LA TERAPIA PER HBV ed HCV Cosa c è di nuovo?

LA TERAPIA PER HBV ed HCV Cosa c è di nuovo? Alfredo Alberti Department of Molecular Medicine Molecular Hepatology Unit Venetian Institute of Molecular Medicine University of Padova ITALY

THERAPY OF HBV and HCV CHRONIC INFECTION two different strategies with an identical aim HBV : DISEASE CONTROL BY COMPLETE VIRUS SUPPRESSION WITH LONG-TERM ANTIVIRAL THERAPY HCV : DISEASE CONTROL BY VIRUS ERADICATION

THERAPY CHRONIC HEPATITIS B 2014 Option A : PEG-IFN (12 mo goal : immune control) depending on : Contraindications Patient s motivation Age ALT / Histologic activity HBV genotype (A and B better) Option B : NUCs Entecavir or Tenofovir (long-term virus suppression) Option C : PEG-IFN followed by NUC with PEG-IFN failure 3

Long-term with ETV or TDF therapy for CHB Viral suppression in >95% naïve/nuc-r patients ALT normalization in ~85% No major safety issues Fibrosis regression in >80% chronic hepatitis Fibrosis regression in >50% early cirrhotics Almost complete prevention of decompensation Reduction but no elimination of HCC risk

How Can We Cure Chronic HBV Infection? 2 Deplete or silence cccdna 1 Antiviral suppression 3 Reactivate disregulated antiviral Immunity HBV Virion ~10 ng/ml ~80% HBV Virion HBV Filament HBV Sphere HBV Virion ~10 ng/ml HBV HBV Virion Filament ~1 g/ml HBV Filament HBV Sphere ~100 g/ml HBV Sphere ~10 ng/ml ~10 ng/ml ~1 HBV g/ml Virion ~1 g/ml HBV ~100 Filament g/ml ~100 HBV g/ml Sphere ~80% HBV Virion HIGH ~10 ng/ml HBV ~85% HBV Virion Filament ~1 g/ml ~90% HBV Filament HBV HBsAg Sphere ~100 g/ml HBV Sphere COPY # ~80% HIGH ~80% HIGH ~10 ng/ml ~85% ~1 g/ml ~90% HBsAg ~10 ng/ml ~85% ~1 g/ml ~90% HBsAg ~100 g/ml ~100 g/ml COPY # COPY # ~80% HIGH MHBsAg LOW ~85% ~90% HBsAg HBV Virion COPY ~80% HIGH ~85% MHBsAg LOW HBV Filament ~80% # COPY # HIGH ~85% MHBsAg HBV Sphere HBsAg ~90% HBsAg LOW ~90% COPY # COPY # ~10 COPY ng/ml # COPY # ~1 g/ml LHBsAg HBV Virion HBV Filament ~5% HBV Sphere ~1% ~100 g/ml MHBsAg LOW ~5% LHBsAg HBV Virion HBV Filament HBV MHBsAg LOW Sphere ~1% HBV Virion LHBsAg ~10 ng/ml HBV Filament ~1 g/ml ~5% HBV COPY HBV Filament HBV Sphere Sphere # ~100 ~1% g/ml MHBsAg LOW ~5% ~1% LHBsAg ~10 ng/ml ~1 ~80% g/ml HIGH ~10 COPY ng/ml ~1 # g/ml ~100 ~85% g/ml COPY ~1 # g/ml ~100 ~90% g/ml HBsAg ~100 g/ml COPY # ~5% ~5% ~1% LHBsAg ~1% LHBsAg ~80% HIGH ~85% ~90% HBsAg COPY HIGH ~80% # HIGH ~85% ~90% HBsAg ~80% HIGH MHBsAg ~85% LOW ~90% HBsAg ~85% ~90% HBsAg COPY # COPY # COPY # COPY # MHBsAg LOW MHBsAg LOW LHBsAg HBV Virion COPY HBV Filament ~5% MHBsAg HBV MHBsAg LOW Sphere ~1% LOW # ~5% ~1% LHBsAg ~10 COPY ng/ml # COPY ~1 # g/ml COPY # ~100 g/ml ~5% ~5% ~1% LHBsAg ~5% ~1% LHBsAg ~1% LHBsAg ~80% HIGH COPY # LOW COPY # ~85% ~5% ~90% HBsAg ~1% PD-1 MHBsAg LHBsAg CD8 + T cell B cell 5

New HBV Treatments Virus Targeting New Nucleos(t)ide Analogues Entry inhibitors sirna antisense oligonucleotides cccdna silencing Immune Targeting TLR agonists Therapeutic vaccination PD-1, PDL-1 Blocking

COMBINATION OF ENTECAVIR plus PD-L1 BLOCKADE AND HBV VACCINE CHRONIC WHV MODEL Entecavir reduced PD-1 expression on CD8 T-cells Combination treatment resulted in enhanced T cell function and sustained immune control of WHV with definitive clearance of chronic infection Liu et al PLOS Pathogens 2014

THERAPY OF HCV IN THE LAST DECADE Lights and shadows of IFN PROOF OF CONCEPT HCV INFECTION CAN BE ERADICATED LIVER (AND EXTRA-HEPATIC) DISEASE CAN BE CURED HOWEVER MARGINAL EFFECT ON INFECTION AND DISEASE BURDEN DUE TO : - limited treatment of mild/asymptomatic cases - limited efficacy in advanced liver disease - many excluded due to side effects/contraindications

STAGES IN THE NATURAL HISTORY OF HCV Minimal Mild Moderate Severe Compensate cirrhosis F0 F1 F2 F3 F4 Decompensated Cirrhosis HCC Death HERAPY Defer Treat or Defer Treat Treatment contraindicated

THERAPY OF HCV the 2013-2014 SOC HCV-2/3/4 DUAL PEG-IFN plus RIBAVIRIN for 24-48 wks HCV-1 TRIPLE FIRST GENERATION PI (BOCEPREVIR/TELAPREVIR) plus PEG-IFN/RIBAVIRIN for 24-48 wks SVR rates : 50-80% Many contraindications and side effects High drop-out rates Complex management High pill burden (up to 18/day 6300 total)

OUTCOMES WITH TRIPLE THERAPY OTTIMO 2013 ON THERAPY VIROLOGICAL RESPONSE 75% Data from 315 HCV-1 patients with F3-F4 SUSTAINED VIROLOGICAL RESPONSE DRUG RESISTANCE SEVERE RASH ANEMIA (< 10 g/dl) SEVERE ANEMIA (< 8 g/dl) EPO USED BLOOD TRANSFUSION REQUIRED PATIENTS HOSPITALISED 57% 25% 4.8% 39% 7% 33% 9% 6%

HCV Life Cycle and DAA Targets NS5A inhibitors Block replication complex formation, assembly Receptor binding and endocytosis Transport and release Translation and polyprotein processing Fusion and uncoating (+) RNA LD ER lumen LD Virion assembly NS3/4 protease inhibitors ER lumen Membranous web LD RNA replication NS5B polymerase RNA inhibitors replication Nucleoside/nucleotide Nonnucleoside Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

NEW COMPOUNDS AVAILABLE IN 2014 SOFOSBUVIR SIMEPREVIR Polymerase (NS5B) inhibitor PI (second wave) inhibitor DACLATASVIR NS5A inhibitor 13

SOFOSBUVIR IFN FREE THERAPY IFN BASED THERAPY

SVR12 (%) SOFOSBUVIR FOR HCV-2 Treatment-Naïve Noncirrhotic Cirrhotic Treatment-Experienced 100% 98% 91% 92% 94% 97% 100% 96% 60% 91% 88% 100% 93% 80% 60% 40% 20% 0% 58/59 10/11 FISSION SOF + RBV 12 wk 85/92 16/17 POSITRON SOF + RBV 12 wk 29/30 2/2 VALENCE SOF + RBV 12 wk 25/26 6/10 FUSION SOF + RBV 12 wk 30/33 7/8 VALENCE SOF + RBV 12 wk 9/9 13/14 LONESTAR-2 SOF + PegIFN + RBV 12 wk Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. Jacobson IM, et al. N Engl J Med. 2013 May 16;368(20):1867-77.

Viral Response Rate (%) Pre-Transplant SOF + RBV to Prevent HCV Recurrence Post-Transplant Virologic Response 100 Post-Transplant Virologic Response 93 80 60 64 40 20 0 41/44* 25/39* Transplant PTVR 12 *3 subjects were >LLOQ at transplant. 1 subject has not reached ptvr12, 1 subject LTFU at Week 8 post transplant. SOF + RBV was effective and well-tolerated in patients with well compensated cirrhosis, and prevented post-transplant HCV recurrence in 64% of patients who had HCV RNA < 25 IU/mL prior to transplant Curry MP, et al. AASLD 2013. Washington, DC. Oral #213

Pre-Liver Transplant Study (SOF+RBV) No Recurrence (n=29) Recurrence (n=10) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days Median days TND No recurrence: 99 Recurrence: 5.5 p <0.001* 28 *Wilcoxon rank sum test. Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation

IFN-Free DAAs COMBINATIONS NI + PI NI + NS5A PI + NS5A + / - Ribavirin NNI + PI +NS5A

Not All Direct-Acting Antivirals are Equal Characteristic Protease Inhibitor * Protease Inhibitor ** NS5A Inhibitor Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Resistance profile Pangenotypic efficacy Antiviral potency Adverse events Good profile Average profile Least favorable profile Poordad F. and Dieterich D. J Viral Hepatitis 2012; 19:449-464 *First generation. **Second/third generation.

COSMOS: SVR12 with SOF (NI) plus SMV (PI) SVR12 (%) GT1b GT1a without Q80K GT1a with Q80K Cohort 1 (F0-F2 Nulls)* [1] Cohort 2 (F3-F4 Naives/Nulls)* [2] 100 80 100 100 89 100 100 100 100 100 89 100 100 83 100 100 89 100 100 100 100 100 100 100 100 100 100 93 88 88 95 96 60 40 20 0 4/ 4 7/ 7 8/ 9 SMV/SOF + RBV 3/ 3 7/ 7 3/ 3 SMV/SOF 6/ 6 12/ 12 8/ 9 SMV/SOF+ RBV SMV/SOF SMV/SOF ± RBV 24 Wks 12 Wks Overall 4/ 4 4/ 4 5/ 6 7/ 17 30/ 30 24/ 27 6/ 6 11/ 11/ 11 11 SMV/SOF + RBV 4/ 4 7/ 7 4/ 4 SMV/SOF 5/ 5 13/ 14 7/ 8 SMV/SOF + RBV SMV/SOF SMV/SOF ± RBV 24 Wks 12 Wks Overall 3/ 3 7/ 8 3/ 3 18/ 18 38/ 25/ 40 26 *Excluding patients who discontinued for nonvirologic reasons. 1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165.

HCV RNA <LLOQ (% patients) All-oral daclatasvir(ns5a) plus sofosbuvir (NI) 100 Genotype 2/3 results 94 86 88 88 86 93 88 Genotype 1 results 93 80 60 40 20 0 Week 4 EOT B: SOF LI + DCV SVR4 SVR12 D: DCV + SOF F: DCV + SOF + RBV Missing SVR24 Week 4 EOT SVR4 SVR12 SVR24 A: SOF LI + DCV C: DCV + SOF E: DCV + SOF + RBV G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk) Adverse events Fatigue 29 50% Headache 16 38% Nausea 16 32% Sulkowski MS, et al. NEJM 2014 Virologic failures G1: Reinfection G3: 1 relapse (baseline A30K); 1 started IFN for LLQ-TD 3 pts missing from SVR4 in G and H were SVR 12 SVR12 in G and H 68/68 to date Ribavirin adds no benefit to SOF+DCV No safety signals Regimen needs evaluation in cirrhosis

Ledipasvir/Sofosbuvir: A Single Tablet Regimen (STR) Ledipasvir Picomolar potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once-daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral activity against HCV GT 1 6 High barrier to resistance Once-daily, oral, 400-mg tablet Ledipasvir/Sofosbuvir STR Once-daily, oral fixed-dose (90/400 mg) combination tablet No food effect >2000 patients treated LDV NS5A inhibitor SOF - NS5B nucleotide polymerase inhibitor SOF - NS5B nucleotide polymerase inhibitor 1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172

SVR12 (%) ION Phase 3 Program (ION-1, ION-2, ION-3) Efficacy Summary SVR rates in different subgroups LDV/SOF LDV/SOF+RBV 100 99 97 98 99 94 93 95 94 96 99 99 80 60 40 20 0 211/ 214 211/ 217 212/ 217 215/ 217 12 Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 GT 1 treatment-naïve including cirrhotics ION-3 GT 1 treatment-naïve non-cirrhotic ION-2 GT 1 treatment-experienced including cirrhotics and PI failures 97% (1886/1952) overall SVR rate 3% (66/1952) did not achieve SVR 1.4% (28) LTFU 0.1% (2) virologic breakthrough (both due to non-adherence) 202/ 215 1.8% (36) relapsed. Patients may be rolled over to a retreatment study 201/ 216 206/ 216 102/ 109 107/ 111 108/ 109 110/ 111

ION-2 (LDV/SOF±RBV x 12 or 24 weeks) LDV/SOF±RBV Safety Summary Patients, n (%) LDV/SOF n=109 12 Weeks 24 Weeks LDV/SOF+ RBV n=111 LDV/SOF n=109 LDV/SOF+ RBV n=111 AEs 73 (67) 96 (86) 88 (81) 100 (90) Grade 3 4 AEs 2 (2) 3 (3) 10 (9) 8 (7) Serious AEs 0 0 6 (6) 3 (3) Treatment D/C due to AEs 0 0 0 0 Death 0 0 0 0 Grade 3 4 laboratory abnormality 5 (5) 15 (14) 9 (8) 27 (24) Hemoglobin <10 g/dl 0 2 (2) 0 9 (8) Hemoglobin <8.5 g/dl 0 0 0 2 (2) Afdhal N, EASL, 2014, O109 Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

ABBVIE 2D and 3D 2D ABT-450/r PI Ombitasvir NS5A inhibitor +/- RBV 3D ABT-450/r Ombitasvir Dasabuvir PI NS5A inhibitor NNI +/- RBV

ABT 450/r + ombitasvir + dasabuvir ± RBV SVR Rates in different groups 3D + RBV, 12 wk 3D RBV, 12 wk 455 473 307 322 148 151 286 297 166 173 119 123 108 109 110 111 102 209 107 109 210 111 207 209 SAPPHIRE-I 1 Treatment-naive SAPPHIRE-II 2 Treatment-experienced PEARL-III 3 Treatment-naive, GT1b Increased incidence of pruritus observed with 3D regimen 1,2,3 High SVR rates achieved with 3D regimen despite baseline resistance-associated variants 4 3D = AbbVie triple combination; GT, genotype; RBV, ribavirin; SVR, sustained virologic response

Poordad et al EASL 2014

HCV -1 POST LIVER TRANSPLANT Kwo et al EASL 2014

MK-5172 (PI) + MK 8742 (NS5A) Phase 2 data HCV-1 naive/ non cirrhotics SVR 97-100% Hezode et al EASL 2014 HCV-1 naive /HIV coinfected SVR 90-97% Sulkowski et al EASL 2014 HCV-1 Cirrhotics/null SVR 94-100% Lawitz et al EASL 2014

FUTURE IMPACT OF IFN-FREE THERAPY Improved efficacy > 90% Extended eligibility > 90% VENETO Treated Predicted 2013-14 2015-2017 Efficient Disease Control Significant Economic Burden 500 7000-8000 10M Cost 150M

THE FUTURE OF HCV THERAPY All Oral Combinations with >90% cure More Efficacy/Safety data needed in advanced disease Costs will influence strategies Individual cure : a reality in few months Disease control : a possibility for many Countries in few years Global HCV eradication-the final goal : can it be achieved in few decades without a vaccine?