Individualni pristup u lije č enju bolesnika s kroni č nim C hepatitisom Smjernice Hrvatske konsenzus konferencije 2009

1. Individualni pristup u liječenju bolesnika s kroničnim C hepatitisomSmjernice Hrvatske konsenzus konferencije 2009 Prof.dr.sc. Adriana Vince Referentni Centar za dijagnostiku i liječenje virusnih hepatitisa RH Zagreb, 15.5.2009

2. Rezolucija o virusnom hepatitisu • 10.03.2009 Odbor za zdravstvo Hrvatskog sabora jednoglasno je usvojio Rezoluciju o virusnom hepatitisu, kojom se ističe javnozdravstveni značaj virusnih hepatitisa i obvezuje Ministarstvo zdravstva na donošenje Akcijskog plana za borbu protiv virusnog hepatitisa (prema Deklaraciji Europskog parlamenta)

5. Hepatitis C Virus InfectionNatural History Acute HCV Resolved 15% (15%) Chronic HCV 85% (85%) Stable 80% (68%) Cirrhosis 20% (17%) Slowly progressive 75% (13%) HCC Liver failure 25% (4%) HCC, hepatocellular carcinoma

6. Putevi prijenosa HCV • Perkutani put • Intravensko uživanje opojnih droga • Transfuzije krvi i krvnih pripravaka • Dijagnostički i terapijski postupci ( hemodijaliza, instrumenti I sl) • Ubodni incidenti • Permukozni • Perinatalno • Spolni put • Ostale nedokazane mogućnosti: frizer, tatoo, kozmetičar, pediker, body piercing

9. Broj genotipova HCV-a analiziranih u novodijagnosticiranih bolesnika u Klinici za infektivne bolesti od 1996. do 2008. HZZT 380-400 genotipizacija godišnje

10. Distribucija genotipova HCV-a u bolesnika liječenih u Referentnom centru za virusni hepatitis tijekom 2008. g.

11. Dosadašnja terapija kroničnog hepatitisa C

12. Učinak kombinirane terapije • Pegilirani interferon • Direktni antivirusni učinak • Imunomodulatorni učinak • Ribavirin • Inhibira sintezu nukleinskih kiselina • Imunomodulatorno djelovanje • Eliminacija zaraženih hepatocita

13. Točke procjene virološkog odgovora • EVR(Early virological response)-nedetektabilna HCV RNA nakon 12 tj. th. • ETR (End of treatment virological response)-nedektabilna HCV RNA nakon završetka th • SVR (Sustained virological response)- nedektabilna HCV RNA 24 tjedna nakon završetka terapije • RVR (Rapid Virological Response)- nedetektabilna HCV RNA nakon 4 tj. th.

14. Ciljevi terapije KHC • Postizanje SVR-a • - u 99 % slučajeva- trajna eradikacija virusa, u većini slučajeva i “izliječenje” • - zaustavlja se daljnje oštećenje jetrenog parenhima • regresija stupnja fibroze • smanjuje se rizik za HCC

15. Histologic Progression of HCV Monitored by Liver Biopsy Inflammation Grade • Measure of severity and ongoing disease activity • 0-4 (METAVIR) • Inflammation leads to scarring/fibrosis Fibrosis Stage • Amount of fibrous scar tissue • 0-4 (METAVIR) • Stage 4 = cirrhosis • Indicates long-term disease progression No fibrosis Cirrhosis Brunt EM. Hepatology. 2000;31:241-246.

16. Pretreatment or fixed Genotype HCV RNA level Histology Race HIV coinfection Steatosis Body weight Adherence Dynamic factors Rapid virologic response (HCV RNA negative at Wk 4) Early virologic response Partial (HCV RNA decline of > 2 logs at Wk 12) Complete (HCV RNA negative at Wk 12) Factors Associated With SVR

17. Definitions of On-Treatment Response

18. Virologic Responses 8 PegIFN/RBV 7 6 5 EVR 2 log10 decline HCV RNA (log10 IU/mL) 4 3 2 Slow virologic response Limit of detection 1 cEVR RVR SVR 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

19. Suboptimal Virologic Responses 8 PegIFN/RBV 7 Relapse Null response 6 5 Partial response 2 log10 decline HCV RNA (log10 IU/mL) Breakthrough 4 3 2 Limit of detection 1 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

20. Duration of Undetectability 106 Undetectable 44 wks 105 Undetectable 36 wks 104 Undetectable 28 wks HCV RNA 103 102 101 UND // 0 4 8 12 20 24 48 Wks of Treatment

21. Viral Kinetics and Outcome Importance of Rapid Virologic Response 100 94 91 91 90 90 86 PegIFN + RBV (N = 453) 80 72 EOT response 60 SVR 60 Virologic Response (%) 48 43 40 20 13 2 0 HCV RNA Status Neg Neg Neg > 2 log Neg Neg < 2 log Neg Neg > 2 log > 2 log Neg < 2 log > 2 log Neg Any Pos Pos Wk 4 Wk 12 Wk 24 Reprinted from Journal of Hepatology, 43, Ferenci P, et al, Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin, 425-433, 2005

22. Molekularna dijagnostika Da bismo točno mjerili virusnu kinetiku moramo imati pouzdane testove za mjerenje viremije

23. Clinical molecular assays for HCV RNA quantification • Automated real-time PCR assays (qualitative and quantitative) • Examples of assays most widely used in Europe: • Cobas Ampliprep/TaqMan HCV RNA test (linear range 10-200 000 000 IU/ml) • Abbot RealTime HCV Assay (linear range 12-100 000 000 IU/ml) • bDNA assay (quantitative) • Versant HCV RNA test (615-7 700 777 IU/ml, Simmens) • Classical RT-PCR assay (qualitative) • Cobas Ampliprep/Cobas Amplicor HCV RNA (50 IU/ml, Roche) • Quantitative assay • Cobas Amplicor Monitor HCV test, konvencionalni PCR, 600-700 000 IU/ml

24. Analytical variability of HCV RNA assays used in clinical diagnostics Significant differences in HCV RNA viremia observed in wk4 and wk12 Between Versant bDNA and Roche TaqMan assay (p<0.001) Halfon et al, J Med Virol, 2006

25. Analytical variability of HCV RNA assays according to genotype Significantly higher viremia measured by Abbott and Roche real-time PCR Compared with bDNA for genotypes 1, 2 and 3 For genotype 4, viremia measured by Abbott and Versant were equivalent but values for Roche PCR assays were lower Caliendo et al, 2006

26. Nove spoznaje • Virusna dinamika/kinetika najbitniji prediktor za postizanje SVR-a • Svi pacijenti s genotipom 2,3 nisu “easy to treat” • Svi pacijenti s genotipom 1,4 nisu “difficult to treat” • Response guided therapy (individualni pristup)

27. Osnovni cilj individualiziranog pristupa liječenju (response-guided therapy) • Povećati postotak SVR-a, osobito u populaciji G1 pacijenata • Produljenjem liječenja (ovisno o virusnoj kinetici) • Povišenjem doze ribavirina

28. Meta-analysis of Response-Guided Treatment for Hepatitis C • 12 published RCTs from 2004-2008 comparing different durations of pegIFN/RBV (N = 2399) • 5 studies compared 48 vs 72 weeks of treatment for slow responders with HCV GT 1 (n = 355) • 7 studies compared 24 vs 12, 14, or 16 weeks of treatment for rapid responders with HCV GT 2/3 (n = 2054) • Studies grouped by fixed-dose (ie, 800 mg/day) or weight-based RBV • HCV GT 2/3 patient analysis also categorized by suboptimal short therapy vs optimal short therapy • Suboptimal short therapy: 12 or 14 weeks of treatment or fixed-dose RBV 800 mg/day administered (n = 1782) • Optimal short therapy: 16 weeks of treatment and weight-based RBV administered (n = 272) Di Martino V, et al. AASLD 2008. Abstract 213.

29. Extended Genotype 1 HCV Peginterferon alfa/ribavirin Treatment to 72 Weeks for Slow RespondersMeta-analysis • Slow virologic responders with genotype 1 HCV • - Pooled estimate of SVR increase with 72 vs 48 weeks of treatment: 12% (95% [CI]: 5% to 19%) • - No benefit of extended treatment observed for patients who had undetectable HCV RNA at Week 12 • 72 weeks of peginterferon alfa/weight-based ribavirin more effective than 48 weeks for producing sustained virologic response (SVR) in patients with genotype 1 HCV who had a slow virologic response to treatment Di Martino V, Richou C, Thévenot T, Sánchez-Tapias JM, Ferenci P. Modulations of peg-interferon plus ribavirin duration according to HCV-genotype and virologic response at W4 and W12: meta-analyses of RCTs with individual data. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 213.

30. POWeR Study • SVR and EOT responses significantly higher in patients with baseline mild to moderate fibrosis (F1-F2) compared with those with baseline fibrosis or cirrhosis (F3-F4) • Relapse rates also higher in F3-F4 patients vs F1-F2: 35% vs 18%, respectively (P = .0009) • Virologic response by baseline HCV RNA (n = 651) • - Among patients with mild to moderate fibrosis (F1-F2) and baseline HCV RNA assessment (n= 391), SVR rates significantly higher for patients with low HCV RNA • - Among patients with bridging fibrosis or cirrhosis (F3-F4) and baseline HCV RNA assessment (n = 260), no significant difference in SVR rate by HCV RNA Marotta P, Cooper C, Wong DK, et al. Impact of advanced fibrosis and cirrhosis on sustained virologic response of HCV G1-infected patients: results of the Canadian POWeR program. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31-November 4, 2008; San Francisco, California. Abstract 1216.

31. ACCELERATE study • Genotype 2/3, peginterferon alfa-2a • Patients with RVR • -SVR (therapy for 24 weeks)- 85% • -SVR (therapy for 16 weeks)-79% • Non-RVR patients • - SVR (therapy for 24 weeks)- 45% • Longer duration of therapy (48 weeks) in non-RVR patients may reduce relapse and lead to signifficantly higher rates of SVR • Shiffman et al. HCV patients with genotype 2 and 3 who do not achieve a Rapid Virological Response (RVR) with peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) are not easy to treat: An analysis of non-RVR patients from the ACCELERATE study. Hepatology 2007:46(Suppl 1):Abstract 164.

32. Lowered RBV Exposure as a Predictor of Relapse Following PegIFN/RBV • Reduced cumulative RBV exposure independently and significantly predicted relapse rates • Individuals receiving 50% of RBV target dose more than twice as likely to relapse • Risk of relapse increased gradually with amount of dose reduction Reddy R, et al. AASLD 2008. Abstract 1283.

33. Dosadašnje smjernice za liječenje kroničnog hepatitisa C u RH

34. Liječenje kroničnog hepatitisa C-HZZO(dopuna 27.05.2008.) • bolesnici u dobi do 65 godina koji apstiniraju od i.v. droga i alkohola najmanje 12 mjeseci uz potvrdu liječnika specijalista koji liječe bolesnika i koji zadovoljavaju slijedeće kriterije: • a. virološki kriteriji: anti HCVpozitivan; HCV RNA (PCR) pozitivan; • viremija dulje od 6 mjeseci; • b.biokemijski kriteriji: 2x povišen ALT u dva uzastopna laboratorijska nalaza, bez obzira na stupanj fibroze; normalan ALT sa stupnjem fibroze većim od F2; • c. histološki kriteriji: dokaz kronične upale, odnosno verifikacija stupnja aktivnosti i stadija fibroze (osim kod kontraindikacija za biopsiju jetre); • d. bolesnici prethodno liječeni konvencionalnim interferonom, koji imaju dokazani relaps bolesti pozitivnim nalazom HCV RNA (PCR metodom) u serumu; • e. isključiti bolesnike s prisutnim kontraindikacijama za terapiju pegiliranim interferonom.

35. Genotip 1 • Pegilirani interferon alfa-2b 1.5 mcg/kg 1xtjedno uz ribavirin/TT u trajanju 48 tjedna • Pegilirani interferon alfa-2a 180 mcg 1xtjedno uz ribavirin/TT u trajanju 48 tjedna • Uz određivanje EVR-a kod osoba s viremijom>600 000 IU/ml • Uz određivanje RVR-a kod osoba s niskom viremijom<600 000 IU/ml seruma

36. Genotip 2 i 3 • Pegilirani interferon alfa-2b 1.5 mcg/kg 1xtjedno uz ribavirin u trajanju 24 tjedna • Pegilirani interferon alfa-2a 180 mcg 1xtjedno uz ribavirin u trajanju 24 tjedna

37. Genotip 4,5,6 • Pegilirani IFN-alfa-2a ili alfa-2b+ribavirin u trajanju od 48 tjedana • Odrediti EVR (12. tj.) • - ako je HCV RNA neg. ili pad viremije 2 log - nastavak th • -ako je HCV RNA poz. - prekid th

38. Rezultati liječenja pegiliranim interferonom od 2003.-2008. godine

39. Demographicand histological profile ofpatients with chronic hepatitis C (GT1) at baseline Baseline serum HCV-RNA < 600,000 IU/mL 24.88% > 600,000 IU/ml 75.12%

40. Sustained viral responsegenotip 1,4 56% SVR 93% EVR 80% ETR 200 pacijenata 7% 20% 44%

41. Patients with SVR vs non-responders

42. Glavni prediktor relapsau naših bolesnika s G1,3 Stadij fibroze 4 (ISHAK)

43. Nove smjernice za liječenje kroničnog hepatitisa C u naivnih bolesnika Hrvatska konsenzus konferencija,studeni 2008 Referentni Centar za dijagnostiku i iječenje virusnih hepatitisa Referentni Centar za kronične bolesti jetre RH

44. Indikacije za liječenje • Dob bolesnika- liječenje bolesnika starijih od 65 godina prema “kondiciji” bolesnika • Biokemijski kriterij- povišen ALT u 2 uzastopna lab. nalaza, bez obzira na stupanj fibroze • Histološki kriteriji- liječenje bolesnika s dokazom fibroze

45. Individulni pristup • Uzima u obzir • Genotip • Viremiju • Stadij fibroze • Virusnu kinetiku (RVR, EVR)

46. Terapija kroničnog hepatitisa C • pegilirani interferon alfa-2b (Pegintron) 1.5 mcg/kg s.c. jednom tjedno • pegilirani interferon alfa-2a (Pegasys) 180 mcg s.c. jednom tjedno • ribavirin 800-1200 mg (ovisno o tjelesnoj masi (11-15mg/kg TT) p.o. svakodnevno

47. Genotip 1, Visoka viremija (>600 000 IU) Fibroza 1-6 cEVR postignut EVR nije postignut pEVR Th kroz 48 tj. Viremija u 24. tjednu Prekid th PCR neg PCR poz Th kroz 72 tj. Prekid th

48. Fibroza 1-4 Fibroza 5,6 Postupak kao kod visoke viremije Genotip 1, Niska viremija (<600 000 IU) RVR postignut RVR nije postignut Th kroz 24 tj. Postupak za visoku viremiju

49. Genotip 4,5,6 EVR postignut EVR nije postignut Th kroz 48 tj. Prekid th

50. Fibroza 1-4 Fibroza 5,6 Th kroz od 48 tjedana (ako HCV RNK negativna nakon 24 tj) Genotip 2,3 Niska viremija (<600 000 IU) RVR postignut RVR nije postignut Th kroz 16 tj Th kroz 24 tj.