che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

Transcription

1 Giovanna Fattovich Professore Associato di Medicina USO Epatologia, UOC di Gastroenterologia do, Dipartimento di Medicina, Azienda Ospedaliera Universitaria Verona La sottoscritta dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

2 Personalizzazione della cura nell epatite cronica B: Cirrosi iniziale (HBeAg positiva/anti-hbe positiva): 1. C è l indicazione al trattamento con IFN? 2. E possibile sospendere la terapia con NUCs? 3. Come valutare la reversione della cirrosi? 4. Come eseguire il monitoraggio clinico e virologico del paziente?

3 Cirrhosis is a series of progressive stages, not a single stage Metavir F Biology: Fibrogenesis & neovasc. Scar X-linking Acellular scar Nodule size Insoluble scar & small nodules HVPG: > 5 >10 >12 Clinical: none none Varices formation increasing vasodilatation Ascites (without VH) VH (+ ascites) Stage: Early stage cirrhosis Compensated (stage 1) Compensated (stage 2) Decompensated (stage 3) Decomp (stage 4) Stages are based on data of D Amico et al, J Hepatol 2006;44:

4 HBeAg positive or negative Hepatitis Cirrhosis Decompensated cirrhosis Fibrosis No Mild Moderate Severe METAVIR Ishak s F0 S0 F1 S 1-2 F2 S3 F3 S4 F4 S5-6 PEG IFN Linee guida italiane, 2011 Statements IFN Necroinflamm. activity > A2 (METAVIR ANY INDEFINITE Treatment with NAs HBVDNA : > 2000 UI/mL > 15 UI/mL ALT: > UNL ANY ALT Carosi G, Rizzetto M, et al. Dig Liver Dis. 2011; 43: Treat

5 Selecting patient with HBeAg positive or negative cirrhosis for Peg-IFN Stage of cirrhosis Child-Pugh A (early/stage 1) No oesophago-gastric varices WBC > 3000/mm 3 (neutrophil > 1800/mm 3 ) Platelets /mm 3 Normal albumin, bilirubin No history of decompensation/variceal bleeding Specific patient demographics Generally young people (<40-45 yrs) Young women wanting pregnancy in near future Any etnicity Absence of comorbidities Patient preference

6 Selecting patient with HBeAg positive cirrhosis for Peg-IFN and adapting treatment Stage of cirrhosis Child-Pugh A (early/stage 1) No oesophago-gastric varices WBC > 3000/mm 3 (neutrophil > 1800/mm 3 ) Platelets /mm 3 Normal albumin, bilirubin No history of decompensation/variceal bleeding Specific patient demographics Generally young people (<40-45 yrs) Young women wanting pregnancy in near future Any etnicity Absence of comorbidities Patient preference Favorable predictors of response Lower HBV-DNA (< 2 x IU/ml) High ALT ( 2 < 5 x ULN) HBV Genotype A > B/C > D Optimization of therapy: 24 wk stopping rule: HBsAg > IU/ml (99 % NPV for HBeAg loss with HBV-DNA < 2000 IU/ml and 100% NPV for HBsAg loss irrespective of HBV genotype ) 1 Early therapy adaptation for probable non responders 1. Sonneveld MJ, Hepatology 2013

7 Selecting patient with HBeAg negative cirrhosis for Peg- IFN and adapting treatment Stage of cirrhosis Child-Pugh A (early/stage 1) No varices WBC > 3000/mm 3 (neutrophil > 1800/mm 3 ) Platelets /mm 3 Normal albumin, bilirubin No history of decompensation/variceal bleeding Specific patient demographics Generally young people (<40-45 yrs) Young women wanting pregnancy in near future Any etnicity Absence of comorbidities Patient preference Favorable predictors of response Lower HBV DNA (< 2 x 10 5 IU/ml) High ALT ( 2 < 5 x ULN) HBV Genotype B/C > D Optimization of therapy: 12 wk stopping rule: < 2 log 10 HBV-DNA decline and no HBsAg decline (95-100% NPV, genotype A-D) 1 Early therapy adaptation for probable non responders 1. Rijckborst V, J Hepatol 2012

8 Buster EHC, Hepatology 2007 Hepatitis flares not associated with clinical decompensation among cirrhotics Dose reduction (63% vs 30%, p = 0.002) or discontinuation of therapy (21% vs 8%, p = 0.05) occurred more often in cirrhosis (n = 24) vs no cirrhosis

9 Personalizzazione della cura nell epatite cronica B: Cirrosi iniziale (HBeAg positiva/anti-hbe positiva): 1. C è l indicazione al trattamento con IFN? 2. E possibile sospendere la terapia con NUCs? 3. Come valutare la reversione della cirrosi? 4. Come eseguire il monitoraggio clinico e virologico del paziente?

10 Anti-HBV therapy: stopping rules for NUCs in HBeAg + CHB CHB treatment guidelines EASL (2012) AISF (2011) AASLD (2009) APASL (2012) HBeAg + HBeAg seroconversion + undetectable DNA for 12 months HBeAg seroconversion + undetectable DNA for 12 months HBeAg seroconversion + undetectable DNA for 6 months HBeAg seroconversion + undetectable DNA for 12 months Treatment of patients with cirrhosis: After at least 12 months of consolidation therapy, NUCs treatment might be stopped in HBeAg positive patients with compensated cirrhosis if they achieve confirmed anti-hbe seroconversion (B1) EASL clinical practical guidelines. J Hepatol 2012; 57:

11 HBV relapse after stringent cessation criteria of NUCs therapy in HBeAg positive CHB * Author race n.pts Mean age (yr) NUC Mean Tx Duration (mo) Mean post Tx FU (mo) Relapse % % Relapse within mo Yeh 2009 asian LAM Lee 2010 asian LAM Wang 2010 asian LAM 17 (7-44) 26 (12-77) 24 (12-89) NA Tseng 2012 asian Reijnders 2010 Caucasian (55%) LAM (92%) ADF (6%) LAM (66%) ADF/ETV/ TDF (33%) 20 (7-80) NA * cirrhotic pts: 0 to 11% HBeAg reversion or HBeAg negative CH

12 Anti-HBV therapy: stopping rules for NUCs in HBeAg negative CHB CHB treatment guidelines EASL (2012) AISF (2011) AASLD (2009) HBeAg - HBsAg seroconversion HBsAg seroconversion Continue untill HBsAg clearance Treatment of patients with cirrhosis: NUCs treatment might be stopped in HBeAg negative patients with compensated cirrhosis if they achieve confirmed HBsAg loss and anti-hbs seroconversion (B1) EASL clinical practical guidelines. J Hepatol 2012; 57:

13 Anti-HBV therapy:stopping rules for NUCs in HBeAg negative CHB CHB treatment guidelines APASL (2012) EASL (2012) AISF (2011) AASLD (2009) HBeAg - Undetectable DNA on 3 occasions 6 mo apart and treated for at least 2 years HBsAg seroconversion HBsAg seroconversion Continue untill HBsAg clearance New stopping rule!?

14 HBV relapse after stringent cessation criteria of NUCs therapy in HBeAg negative CHB Author Race/HBV genotype n. pts Mean age (yr) NUC Mean Tx Duration (mo) Mean post Tx FU (mo) Relapse * % % Relapse (within, mo) Liu 2011 Asian/C LAM (3 mo) Liang 2011 Asian LAM (55%) ADF/ETV (6 mo) (45%) Ha 2012 Asian/C ADF (3 mo) Jeng 2013 Asian/ B (72%) or C (26%) ETV 24 > (all pts) 43 ^ (cirrhotics) 74 (after 6 mo) Hadziyannis 2012 Caucasian/ D (100%) ADF (after 6 mo) * Defined as reappearance of HBV-DNA 10 4 copies/ml ( 2000 UI/ml) ^ 1 (2.5%) of 39 cirrhotic developed decompensation, but rescued by ETV retreatment

15 Liaw YF, Hepatol Int 2012 Therapy with NUCs: statement HBsAg clearance is a remote ideal endpoint to stop antiviral agents, and quantitative HBsAg will be a potential marker to guide treatment cessation

16 Prediction of off-treatment response to LAM by serum HBsAg quantification in HBeAg negative CHB 53 chinese patients: mean age 56 yrs, 24 HBV genotype B, 29 HBV genotype C, 18 (34%) cirrhotics, mean treatment duration 27 months Chang HLY et al. Antivir Ther 2011 HBeAg negative pts (n = 53) HBsAg at the last follow-up 100 IU/ml and > 1 log IU/ml reduction (n = 5) 100 IU/m or > 1 log IU/ml reduction (n = 8) < 100 IU/ml and 1 log IU/ml reduction (n = 40) SVR at 12 mos post tx (HBV-DNA <200 IU/ml) 5 patients 100% 4 patients 50% 0 patients 0% PPV = 100% NPV = 100

17 Personalizzazione della cura nell epatite cronica B: Cirrosi iniziale (HBeAg positiva/anti-hbe positiva): 1. C è l indicazione al trattamento con IFN? 2. E possibile sospendere la terapia con NUCs? 3. Come valutare la reversione della cirrosi? 4. Come eseguire il monitoraggio clinico e virologico del paziente?

18 Micronodular cirrhosis induced in rats after 12 weeks of CCl4 intoxication Over 366 days of recovery, micronodular cirrhosis underwent significant remodeling to a macronodular cirrhosis GASTROENTEROLOGY 2004;126: ARCH PATHOL LAB MED 2000;124:

19 Chan HLY, J Viral Hepat 2009 Normal ALT Elevated ALT (>1-5 ULN) >9.0 kpa- 12 kpa 100 % specificity to diagnose bridging fibrosis >12 kpa 95 % specificity to diagnose cirrhosis > kpa 98 % specificity to diagnose bridging fibrosis >13.4 kpa 93 % specificity to diagnose cirrhosis

20 How to assess regression of cirrhosis? Histology: Fibrosis scoring systems: sampling error Non-invasive methods (transient elastography): Controversial results Limitations: - Values influenced by ALT levels - How well do the non invasive tests distinguish between grades of fibrosis?

21 Personalizzazione della cura nell epatite cronica B: Cirrosi iniziale (HBeAg positiva/anti-hbe positiva): 1. C è l indicazione al trattamento con IFN? 2. E possibile sospendere la terapia con NUCs? 3. Come valutare la reversione della cirrosi? 4. Come eseguire il monitoraggio clinico e virologico del paziente?

22 Clinical management of Patients With HBV Compensated Cirrhosis Pre-therapeutic assessment liver function (whether compensated or decompensated), blood count presence of oesophago-gastric varices liver ultrasound History of decompensation, family history of serious HBV liver disease AST/ALT levels HBV-DNA levels (HBsAg quantification and HBV genotype may provide additional informations) co-morbidities and co-factors potentially worsening liver disease During and after treatment HCC surveillance regardless of response to therapy Liver ultrasound/6 months Treatment discontinuation requires close monitoring for flare or relapse