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Incidence and Predictors of Hepatocellular Carcinoma In Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy The revolving alphabet soup of hepatitis viral infections Hepatitis C drug therapy – present© by and author future ESCMID Online Lecture Library Hepatitis C drug therapy • The present • The future © by author ESCMID Online Lecture Library Anti HCV agents Interferon and Ribavirin © by author ESCMID Online Lecture Library Viral Load vs. Time 1.E+08 • Lack of sensitivity to IFN 1.E+07 • Insufficient antiviral activity 1st phase 1.E+06 2nd phase • Defective clearance of DNA (cp/ml) DNA - 1.E+05 3rd phase infected cells HBV 1.E+04 4th phase 1.E+03 -7 7 21 35 ©49 by63 author77 91 105 119 133 147 161 175 Time (days) • In theESCMID first 2-3 weeks of therapy, Online the viral load Lecturedecline derives mainly Library from the reduction of viral production direct antiviral effect of the drug • Thereafter the viremia decline derives mainly from the clearance of infected cell Colombatto P et al.. Antiv Ther, 2003 Patterns of Virologic Response 7 Null response [1] 6 5 IU/mL) 10 4 Partial response 3 Relapse 40% chance 2 of SVR with © by author pegIFN/RBV[2] HCV RNA (log HCV RNA 1 Undetectable RVR EVR EOT SVR 0 ESCMID-8 -4 -2 0 4Online 8 12 16 Lecture20 24 32 40 48Library 52 60 72 Wks After Start of Therapy 1. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 2. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. WHAT WE HAVE LEARNED ABOUT TREATMENT (IFN) FAILURE Response to IFN alfa depends on : . HCV Genotype : 1 < 4 < 3 < 2 . Stage of liver disease : F4< F3 < F2 < F0-F1 . Host Genetics : IL28BTT < CT < CC © by author . Patient age : tolerability and immunecontrol ESCMID Online Lecture Library . Insulin Resistance RESPONSE GUIDED THERAPY WITH PEG-IFN and RIBAVIRIN SVR Duration of undetectable HCV RNA = 46 Weeks (45) 96 % = 44 Weeks (72) 89 % = 36 Weeks (300) 76 % = 24 Weeks (156) 44 % © by author HCV RNA HCV RNA ESCMID Online Lecture LibraryLimit of detection 0 2 4 8 12 24 48 72 End of treatment McHutchison JG et al. NEJM 2009;361:580-93. HCV-RNA Gen 4 Week 0 4 12 24 Neg Pos < 2 Pos Stop Tx RVR log drop Pos Pos >2 log drop Neg © by author DVR Neg ESCMID Online LecturecEVR Library 24 weeks of treatment, if 48 weeks 72 weeks BL HCV-RNA of therapy of therapy 5 < 4-8 x 10 IU/ml EASL Clinical practice guidelines Hepatitis C, J Hepatol, 2011 HCV-RNA Gen 2,3 Week 0 4 12 Neg Pos < 2 log drop Pos Stop Tx RVR or pos w 24 Pos > 2 log drop but neg thereafter DVR Risk factors© by author fibrosis, IR Neg ESCMID Online LectureEVR Library 12-14 weeks 24 weeks 48 weeks of treatment* of therapy of therapy * Marginally less effective due to higher relpase rates, especially for gen 3 with high viral load EASL, JHep 2011 SVR24 rates with PegIFN alfa/RBV: by fibrosis status Data from the real-world PROPHESYS cohort study Treatment-naive patients treated with PegIFN alfa-2a or PegIFN alfa-2b plus RBV No bridging fibrosis or cirrhosis Bridging fibrosis or cirrhosis SVR24 (%) SVR24 © by author ESCMID1101 362 Online347 75 Lecture403 82 Library89 14 2155 1032 431 109 544 158 188 47 HCV genotype Patients with sufficient follow-up data Marcellin P et al. Hepatology 2012; 56: 2039–50 Present of anti HCV Tx • PEG IFN + RBV: – virus/host targeted antivirals side effects – Efficacy related to host sensitivity and expressed by HCVRNA kinetics Response Guided Treatment Duration – SOC in HCV G non 1 – SVR rates according to fibrosis stage (F0-2 - F3-4): • HCV G2 80 - 69% • HCV G3 74 - 52% • HCV G4 47 - 30%© by author ESCMID Online Lecture Library HCV targets for therapy FLB2 hVAP-A CyPBX NS5A NS5B NS3 X X cytosol “entry inhibitors” 4A 4B mAbs anti-E2/CD81, Receptors binding And endocytosis PRO 206 Ezetimibe Transport and release miRNA ER lumen ISIS 14803 (antisense) Fusion and AVI- 4066 (antisense) decapsidation Inhibitors of Heptazyme (ribozyme) VGX-410C (small molecules IRES (+) RNA viral assembly Trasltion Virion assembly inhibitor) TT 033 (sIRNA) and rekaese : eIF2α phosphorilation inhibitors: Celgosivir Nitazoxanide Translation and processing of polyprotein Protease inhibitors RNA replication Replication © by author inhibitors: • NS2–NS3 NS5b •NNI, protease NS3 protease Drugs active on viral enzymes • NI Drugs activeESCMID on host cell enzymes Online Lecture Library •NSa •Ciclophyllin B C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Membrana Serine protease RNA-dipendent RNA domain polymerase 1. Lindenbach BD & Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436:933-938 Emergence of Pre-existing Resistant Variants During Treatment with DAA Drug Potency Baseline HCV RNA Viral breakthrough Resistance Barrier X X X X HCV RNA X X X © Xby X author ESCMID Online Lecture Library Before Treatment Time on Treatment with DAA Alone Resistant virus Sensitive virus DAA Classes and Subclasses Drug Class Subclass Potency Resistance Barrier Protease 1st Generation i.e. Medium- Low inhinbitors Telaprevir/Boceprevir Low 2nd Generation i.e. Medium - Low Faldaprevir/Simeprevir High 3rd Generation High Medium-High ABT450/r MK5172 NS5a Inhibitor 1st Generation High Low (HCVG1a) Daclatasvir Ladipasvir ABT High 267 2nd Generation© by author High High NN Polymerase ABT 333 GS 9669 Low- Low Inhibitors BI 1072 Medium Nucleosides/tiESCMID1st Generation:Online Mericitabine Lecture LowLibrary High des 2nd Generation : Sofosbuvir High High Polymerase inhibitors 14 How to avoid resistance to DAA monotherapy: combo with PEGIFN + RBV Potent IFNα-ribavirin effect 1 0 DAA Monotherapy IU/mL) Wild-type, sensitive HCV 10 -1 Triple Combo -2 Resistant HCV -3 © by author Median HCV RNA change HCV RNA Median -4 from baseline (log ESCMID-5 Online Lecture Library Time on treatment How to avoid resistance to DAA monotherapy: combo with PEGIFN + RBV Weak IFNα-ribavirin effect 1 0 DAA Monotherapy IU/mL) Wild-type, sensitive HCV 10 -1 Triple Combo -2 Resistant HCV -3 © by author Median HCV RNA change HCV RNA Median -4 from baseline (log ESCMID-5 Online Lecture Library Time on treatment Addition of BOC or TVR to PegIFN/RBV improves SVR in G1 Patients Treatment-naive1–3 Treatment-experienced Relapsers4–6 Partial Null 100 responders4,5 responders4,7 69–88 80 63–75 40–59 60 38–44 29–40 40 SVR24 SVR24 (%) ©24–29 by author 20 7–15 ESCMID Online Lecture Library5 0 1. Poordad et al. New Engl J Med 2011; 364: 1195–206; 2. Jacobson et al. New Engl J Med 2011; 364: 2405–16; P/R BOC or TVR + P/R 3. Sherman et al. New Engl J Med 2011; 365: 1014–24; 4. Zeuzem et al. New Engl J Med 2011; 364: 2417–28; 5. Bacon et al, New Engl J Med 2011; 364: 1207–17; 6. Flamm et al. Clin Gastroenterol Hepatol 2013; 11: 81–87; BOC = boceprevir; P/R = peginterferon/ribavirin; TVR = telaprevir 7. Bronowicki et al. EASL 2012; abstract 11 Telaprevir in Genotype 1 Patients . 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g) Treatment Naive and Previous Relapsers eRVR non cirrhosis; stop at Wk 24: 63% TVR + PR PR No eRVR or cirrhosis; PR Previous Partial or Null Responders TVR + PR PR 0 4 12 24 48 eRVR: HCVRNA© undetectable by author at 4 & 12 weeks Time Point Criterion Stopping Rule Wk ESCMID4 or 12 HCV Online RNA > 1000 IU/mL Lecture LibraryDiscontinue all therapy Wk 24 Detectable HCV RNA Discontinue PR Any Discontinuation of PR for any reason Discontinue TVR Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011. Boceprevir in Genotype 1 Patients . 800 mg (four 200-mg capsules) q8hr with meal or light snack Treatment Naïve w/o cirrhosis BOC + PR Early response stop at Wk 28: 59% PR BOC + PR PR Previous Relapsers or Partial Responders w/o cirrhosis PR BOC + PR PR Pts with cirrhosis or Null Responders PR BOC + PR 0 4 8 12 24 28 36 48 Wks Early response: HCVRNA undetectable at 8 & 24 weeks . All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks . If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks . EMA label recommends fixed-duration therapy for all trt-expd patients: LI + 32 wks triple + 12 wks PR © by author Time Point Criterion Stopping Rule Wk 12ESCMID HCV Online RNA ≥ 100 IU/mL LectureDiscontinue Library all therapy Wk 24 Detectable HCV RNA Discontinue all therapy Any Discontinuation of PR for any reason Discontinue BOC Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011. Advantages and disadvantages of triple therapy with BOC and TVR Advantages Disadvantages – Increased SVR rates1,2 – Complex treatment regimens2 – Potential for shorter – Development of resistance2,3 1,2 treatment duration – Increased side effect and – Potential cure for difficult- toxicity burden and risk of DDIs2 to-treat patients – Limited efficacy in some patient subgroups © by author ESCMID Online Lecture Library 1. Ghany et al. Hepatology 2011; 54: 1433–44; 2. Ferenci & Reddy. Antivir Ther 2011; 16: 1187–201; DDI = drug-drug interactions 3. Pawlotsky. Hepatology 2011; 53: 1742–51 Which patients are easy to treat? Influence of fibrosis on SVR with PI SPRINT-2: Treatment-naive G1 patients1 ADVANCE: Treatment-naive G12 (data from TVR12 + PegIFN/RBV arm) 100 78 75 67 67 62 52 50 41 SVR (%) SVR © by author 25 211 213 22 14 226 45 313 319 42 34 290 73 0ESCMID Online Lecture Library F0–2 F3/F4 F0–2 F3/F4 BOC + PegIFN/RBV 48 weeks BOC + PegIFN/RBV RGT 1.
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