doses of PEG IFN alfa 2 a+ RBV (48 wk) in CHC: G-1,High viral load and weight >85 Kg PEG IFN 180 PEG IFN 270 RBV mg SR % RR % SAE % STOP % Dose IFN RBV M.Fried et Al AASLD 2006 (abs 335)

14 CH-C : Dose RBV and duration of therapy Therapy PEG-IFN + RBV Dose Dose Genotype 1 RBV 800 mg RBV 1000/1200 mg Genotype 2/3 2/3 RBV 800 mg RBV 1000/1200 mg 24 ws Duration 48 ws 29% 40% 41% 51% 78% 78% 73% 77% International trials

15 CH-C : INDIVIDUALIZED THERAPY 0 Null Response Genotype 1 Low HCV-RNA > 0.5 vrna- 4 ws Rapid response SR Relapse 1-2 days 3-12 months Therapy Duration 48 ws 24 ws 85 % 89 % SR 235 pts Zeuzem, 2006 Genotype 24 ws Duration 12 ws % 85 % SR 283 pts Mangia, 2005 Duration 24 ws 16 ws * 80% 82% SR 142 pts * Genotype 3 high viremia 54% Von Wagner, 2005

16 There are two types of chronic hepatitis B HBeAg positive (predominant HBV wild type) anti-hbe positive (predominant core/pre-core HBV mutant) These two types of chronic hepatitis B differ for: virological (predominant HBV population) clinical course response to therapy end-point of treatment response

17 Chronic HBsAg carriers: HBV DNA level Serum HBV DNA (copies/ml) CHB HBeAg + CHB HBeAg Inactive Patients Villeneuve JP et al. Gastroenterology Martinot Peignoux M et al. J.Hepatol Hsu et al Hepatology Mommeja-Marin H et al. Hepatology 2003; Manno,Gastroenterology 2004.

18 Inactive HBV carrier Absence of HBeAg (anti-hbe+) Persistent normal ALT Serum HBV-DNA < cp/ml 20-40% of HBeAg negative hepatitis with intermittent normal ALT and low HBV-DNA are misclassified inactive carriers Many patients with cirrhosis or HCC are HBeAg with normal ALT and low HBV-DNA at presentation

19 Chronic Hepatitis B: Which patients should be treated? Patients with moderate to severe chronic hepatitis (ALT> 2 x ULN, moderate/severe necroinflammation and fibrosis on biopsy) and Active viral replication (HBV DNA>10 5 copies/ml) EASL Consensus Conference 2002

20 Cumulative incidence of cirrhosis N = 3582 P <0.001 Log rank test Iloeje et al, Gastroenterology 2006; 130:

21 General Remarks 1. Although the number (and cost) of drugs approved as first line therapies for chronic hepatitis B is in continuous increase, nevertheless none of them can achieve the goal of eradication of HBV infection. 2. Currently the most ambitious (and closest to cure ) goal of in chronic hepatitis B is HBsAg seroconversion but actually this can be achieved only in a small minority of patients (<10%).

22 Differing Options and Contrasting Views for Duration of Treatment and Choice of Drugs According to: HBeAg/anti-HBe status HBV DNA and ALT levels and patterns Stage of HBV liver disease (no cirrhosis, compensated cirrhosis, de-compensated cirrhosis, transplant setting) Co-infections (HIV, HCV, HDV), co-morbid conditions and other factors

23 Therapy for Chronic Hepatitis B Approved Interferon alfa IFNα 1988 Lamivudine LAM 1999 Adefovir Dipivoxil ADV 2004 Peg-IFNα-2a 2005

24 Treatment Strategies and Approved Drugs A. Treatment courses of finite duration * - Aiming at responses under treatment that can be sustained after therapy is stopped (SR). *Applicable with all available drugs B. Long-term/indefinite antiviral treatment * - Aiming at on-therapy effective HBV suppression maintained without viral resistance (and hopefully followed by SR after therapy is stopped). *Applicable only with nucleos(t)ide analogues in monotherapy and in combination schemes.

25 Conventional IFNα Therapy For HBeAg-negative Patients Dose range: 3 10 MIU tiw Duration of treatment 6 months 1-5 On-therapy response (%) Sustained response (%) months 6, Brunetto et al 1989; 2. Brunetto et al 1995; 3.Hadziyannis et al 1990; 4. Pastore et al 1992; 5. Oliveri et al 1999; 6.Manesis and Hadziyannis 2001; 7. Lampertico et al 2003

26 Interferon in HBeAg-negative CHB: Duration of treatment % patients with sustained response cases treated for 12 mo (median) 78 cases treated for 5 mo (median) p = % 11% end tx Years after ending IFN therapy (Manesis et al., 2001)

27 HBeAg-negative CHB RCT of 48 wk PEG-IFN α-2a + Lam versus Lam End of Follow-up Response (24 wks post-rx) % PATIENTS * * PEG-IFN α-2a 180 ug/wk (n=177) PEG-IFN α-2a + Lam (n=179) Lamivudine 100 mg/die (n=181) Normal ALT HBV-DNA <20,000 cp/ml HBV-DNA <400 cp/ml 7* 4 3 0* HBsAg loss * Significantly higher rates of response with peg-ifn nd Peg-IFN+LAM than with LAM Marcellin et al, NEJM 2004

28 Long-term Outcome in Lamivudine Treated Patients Virological and biochemical response may be maintained in a subset of patients Durable viral suppression delays clinical progression Drug resistance increases over time inducing Reversal of histological benefit Hepatitis flare Disease worsening

29 Adefovir Dipivoxil (ADV) First in a new class Nucleotide analogue of adenosine monophosphate Chain terminator of HBV DNA Durable HBV DNA suppression with a high threshold for the development of resistance Activity against wild type and lamivudine-resistant HBV Renally excreted (Dose interval modified for CCL < 50 ml/min) One 10 mg tablet, once daily orally

30 ADV monoterapia per 5 anni in pazienti affetti da EC HBeAg negativa HBV DNA < 1000 cp/ml ALT normale HBsAg neg = 5% anni Hadziyannis et al, AASLD 2005

31 Cumulative Incidence of ADV resistance ADV (N236T/A181V) % year 1 year 2 year 3 year 4 year 5 Hadzyannis et al AASLD 2005

32 Therapy of HBV The nucleos(t)ide strategy When and Why? Advanced/decompensated liver disease to stop/reduce progression IFN non response/intolerance Resistance is the issue Resistance associated with disease worsening and cross resistance for future therapies Combination therapy might be the solution

33 Diagnosi e terapia delle epatiti croniche virali Fabrizio Magnolfi Direttore della Struttura Complessa di Gastroenterologia Ospedale S. Donato - Arezzo

34 Biochemical and virological patterns in HBeAg-ve CHB (164 untreated patients monthly monitored for a median period of 21 months, range 12-36) ALT Flares with normalization DNA 164 pts 45 % Flares without normalization 20% Without flares 35 % Brunetto, J Hepatol 2002; 36:263-70

35 HBV therapy includes numerous end-point overtime Decline of HBV-DNA Decline of ALT HBeAg loss/anti-hbe HBsAg loss HBeAg+ HBeAg anti-hbe+ IMPROVEMENT OF HISTOLOGY Years

36 IFN therapy reduces cirrhosis and HCC in HBeAg+ CH-B Follow-up: years IFN treated n. 233 Controls n. 233 p HBeAg seroconversion 75% 54% 0.03 Development of cirrhosis 18% 34% 0.04 Development of HCC 2.7% 12.5% 0.01 HBsAg neg. 3% 0.4% 0.03 Lin et al. EASL 2006

37 IFN therapy reduces cirrhosis and HCC in HBeAg+ CH-B Follow-up: years IFN treated n. 233 Controls n. 233 p HBeAg seroconversion 75% 54% 0.03 Development of cirrhosis 18% 34% 0.04 Development of HCC 2.7% 12.5% 0.01 HBsAg neg. 3% 0.4% 0.03 Lin et al. EASL 2006

38 Marcatori sierici Diretti di Fibrosi Epatica Collageni: Collagene I Collagene III Collagene IV Glicoproteine e proteoglicani: Acido Ialuronico Laminina Tenascina YKL-40 MMPs and TIMPs: MMP-1 MMP-2 TIMP-1 Citochine TGF-β Non attendibili, ancora da validare nella pratica clinica

39 Stadio istologico: per misurare la Qualità della fibrosi

40 C I R R H O S I S S T A G E 2

41 Biopsia epatica Moderata (9-12) Mite (4-8) Minima (1-3) Normale (0) Severa (13-18) 18) Rapida(M>40 anni,alcool>50g/die) 1 NECROINFIAMMAZIONE Moderata Cofattori : Alcool, Steatosi, Età, Coinfezioni, etc. 2 Lenta(D<40 anni, Alcool<50g/die) 3 FIBROSI 4

42 CH-C : INDIVIDUALIZED THERAPY 0 > 0.5 Null Response Slow response 24 ws Relapse Genotype Extended treatment duration 1 vrna- Rapid response SR 1-2 days 3-12 months Therapy to improve therapy outcome HCV-RNA neg. 12 ws 24 ws Duration 48 ws 72 ws 53 % 54 % 17 % 29 % SR Should be reserved for pts with slow VR Berg, pts