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 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

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 < 4-8 x 105 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

ESCMIDBefore Treatment Online Time on Lecture Treatment with DAA Library 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

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

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. Poordad et al. N Engl J Med 2011; 364:1195–1206 & Suppl. appendix; RGT = response guided therapy 2. Jacobson et al. N Engl J Med 2011; 364: 2405–16 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% – PEG IFN + RBV + TEL/BOC (low potency low genetic barrier less convenience more side effects) • New standard of care© efficacy by relatedauthor to PEG + RBV backbone : – 63-88% naive & relapsers – < 50% in partial & null response ESCMID• Increased response Online rate and shorterLecture Tx duration thanLibrary PEG+RBV • Several challenges ( AE, DDI, Complex schedules, adherence, resistance)

Hepatitis C drug therapy

• The present • The future

nd 2nd. Generation PI Asunaprevir (2 gen PI) Triple MK 5172 (3rd gen PI) Peg IFN a Faldaprevir Daclatasvir (1st gen NS5A) Containing Simeprevir Regimens NUC Asunaprevir (2nd gen PI) + Daclatasvir Triple

Sofosbuvir GS 5885 (NS5A) + GS59451 (PI)

2013 2014 2015 2016 2017

2nd wave PI+ PEG RBV in HCV G1 : medium potency higher convenience (1 pill/d; less DDI; less AE): Phase III studies

PI N Treatment % SVR % qualified % SVR in (% duration Overall for short short tx Cirrhotics) In treatment cirrhotics Faldaprevir1 652 12-24 w 24- 414/570 75% 402/459 (120 vs 240 (31; 5%) 48 RGT (73%) 88% mg) Simeprevir 521 12 w 419/521 91% 383/437 Quest 12 & ( 50; 10%) 24-48 w 80% 88% Quest23 RGT© by author29/48 (60%) ESCMID Online Lecture Library 1. Ferenci F et al EASL 2012 2. Manns MP et al EASL 2012 3. Jacobson EASL 2012 25 3rd wave PI + PEG + RBV : high potency higher convenience (1 pill/d; less DDI; less AE): Phase II study

PI N Treatment % SVR % qualified % SVR (% duration (95% CI) for short (95%CI) in Cirrhotics) In treatment short tx cirrhotics MK5172 66 12-24 w 61/66 91% 98% 100 mg ((0) RGT 24- (92%) 48w © by author ESCMID Online Lecture Library Manns MP et al EASL 2012

26 NUC Polymerase inhibitor + PEG+ RBV in HCV G1,4,5,6: high potency high resistance barrier Phase III study

PI N Treatment % SVR overall (% Cirrhotics) duration I% n cirrhotics Sofosbuvir 327 12 w 295/327 (90%) (17%) 80%

27 Genetic barrier to resistance can be increased by combination drug regimens PEG IFN + RBV +DAA monotherapy

Baseline

Sensitive virus Resistant virus Previous Null Responders: Quad Therapy

Daclatasvir (NS5A) + Asunaprevir (PI) Danoprevir/r (PI) + Mericitabine (Nuc) + PegIFN/RBV x 24 wks (Quad) + PegIFN/RBV x 24 wks (Quad)[3] 88% GT1a 61% GT1a 100 93*[2] 100 90[1] 84 80

60 60

n/N = 9/10 38/41 n/N = 62/74 0 0 *AsunaprevirESCMID QD and BID combined. Online Lecture Library . Quad therapy may be a good option for null responders . Well tolerated BUT cirrhotics excluded 1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79. 3. Feld JJ, et al. AASLD 2012. Abstract 81. Genetic barrier to resistance can be increased by combination drug regimens PEG IFN + RBV +DAA monotherapy

Baseline

Sensitive virus Resistant virus Factors related to response to IFN free DAA combos

. Resistance Barrier . Infected cells cure . Definition – Death rate of infected cells (natural) – Cell cure: Rate of loss of the ability of infected cells to produce virions as “blocked” viral RNA degrades . Related factors – Factors that cannot be modified . Liver disease© by stage author . Host genetics ESCMID– Factors Online that can be modifiedLecture Library . Potency of antiviral (1st phase slope) . Ribavirin use . Treatment duration 31 Pawlotsky JM EASL 2012

Future HCV treatment strategies Next wave of Phase III triple quadrulple regimens

nd 2nd. Generation PI Asunaprevir (2 gen PI) Triple MK 5172 (3rd gen PI) Peg IFN a Faldaprevir Dacltasvir (1st gen NS5A) Containing Simeprevir Regimens NUC Asunaprevir (2nd gen PI) + Daclatasvir Triple

Sofosbuvir GS 5885 (NS5A) + GS59451 (PI)

2013 2014 2015 2016 2017

IFN free Faldaprevir (3rd g PI) + BI 207127(NNUC) + RBV regimens Sofosbuvir + RBV ESCMID Online LectureSimeprebir 23nd g PI) Sofosbuvir Library (NUC) + RBV HCV G2 & G3 (?) Daclatasvir(NS5A) + Sofosbuvir (NUC) + RBV

Ladipasvir (NS5A) + Sofosbuvir (NUC) + RBV

Asunaprevir (2nd gen PI) Daclatasvir (NS5A) + GS 791385

Sofosbuvir in HCV G2 (high potency + high resistance barrier + RBV)

Regimen N Duration Exp/naive Cirrhosis SVR % Sofosbuvir 10 12 w Naive no 10% Sofosbuvir + RBV 59 12 w Naive no 98% Sofosbuvir + RBV 11 12 w Naive yes 91% Sofosbuvir + RBV 118 12 w Exp/Intol no 96% Sofosbuvir + RBV 27 12 w Exp/Intol yes 60% Sofosbuvir + RBV 23 16 w Exp/Intol no 100% Sofosbuvir + RBV 9 16 w Exp/Intol yes 78% © by author Strategy in HCV G 2 : ESCMIDAdd Ribavirin Onlineand increase Lecture treatment Library duration in difficult to treat

Gane D et al. AASLD 2011 Jacobson IM et al. NEJM 2013

33 Sofosbuvir + RBV in HCV G3 (high potency + high resistance barrier + RBV)

N Duration Exp/naive HCV Cirrhosis SVR % Genotype 145 12 w Naive 3 no 61% 38 12 w Naive 3 yes 34% 122 12 w Exp/intol 3 no 37% 40 12 w Exp/Intol 3 yes 19% 40 16 w Exp/Intol 3 no 63% 23 16 w Exp/intol 3 yes 61% © by author Strategy in HCV G 3 : ESCMIDIncrease treatment Online duration Lecture but is not Library enough

Jacobson IM NEJM 2013 34 Sofosbuvir + RBV + …….in HCV G1-4,5,6 (high potency + high resistance barrier + RBV ) Regimen N Duration Exp/naive SVR n/n % Sofosbuvir + RBV 25 12 w Naive 56% Sofosbuvir +RBV 10 12 w Null 10% Sofosbuvir + RBV 124 24 w Naïve 63%

Gane EJ EASL 2013

35 Sofosbuvir + RBV + another DAA.in HCV G1 (high potency + high resistance barrier + RBV )

Regimen N Duration Exp/naive SVR % Sofosbuvir +RBV + Ladipasvir 25 12 w Naive 100% Sofosbuvir +RBV + Ladipasvir 9 12 w Null 100% Sofosbuvir + RBV + GS 9669 25 12 w Naïve 92% Sofosbuvir + RBV + GS 9669 3 12 w Null 100% Sofosbuvir + Simeprevir 27 12 w Null 96% Sofosbuvir+ Simeprevir + RBV 14 12 w Null 92% Sofosbuvir + Daclatasvir 21 24 w NR to 100% BOC/TEL Sofosbuvir + Daclatasvir +© by21 author24 w NR to 100% RBV BOC/TEL ESCMID Online Lecture Library Strategy in HCV G 1 : Add an antiviral to sofosbuvir

36 Gane EJ EASL 2013; Lawitz E CROI 2013; Sulkowski M EASL 2013 SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY

Kowdley KV EASL 2013 Future of anti HCV Tx IFN based Regimens with Antivirals (AE with interferon) More convenience (schedule & duration) Quadruple therapy an option for difficult to treat patients IFN free Easy to treat RBV + one robust antiviral (high potency high genetic barrier) Difficult to treat: HCV G3 increased treatment© by duration author but something is lacking HCV G1 antiviral cocktails: more difficult to treat  more drugs ESCMID Online Lecture Library Where we go: The Future Ten Commandments for the Magic Drug

1 HIGH EFFICACY 2 LOW RESISTANCE (high genetic barrier) 3 FOR ALL-GENOTYPES 4 SHORT DURATION 5 TOLERABILITY 6 PHARMACOKINETIC (Low pill burden) 7 ONLY ORAL ©REGIMEN by author (IFN free) 8 DRUGS INTERACTION ESCMID9 AVAILABLE Online : CIRRHOSIS, Lecture ELD, HIV-HCV… Library 10 COST REDUCTION (access program)

HCV ERADICATION WORLWIDE AD 2013: To treat or to wait ?

• When to treat is an individualised decision made between the physician and patient  5 issues 1. Urgency of treatment 2. Probability of SVR 3. Relative contraindications and probability of side effects © by author 4. Patient motivation 5.ESCMIDSustainability Online of present Lecture and future Librarytherapies AD 2013: To Treat or to wait ? • Treat now: high SVR rates with acceptable side effects can be achieved in many patient groups with an urgent need • Wait: Potential benefits: – with quad or intense oral treatment regimen in difficult-to-treat ©patients by author – with all oral DAA regimens in: ESCMID• IFN intolerant Online or advanced Lecture cirrhotic patients Library • patients with very mild disease, only in the long term