L’inizio di una nuova era? University of Palermo, Italy

L’inizio di una nuova era? University of Palermo, Italy
Malattia da HCV: L’inizio di una nuova era? Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S., University of Palermo, Italy

Obiettivi e strategie di un futuro IFN-free
Ottimizzare la gestione clinica della monoinfezione HCV oggi

HCV: a long list of problems
Efficacy = Difficult to Cure Host Prior non-responders Unfavourable IL28B Cirrhosis Co-morbidities - HIV/OLT/ESRD/DM Virus HCV genotype HCV viral load Resistance Tolerability/Safety = Difficult to Treat Host Age Cirrhosis Co-morbidities ESRD/Autoimmunity/Psych… Treatment RGT Injections, pill burden, Adverse reactions Drug interactions Identification/Access/Uptake

Second wave DAAs for Gt 1 Simeprevir + PR x 24 weeks Sofosbuvir + PR
100 80 60 40 20 SVR12 (%) 89 261/ 292 NEUTRINO Sofosbuvir + PR X 12 weeks PR + SMV PR Prior Relapsers Treatment Naïve 100 80 60 40 20 SVR12 (%) 50 211/ 264 65/ 130 84 208/ 257 67/ 134 QUEST 1 QUEST 2 100 79 80 60 SVR12 (%) 40 36 20 206/ 260 48/ 133 PROMISE Great data BUT – still requires IFN Jacobson I, et al. EASL Abst Manns M, et al. EASL Abst Lawitz E, et al. NEJM 2013

Impact of cirrhosis on SVR12 with Simeprevir + P/R
QUEST-1: Simeprevir + P/R Treatment-Naive GT1 Simeprevir + P/R P/R 100 82 80 58 60 53 SVR12 (%) 40 29 20 188/ 229 60/ 113 18/ 31 5/ 17 n/N = No Cirrhosis Cirrhosis Jacobson I, et al. EASL Abstract 1425.

The tornado of HCV drug development Polymerase inhibitors
Preclinical Phase I Ciluprevir Combinations (± P ± R) Protease inhibitors Phase II > 95% SVR ASV DCV Danoprevir (DNVr) BMS791325 DBV FDV Phase III Vedroprevir VX985 ABT450r MCB DNVr Sovaprevir SOF LDV Filed Faldaprevir (FDV) IDX320 SOF LDV ASV DCV Vaniprevir Narlaprevir GS9669 Ombitasvir Simeprevir (SMV) MK5172 ABT450r MK8742 MK5172 Approved Telaprevir (TVR) Asunaprevir (ASV) Neceprevir Dasabuvir Boceprevir (BOC) Alisporivir (ALV) Dasabuvir Samatasvir BIT225 ACH3102 Sofosbuvir (SOF) Ledipasvir (LDV) GSK SCY635 PEG-IFN  Daclatasvir (DCV) MK8742 ITX5061 ACH2928 Telaprevir (TVR) = VX950 Boceprevir (BOC) = SCH503034 Simeprevir (SMV) = TMC435 Faldaprevir (FDV) = BI201335 Vaniprevir = MK7009 Asunaprevir (ASV) = BMS650032 Danoprevir (DNV) = IMN191/RG7227 Vedroprevir = GS9451 Sovaprevir = ACH1625 MK5172 = 2nd generation Neceprevir = ACH2684 = 2nd generation Narlaprevir = SCH900518 Ciluprevir = BILN2061 Daclatasvir (DCV) = BMS790052 Ledipasvir (LDV) = GS5885 Samatasvir = IDX719 Sofosbuvir (SOF) = GS7977 Mericitabine (MCB) = VX135 = ALS2200 BMS = INX189 Deleobuvir (DBV) = BI discontinued Tegobuvir (TGV) = GS9190 Setrobuvir = ANA598 Lomibuvir = VX222 Filibuvir = PF (discontinued) Nesbuvir = HCV796 (discontinued) Mira- virsen Ombitasvir PPI461 Mericita- bine (MCB) ABT072 PPI668 GS5816 GS9620 Others Deleobuvir GS9669 BMS824393 NS5A inhibitors IDN6556 VX135 BMS791325 Lomibuvir Tegobuvir Setrobuvir BMS986094 IDX184 TMC647055 PSI938 Polymerase inhibitors Coformulation Status 04/2014 (selection)

New DAAs available over the next 12 months
Mid 2014 Triple therapy with PEG IFN and ribavirin Sofosbuvir Nucleotide polymerase inh. All Gts (3) Simeprevir Protease inh. Gt 1, 4 Daclatasvir NS5A inh. Gt 1, 3, 4, 5, 6 Combination of one DAA and ribavirin Combination of two DAAs  ribavirin Mid 2015 Dasabuvir Non-Nuc Polymerase Inh. Pangenotipic (±) Ledipasvir NS5A inh Gt 1 (4?) Sofosbuvir Nucleotide polymerase inh. Ombitasvir NS5A inh. ABT 450/R Protease inh./ Ritonavir Fixed dose combination of three DAAs  ribavirin Fixed dose combination of two DAAs  ribavirin.

Further DAA combos available within 2016
Late 2015 Fixed dose combination of two DAAs Pangenotipic (±) Pangenotipic MK 8742 2nd generation NS5A inh GS 5816 2nd generation NS5A inh. MK 5172 2nd generation protease inh. Sofosbuvir Nucleotide polymerase inh. Idenix Polymerase Inh. ??? 2016 BMS 325 Polymerase Inh. Fixed dose combination of three DAAs Pangenotipic Daclatasvir NS5A inh. - Ultra-short therapy (6 weeks) Pangenotypic One-pill regimen Asunaprevir Protease inh.

Direct-Acting Antiviral Class Profiles: Backbone/Anchor Strategy
NS31 NS32 NS5A1 NS5A2 Non Nuc NS5B Nuc Efficacy Resistance Profile Pangenotypic Activity Adverse events Drug-drug interactions Good profile Average profile Least favorable profile 1 1st generation. 2 2nd generation. Adapted from Schinazi et al, 2013

Direct-Acting Antiviral
Direct-Acting Antiviral Class Profiles: Multi-Drug Combination Strategy Direct-Acting Antiviral NS31 NS32 NS5A1 NS5A2 Non Nuc NS5B Nuc Efficacy Resistance Profile Pangenotypic Activity Adverse events Drug-drug interactions Good profile Average profile Least favorable profile 1 1st generation. 2 2nd generation. Adapted from Schinazi et al, 2013

Genotype 1

Sofosbuvir + PegIFN/RBV: NEUTRINO Phase III Study Design
Wk 12 24 Sofosbuvir + PegIFN/RBV (N = 327) SVR12 Open label Sofosbuvir 400 mg QD + pegIFN alfa-2a 180 µg/wk + RBV mg/day for 12 wks (no response-guided therapy) Treatment-naive, genotype 1, 4, 5, and 6 HCV-infected patients 89% of patients had genotype 1 HCV 17% of patients with cirrhosis HCV, hepatitis C virus; PegIFN, peginterferon; QD, every day; RBV, ribavirin; SVR sustained virologic response. Lawitz E, et al. N Engl J Med. 2013;368:

NEUTRINO Study: Virologic Response
Sofosbuvir + P/R x 12 Wks 100 90 89 80 80 60 SVR (%) 40 GT1, genotype 1; ITT, intent to treat; P/R, peginterferon/ribavirin; SVR, sustained virologic response. 20 ITT SVR12 GT1 Cirrhosis n = 327 n = Lawitz E, et al. N Engl J Med. 2013;368:

NEUTRINO: SOF + P/R SVR12 Rates in Genotype 1, 4-6 by Fibrosis
SVR12 Rates by Biopsy Fibrosis Stage SVR12 Rates by FibroTest Stage 100 97 96 100 91 89 100 85 79 78 80 80 60 60 SVR12 (%) GT, genotype; P/R, peginterferon/ribavirin; SVR, sustained virologic response. SVR12 (%) 40 40 20 16/ 16 124/ 137 34/ 38 32/ 41 20 76/ 78 101/ 105 46/ 54 63/ 86 n = n = F0 F1-2 F3 F4 F0 F1-2 F3 F4 Patel K, et al. AASLD Abstract 1093.

ELECTRON: Sofosbuvir + RBV 12-Wk Regimen in Genotype 1 Patients
Patients With HCV RNA < LOD* Over Time, n/N (%) SOF + RBV Naive (n = 25) Null (n = 10) Wk 1 8/25 (32) 1/10 (10) Wk 2 17/25 (68) 7/10 (70) Wk 4 25/25 (100) 10/10 (100) EOT SVR4 22/25 (88) SVR12 21/25 (84) AE, adverse effect; EOT, end of treatment; HCV, hepatitis C virus; LOD, limit of detection; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. *Analyzed by TaqMan HCV Test 2.0 with LOD of 15 IU/mL. †Includes 1 patient who stopped all treatment due to a serious AE at Wk 8; this patient subsequently achieved SVR12. Gane E, et al. EASL Abstract 14.

Sofosbuvir + Low-Dose RBV
NIH SPARE Study (No Interferon): Sofosbuvir + RBV in HCV GT1-Infected Pts 24 wks sofosbuvir + WB or low-dose (600 mg) RBV in treatment-naive subjects Primarily GT1a (70%), male (66%), black (83%), IL28B CT/TT (81%) Advanced liver disease 23%; median BMI ranged from 26-30; high median HCV RNA Part 1 (Stage F0-F2) Part 2 (All Stages) 100 96 90 90 EOT SVR24 88 80 68 60 48 Patients (%) BMI, body mass index; EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; NIH, National Institute of Health; RBV, ribavirin; SVR, sustained virologic response; WB, weight-based. 40 20 Sofosbuvir + WB RBV Sofosbuvir + Low-Dose RBV Sofosbuvir + WB RBV N = 10 N = 50 Osinusi A, et al. JAMA. 2013;310:

Response-Guided Treatment
Simeprevir + PEG/RBV in GT1, Tx-Naive Patients: QUEST-1/2 Phase III Trial Design Response-Guided Treatment SMV 150 mg QD + P/R P/R P/R N = 521* Placebo + P/R P/R P/R N = 264† Wk 12 24 48 72 RGT in simeprevir arm: if HCV RNA < 25 IU/mL at Wk 4 and undetectable at Wk 12, complete treatment at Wk 24; otherwise, continue treatment to Wk 48 Stopping rules If HCV RNA > 1000 IU/mL Wk 4, stop SMV/placebo If HCV RNA < 2 log10 IU/mL reduction at Wk 12, or confirmed > 25 IU/mL at Wk 24 or 36, stop all treatment GT, genotype; PEG/RBV, peginterferon/ribavirin; P/R, peginterferon alfa-2a 180 µg/wk + ribavirin mg/day; QD, every day; RGT, response-guided treatment; SMV, simeprevir; Tx, treatment. *QUEST-1: n = 264; QUEST-2: n = 257. †QUEST-1: n = 130; QUEST-2: n = 134. Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract 1413.

Simeprevir + PEG/RBV: Phase III QUEST-1: Impact of Subtype & Fibrosis Stage in GT1
Overall GT1a GT1b F0-F F F4 100 90 100 83 80 78 80 71 80 58 60 60 52 60 50 49 SVR (%) 40 40 26 29 20 20 GT, genotype; pegIFN/RBV, peginterferon/ribavirin; SVR, sustained virologic response. Simeprevir PegIFN/RBV Simeprevir PegIFN/RBV SVR: GT1b > GT1a SVR is lowest for patients with GT1a and baseline Q80K mutation SVR: F0-F2 > F4 Jacobson I, et al. EASL Abstract 1425.

COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV: Phase IIa Study Design
4 12 24 36 48 Wk Arm 1 SMV + SOF + RBV Posttreatment follow-up Arm 2 SMV + SOF Posttreatment follow-up Enrolment ratio 2:1:2:1 Arm 3 SMV + SOF + RBV Posttreatment follow-up Arm 4 SMV + SOF Posttreatment follow-up GT, genotype; HCV, hepatitis C virus; QD, every day; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir. Cohort 1: previous null responders (METAVIR F0-F2) Cohort 2: treatment naive and previous null responders (METAVIR F3-F4) SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day Jacobson I, et al. AASLD Abstract LB-3. Lawitz, et al. EASL Abstract 165.

Prevalence of Q80K Mutations by Region in Phase III Simeprevir Studies
Patients, n/N (%) All GT HCV GT1a HCV GT1b HCV Overall 274/2007 (13.7) 269/911 (29.5) 5/1096 (0.5) Europe 76/1254 (6.1) 73/377 (19.4) 3/877 (0.3) North America 185/538 (34.4) 185/385 (48.1) 0/153 (0) South America 2/60 (3.3) 2/22 (9.1) 0/38 (0) Includes 15 subjects with non-1a/b GT FDA, US Food and Drug Administration; GT, genotype; HCV, hepatitis C virus. FDA advises Q80K polymorphism testing when using simeprevir Lenz O, et al. AASLD Abstract 1101.

Combination of Sofosbuvir (NUC) and Simeprevir (PI): COSMOS
Cohort 1 (F0-F2 Nulls): SVR12 (N = 80, all arms) Cohort 2 (F3-F4 Naives/Nulls): SVR12 (N = 87, all arms) SMV + SOF + RBV SMV + SOF 100 100 96.3 100 93.3 92.9 93 93 93 79.2 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 20 AE, adverse effects; BL, baseline; GT, genotype; NUC, nucleotide analogue; PI, protease inhibitor; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. 20 19/24 14/15 26/27 13/14 28/30 16/16 25/27 13/14 24-Wk Arms 12-Wk Arms 24-Wk Arms 12-Wk Arms Relapse in 3 pts in Cohort 1 and 3 pts in Cohort 2; all with GT1a and GT2 with Q80K polymorphism at BL AEs (anemia and indirect bilirubin increases) largely confined to RBV arms SVR in patients with GT1a and Q80K+ = 88% to 100% Jacobson I, et al. AASLD Abstract LB-3. Lawitz E, et al. EASL Abstract 165.

DCV + SOF for Previously Treated or Untreated Chronic HCV Infection
Wk 1 Wk 12 Wk 24 SVR12, % N = 15 SOF DCV + SOF 100 N = 14 DCV + SOF 100 126 HCV GT-1 Treatment Naive N = 15 DCV + SOF + RBV 100 N = 41 DCV + SOF 100 BOC, boceprevir; DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir; SVR, sustained virologic response; TVR, telaprevir. N = 41 DCV + SOF + RBV 95 41 HCV GT-1 TVR/BOC Treatment Failures N = 21 DCV + SOF 100 N = 20 DCV + SOF + RBV 95 Sulkowski MS, et al. N Engl J Med. 2014;370:

EASL HCV Guidelines 2014: Genotype 1
Options for Therapy Genotype 1* PegIFN/ribavirin + sofosbuvir: 12 wks (A1) PegIFN/ribavirin + simeprevir†: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously untreated pts and prior relapsers (A1), or 36 wks of pegIFN/ribavirin in previous partial responders and null responders (B1) PegIFN/ribavirin + daclatasvir (genotype 1b only; B1): 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir (response-guided therapy) (B2) Sofosbuvir + ribavirin: 24 wks for interferon-intolerant pts only, where no other interferon-free option available (B2) Sofosbuvir + simeprevir: 12 wks (ribavirin may be added for previous nonresponders & cirrhotics) (B1) Sofosbuvir + daclatasvir: 12 wks in previously untreated pts; 24 wks in treatment- experienced patients (including TVR/BOC-experienced patients) (ribavirin may be added in previous nonresponders and cirrhotics) (B1) BOC, boceprevir; HCV, hepatitis C virus; pegIFN, peginterferon; TVR, telaprevir. *In settings where recommended options are not available, treatment with pegIFN/ribavirin + TVR or BOC remains acceptable. †Not recommended in pts with genotype 1a and detectable Q80K polymorphism. EASL. J Hepatology. 2014;60:

ION-2[3]: Treatment-experienced HCV GT1; 20% cirrhotics (N = 440)
Phase III Studies of SOF/LDV FDC ± RBV for 12 or 24 Wks in GT1 Patients Wk 12 Wk 24 SVR12, % 99 97 98 SOF/LDV (n = 214) ION-1[1,2]: Treatment-naive HCV GT1; cirrhosis in 15% to 17% per arm (N = 865) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Wk 12 Wk 24 94 96 99 ION-2[3]: Treatment-experienced HCV GT1; 20% cirrhotics (N = 440) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response. SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure 1. Mangia A, et al. EASL Abstract O Afdhal N, et al. N Engl J Med. 2014;370: Afdhal N, et al. N Engl J Med ;370:

Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647)
ION-3: Phase III Study of SOF/LDV FDC ± RBV for 8-12 Wks in Tx-Naive Noncirrhotic GT1 Patients Wk 8 Wk 12 SVR12, % SOF/LDV (n = 215) 94 93 95 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response; Tx, treatment. Kowdley KV, et al. N Engl J Med. 2014;

Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1: ION-2 Special Subgroups
Wk 12 Wk 24 SVR12, % SOF + LDV 86% ION-2 N = 22 Treatment-Experienced Cirrhotics N = 22 SOF + LDV + RBV 82% N = 22 SOF + LDV 100% N = 22 SOF + LDV + RBV 100% LDV, ledipasvir; NUC, nucleotide; PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. SOF + LDV 94% ION-2 N = 66 Treatment- Experienced PI Failures N = 64 SOF + LDV + RBV 97% N = 50 SOF + LDV 98% N = 51 SOF + LDV + RBV 100% Afdhal N, et al. N Engl J Med. 2014;370:

SOF + GS-5816 in Treatment-Naive Noncirrhotic Patients With GT1-6 HCV
Open-label phase II study N = 154 patients randomized to 12 wks SOF + GS mg or 100 mg daily GS-5816: investigational NS5A inhibitor 100 93 93 SOF + GS mg SOF + GS mg 80 GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir; SVR, sustained virologic response. 60 SVR12 (%) 40 20 25/27 25/27 Genotype 3 Everson GT, et al. EASL Abstract O111.

SOF + GS-5816 in Treatment-Naive Noncirrhotic Patients With GT1-6 HCV
Open-label phase II study N = 154 patients randomized to 12 wks’ SOF + GS mg or 100 mg/day GS-5816: investigational NS5A inhibitor 100 100 91 SOF + GS mg SOF + GS mg 80 60 SVR12 (%) GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir; SVR, sustained virologic response. 40 20 n/N = 10/11 10/10 Genotype 2 Everson GT, et al. EASL Abstract O111.

ELECTRON: Sofosbuvir/Ledipasvir ± RBV or GS-9669 in Cirrhotic GT1 HCV Pts
Open-label phase II trial SVR12 rate enhanced with addition of RBV or GS-9669 Wk 12 SVR12, % 70 100 SOF/LDV FDC (n = 10) Treatment-experienced pts with HCV GT1, F4 (N = 19) SOF/LDV FDC + RBV (n = 9) FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; QD, once daily; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. David R. Nelson, MD: ELECTRON is a combination of many small ,phase II studies. The arms we address on this slide are evaluating sofosbuvir/ledipasvir, the single-pill fixed-dose combination, with and without ribavirin and with or without the nonnucleoside polymerase inhibitor GS-9669. This first 2 arms shown are particularly important because the study population was a small number (N = 20) of treatment-experienced cirrhotic patients—probably the most challenging to treat population. As we noted previously in SYNERGY, the sofosbuvir/ledipasvir combination for 12 weeks in treatment-naive patients was associated with a 100% SVR12 rate. In this small, more challenging patient population, the 2-drug combination for 12 weeks resulted in a lower SVR12 rate of 70%. However, by the simple addition of ribavirin, SVR12 rates climbed to 100%. In the 2 arms that included patients with F3 and F4 fibrosis, combining sofosbuvir/ledipasvir with either ribavirin or GS-9669 again resulted in very high cure rates. These data suggest that 2-drug therapy (including a nucleotide polymerase inhibitor) for 12 weeks may cure most patients. On the other hand, harder-to-treat populations may require the addition of a third agent. As such, I think many of the discussions we will have in the next years will focus on duration of therapy, number of antiviral agents, and the type of patient population that is being treated. Stefan Zeuzem, MD: I anticipate much debate on the benefits of adding ribavirin vs a third direct-acting antiviral in patients in whom 2-drug therapy may be suboptimal, particularly since generic ribavirin is very inexpensive, and some direct-acting antivirals may be quite expensive. Graham R. Foster, FRCP, PhD: It is important to note that we have reached a time when we are looking at SVR rates of 70% and saying, “This isn’t good enough.” This gives us an idea of how quickly we have moved to a very satisfactory state of affairs. For more information about this study, please see the CCO Capsule Summary at: SOF/LDV FDC + RBV (n = 25) Treatment-experienced pts with HCV GT1, F3 or F4 (N = 51) SOF/LDV FDC + GS-9669 (n = 26) Sofosbuvir 400 mg QD/ledipasvir 90 mg QD; GS mg QD; weight-based RBV mg/day Gane EJ, et al. Gastroenterol. 2014;146: 31

Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631)
SAPPHIRE I & II: Phase III Studies of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Noncirrhotic GT1 Pts Wk 12 SVR12, % SAPPHIRE-I Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473) 96 Placebo (n = 158)* SAPPHIRE-II Treatment-experienced noncirrhotic pts with HCV GT1[3,4] (N = 394) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297) GT, genotype; HCV, hepatitis C virus; NNI, nonnucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. Placebo (n = 97) SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment failure *Placebo recipients crossed over to active treatment regimen at Wk 12. 1. Feld JJ, et al. EASL Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med. 2014;370: Zeuzem S, et al. EASL Abstract O1. 4. Zeuzem S, et al. N Engl J Med. 2014;370:

TURQUOISE II: Phase III Study of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Cirrhotic GT1 Patients Wk 12 Wk 24 SVR12, % DAA-naive cirrhotic pts with HCV GT1; 58% of patients were treatment experienced, and 36% were previous null responders (N = 380) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) 92 96 ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 172) DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; NNI, non-nucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. No significant difference in 12 vs 24 wks; high SVR in all subgroups analyzed ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV mg/day. Poordad F, et al. N Engl J Med. 2014;370:

Ribavirin-Free Therapy in GT1b
Wk 12 SVR12, % PEARL-II[1] ABT450/RTV/Ombitasvir + Dasabuvir (n = 95) 100 GT1b Tx-Experienced ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 91) 97 PEARL-III[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 209) 99 GT1b Tx-Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 210) 99 GT, genotype; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response; Tx, treatment. PEARL-IV[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 205) 90 GT1a Tx-Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 100) 97 1. Andreone P, et al. Gastroenterology Epub ahead of print. 2. Ferenci P, et al. N Engl J Med ;370:

C-WORTHY: MK-5172 + MK-8742 ± RBV in GT1 Patients With Cirrhosis and in Null Responders
Wk 12 Wk 18 SVR4/8, % MK MK RBV (n = 31) 90 97 94 91 100 Treatment-naive patients with GT1 HCV and cirrhosis (N = 123) MK MK-8742 (n = 29) MK MK RBV (n = 32) MK MK-8742 (n = 31) MK MK RBV (n = 31) Patients with GT1 HCV and null response to pegIFN/RBV (N = 130) GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. MK MK-8742 (n = 33) MK MK RBV (n = 33) MK MK-8742 (n = 32) MK mg once daily; MK mg once daily, RBV mg divided twice daily. Lawitz E, et al. EASL Abstract O61.

AI : Phase IIb Study of Daclatasvir + Asunaprevir + BMS in Noncirrhotic GT1 HCV Patients Stratified by GT1 subtype and biopsy-confirmed cirrhosis Wk 12 SVR12*, % Daclatasvir + Asunaprevir + BMS mg BID (n = 80) 89 90 Tx-naive pts with GT1 HCV (N = 166) Daclatasvir + Asunaprevir + BMS mg BID (n = 86) BID, twice daily; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; P/R/ peginterferon/ribavirin; SVR, sustained virologic response; Tx, treatment. Daclatasvir 30 mg BID; asunaprevir 200 mg BID *Modified ITT analysis: missing data, breakthrough, relapse, or addition of P/R equals failure. Everson GT, et al. AASLD Abstract LB-1.

SOF + RBV ± PegIFN Administered ≤ 48 Wks at Physician’s Discretion
100 SVR4 SVR12 *Defined as LLOD or LLOQ, depending on center. 80 74 69 60 57 56 60 50 Undetectable HCV RNA (%)* 40 20 25/36 16/28 20/27 12/20 5/9 4/8 Overall SOF + RBV SOF + PEG/RBV Response, n/N (%) Overall SOF + RBV SOF + PEG/RBV SVR2 SVR12 SVR4 SVR 25/36 (69) 16/28 (57) 20/27 (74) 12/20 (60) 5/9 (56) 4/8 (50) Overall failure Relapse 2/36 (6) 4/28 (14) 1/27 (4) 2/20 (10) 1/9 (11) 2/8 (25) On-treatment nonresponse 1/36 (3) 1/28 (4) 1/8 (13) Death 8/36 (22) 7/28 (25) 6/27 (22) 6/20 (30) 2/9 (22) LLOD, lower limit of detection; LLOQ, lower limit of quantification; PEG, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. Forns X, et al. AASLD Abstract 1084.

Outcomes in Patients With Cirrhosis
Trial Regimen Duration, Wks SVR in Advanced Fibrosis, % COSMOS[1,2] SMV + SOF ± RBV 12-24 93-100 Electron[3] SOF + LDV 12 70 SOF + LDV + RBV 100 SOF + GS9669 Electron-2[4] Child B 65 ION-2[5] SOF + LDV ± RBV 82-86 24 Turquoise-II[6] GT1a ABT-450/r + OBV + DSB ± RBV 89-94 GT1b 99-100 DSB, dasabuvir; GT, genotype; LDV, ledipasvir; OBV, ombitasvir; r, ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. 1. Sulkowski M, et al. EASL Abstract O7. 2. Lawitz E, et al. EASL Abstract O Gane EJ, et al. AASLD Abstract Gane EJ, et al. EASL Abstract O6. 5. Afdhal N, et al. N Engl J Med. 2014;370: Poordad F, et al. N Engl J Med. 2014;370:

Genotype 2

FISSION: SVR12 in Genotype 2 Patients by Fibrosis Level
Wk 12 Wk 24 Randomized, open-label phase III trial 20% to 21% had cirrhosis; 72% had GT3 Sofosbuvir 400 mg QD + RBV mg/day (n = 256) Treatment-naive pts with GT2/3 HCV (N = 499) Genotype 2 98 100 PegIFN + RBV 800 mg/day (n = 243) 91 82 80 62 60 SVR12 (%) GT, genotype; HCV, hepatitis C virus; PegIFN, peginterferon; QD, once daily; RBV, ribavirin; SVR, sustained virologic response. 40 Sofosbuvir + RBV 20 PegIFN + RBV n/N = 58/59 44/54 10/11 8/13 No Cirrhosis Cirrhosis Gane E, et al. EACS Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:

FISSION: Better Tolerability Profile With Sofosbuvir/RBV vs PegIFN/RBV
Grade ≥ 3 AEs: 7% with SOF/RBV vs 19% for pegIFN/RBV Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegIFN/RBV GT2/3 Pts, AEs Occurring in ≥ 15% in Either Arm, % SOF/RBV (n = 256) PegIFN/RBV (n = 243) P Value Fatigue 36 55 < .0001 Headache 25 44 Nausea 18 29 .0057 Insomnia 12 Rash 9 17 .0052 Diarrhea .0075 Irritability 10 .0328 Decreased appetite 7 .0001 Myalgia 8 .0060 Pruritus .0009 Influenzalike symptoms 3 Chills AE, adverse effect; GT, genotype; PegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir. Gane E, et al. EASL Abstract 5.

FUSION: Sofosbuvir + RBV by Fibrosis Level in Treatment-Experienced GT2 Pts
Randomized, double-blind, phase III trial 62% to 64% had GT3 HCV; 33% to 35% had cirrhosis; 75% to 76% were previous relapsers 100 SOF + RBV for 12 wks 96 100 SOF + RBV for 16 wks 78 80 60 60 SVR12 (%) GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. 40 20 n/N = 25/26 23/23 6/10 7/9 No Cirrhosis Cirrhosis Jacobson IM, et al. N Engl J Med ;368: Genotype 2

POSITRON: Sofosbuvir + RBV in GT2/3 IFN-Unwilling/Intolerant/Ineligible Pts
Randomized, double-blind, placebo-controlled phase III trial No cirrhosis Cirrhosis Wk 12 100 92 94 80 IFN-unwilling, IFN-intolerant, or IFN-ineligible pts with GT2/3 HCV (N = 278) SOF 400 mg QD + RBV mg/day (n = 207) 60 GT, genotype; HCV, hepatitis C virus; IFN, interferon; QD, once daily; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. SVR12 (%) 40 Placebo (n = 71) 20 85/92 16/17 GT2 Jacobson I, et al. EASL Abstract 61.

PegIFN wkly + RBV 1000 mg or 1200 mg
LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Exp’d GT2/3 HCV Pts Single-arm trial of pts with treatment failure on P/R Approximately 50% with compensated cirrhosis Wk 12 Pts with HCV GT2 or GT3 and previous treatment failure with P/R (N = 47) SOF 400 mg QD + PegIFN wkly + RBV 1000 mg or 1200 mg 100 100 96 93 80 GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; P/R, peginterferon/ribavirin; QD, once daily; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. 60 SVR12 (%) 40 20 n/N = 22/23 13/14 9/9 GT2 All GT2 F4 GT2 F0-3 Lawitz E, et al. AASLD Abstract LB-4.

Genotype 3

FISSION: SVR12 in Genotype 3 Patients by Fibrosis Level
Randomized, open-label phase III trial 20% to 21% had cirrhosis; 72% had GT3 Wk 12 Wk 24 Sofosbuvir 400 mg QD + RBV mg/day (n = 256) Genotype 3 100 Treatment-naive patients with GT2/3 HCV (N = 499) 80 71 PegIFN + RBV 800 mg/day (n = 243) 61 60 SVR12 (%) GT, genotype; HCV, hepatitis C virus; PegIFN, peginterferon; QD, once daily; RBV, ribavirin; SVR, sustained virologic response. 34 40 30 Sofosbuvir + RBV 20 PegIFN + RBV n/N = 89/145 99/139 13/38 11/37 No Cirrhosis Cirrhosis Gane E, et al. EACS Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:

FUSION: SVR12 With Sofosbuvir + RBV by Genotype and Fibrosis Level
Randomized, double-blind, phase III trial 62% to 64% had GT3 HCV; 33% to 35% had cirrhosis; 75% to 76% were previous relapsers 100 Sofosbuvir + RBV for 12 wks Sofosbuvir + RBV for 16 wks 80 63 61 60 SVR12 (%) GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response. 37 40 19 20 14/38 25/40 5/26 14/23 No Cirrhosis Cirrhosis Genotype 3 Jacobson IM, et al. N Engl J Med ;386:

Treatment Experienced
VALENCE: Sofosbuvir + RBV for 24 Wks in GT3 IFN-Naive/Ineligible/Tx Failures Phase III study in Europe Genotype 2/3, naive/experienced Genotype 3 100 94 92 87 80 60 60 SVR12 (%) GT, genotype; IFN, interferon; SVR, sustained virologic response; RBV, ribavirin; TX, treatment. 40 20 86/92 12/13 87/100 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naive Treatment Experienced Zeuzem S, et al. AASLD Abstract 1085.

Impact of Duration on Efficacy of SOF in Treatment-Experienced GT3 Pts
FUSION: 12 wks of SOF/RBV FUSION: 16 wks of SOF/RBV 100 VALENCE: 24 wks of SOF/RBV 87 80 63 61 60 60 SVR12 (%) 37 40 GT, genotype; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. 19 20 14/ 38 25/ 40 87/ 100 5/ 26 14/ 23 27/ 45 n/N = No Cirrhosis Cirrhosis Genotype 3 Jacobson IM, et al. N Engl J Med. 2013;368: Zeuzem S, et al. N Eng J Med [Epub ahead of print]

SOF + RBV Retreatment in GT3 Patients With Previous SOF + RBV Failure
Open-label, nonrandomized trial 34% to 41% compensated cirrhosis No cirrhosis Cirrhosis 100 93 88 80 74 60 SVR12 (%) 47 GT, genotype; PEG, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. 40 20 n = 13/14 7/8 17/23 7/15 12 Wks of SOF + PEG/RBV 24 Wks of SOF + RBV Esteban R, et al. EASL Abstract O8.

LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Experienced GT3 HCV Pts
Single-arm trial of pts with treatment failure on P/R Approximately 50% with compensated cirrhosis Similar rates of SVR12 in pts with and without cirrhosis 100 Wk 12 83 83 83 80 Pts with HCV GT2 or GT3 and previous treatment failure with P/R (N = 47) SVR12 (%) 60 Sofosbuvir 400 mg QD + PegIFN + RBV mg SVR12 (%) 40 GT, genotype; HCV, hepatitis C virus; PegIFN, peginterferon; P/R, peginterferon/ribavirin; RBV, ribavirin; QD, every day; SVR, sustained virologic response. 20 n/N = 20/24 10/12 10/12 GT3 All GT3 F4 GT3 F0-3 Lawitz E, et al. AASLD Abstract LB-4.

EASL HCV Guidelines 2014: Genotype 2-6
Options for Therapy Genotype 2* Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment experienced) (A1) PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1) Genotype 3* Sofosbuvir + ribavirin: 24 wks (unsuitable for treatment-experienced cirrhotics, no specific alternative proposed) (A2) PegIFN/ribavirin + sofosbuvir: 12 wks (A2) Sofosbuvir + daclatasvir: 12 wks (24 wks for treatment-experienced patients) (B1) Genotype 4* PegIFN/ribavirin + sofosbuvir 12 weeks (B1) PegIFN/ribavirin + simeprevir: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously untreated patients & prior relapsers (B1), or 36 wks of pegIFN/ribavirin in previous partial responders & null responders (B1) PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir (response-guided therapy) (B1) Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2) Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics) (B2) Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced patients (ribavirin may be added in previous nonresponders and cirrhotics) (B2) Genotype 5/6* PegIFN/ribavirin + sofosbuvir 12 wks (B1) HCV, hepatitis C virus; pegIFN, peginterferon. *In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable. EASL. J Hepatology. 2014;60:

Daclatasvir + Sofosbuvir ± Ribavirin for GT2/3 HCV Treatment-Naive Patients
Wk 24 n = 16 SOF × 7 days, then DCV + SOF SVR12 = 88% Rx naive GT2 or GT3 (N = 44) n = 14 DCV + SOF SVR12 = 93% n = 14 DCV + SOF + RBV SVR12 = 86% Phase III Trial (NCT ): Currently enrolling DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; Rx, therapy; SOF, sofosbuvir; SVR, sustained virologic response. Wk 12 Naive or experienced GT3 (N = 150) Drug Dosing DCV 60 mg once daily SOF 400 mg once daily DCV + SOF Sulkowski MS, et al. N Engl J Med. 2014;370: ClinicalTrials.gov.

ELECTRON 2: SOF/LDV FDC ± RBV in Diverse Hard-to-Treat Patients
Partially randomized, open-label phase II trial Phase II Trial (NCT ): Currently enrolling Genotype 3, treatment-naive and treatment-experienced patients Study regimens include SOF/LDV ± RBV, SOF + GS-5816 ± RBV Wk 12 SVR12, % 64 100 SOF/LDV FDC (n = 25) Treatment-naive patients with GT3 HCV (N = 51) SOF/LDV FDC + RBV* (n = 26) FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. *Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV mg/day. Additional nonrandomized arms conducted in patients with GT1 HCV not shown. Gane EJ, et al. EASL Abstract O6. Reproduced with permission.

Antiviral Activity of Simeprevir in Patients With Genotypes 2-6 HCV
TMC435-C202: open-label phase IIa study Simeprevir active against all HCV genotypes except GT3 Simeprevir 200 mg QD PegIFN/RBV 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 -1 -2 Mean (± SE) Change From Baseline in HCV RNA (log10 IU/ml) GT, genotype; HCV, hepatitis C virus; PegIFN/RBV, peginterferon/ribavirin; QD, once daily; SE, standard error. -3 -4 -5 -6 10h 2 3 4 5 6 7 8 9 10 11 21 37-42 Time (Days) Moreno C, et al. J Hepatol. 2012;56:

Future treatment of hepatitis C
IFN-free and partially RBV-free 8–12 (24) weeks of therapy Different regimens for different genotypes Response rates >>90%

Obiettivi e strategie di un futuro IFN-free
Ottimizzare la gestione clinica della monoinfezione HCV oggi

IFN free DAA will expand the pool of treatable patients
Mild Severe Decomp HCV chronic disease spectrum Currently treated We must strive to obtain appropriate and effective treatment for all patients

Factors affecting treatment choice
Costs and availability of drug (s) Disease stage/type Probability of SVR Urgency of HCV clearance Inability to tolerate P/R Expectancy for newer regimens HCV related extrahepatic disease Costs and availability of drug (s) Patient’s preference Comorbidity

HCV therapy 2014: three different scenarios
Access to new DAAs after «breakthrough»registration mostly unrestricted Off-label and combo use feasible (ATU) P/R containing regimens on the way out Modest warehousing of patients for even better regimens P/R containing regimens, mostly with 1st generation PIs, available Access to new DAAs absent or severely limited (EAPs, RCTs) Off-label and combo use scarcely feasible Extensive warehousing of patients for IFN free DAAs P/R available as the only therapeutic options 1st generation PIs unavailable Access to new DAAs absent Warehousing limited

F3-F4: Priority F2: Reasonable F0-F1: Debatable
Who should be treated: EASL recommendations 2014 In principle, all patients with chronic HCV infection, but in a situation of limited availability: F3-F4: Priority F2: Reasonable F0-F1: Debatable Informed deferral of treatment for patients with mild disease EASL Online Recommendations on Treatment of Hepatitis C, April 2014

How to optimize HCV therapy in a limited-resource scenario
Is still a role left for dual P/R therapy? What is the cost-effective use for triple therapy with 1st generation PIs? How to allocate money on sofosbuvir and simeprevir (daclatasvir, ABT450/R …)?

Identification of naïve HCV Gt1 patients who may benefit from dual therapy with P/R
SVR rates following PegIFN/RBV in 1045 HCV genotype 1 patients. Stratified according to independent predictors for SVR at baseline; Stratified according to baseline predictors and on-treatment virologic response. A. Andriulli, et al J Hepatol 2013

Identification of naïve HCV Gt 1 patients who may benefit from dual therapy with P/R
50 100 <25% 80% 426/1259 (34%) 188/1259 (15%) Outcome after P/R SVR 68 (16%) Outcome after P/R SVR 167 (89%) Strategy No P/R Treat with 1st generation triple therapy (BOC or TPV) Wait for new regimens when feasible Andriulli et al, submitted

Treatment decisions for 2014 in a limited-resource scenario
Can be treated with P/R (all naives): Gt 1, F0 to F2 plus IL 28 cc or RVR after lead-in, no factors reducing IFN responsiveness (obesity, metabolic syndrome) Gt 2 and 3, F2 - F3 Gt 4, 5, 6, F2 - F3 Expected SVR Priority >80% Low 50 to 70% High 40 to 60%

Cost-effective use of 1st generations PIs for HCV Gt 1
Telaprevir Boceprevir Dual Naive No CC No RVR RVR - CC Relapsers +++ ++ Partial responders + Null responders >1 log drop HCV-RNA in lead-in Cammà et al. Hepatology 2012 Cammà al. J Hepatol 2013

Predictors of SVR to Boc in HCV Gt 1 naive pts
2 3 4 Poordad et al. Gastroenterology 2012

Boceprevir plus PR in HCV Gt 1 treatment experienced F3-F4: SVR according to week 8 virological response PPV=72,3% NPV=91,7% Bruno S et al. , submitted

Treatment decisions for 2014 in a limited-resource scenario
Can be treated with P/R plus a 1st generation PI (BOC or TPV): Naive Gt 1, F3 - F4 plus IL 28 not cc or no RVR after lead-in Gt 1 relapsers to P/R, F3 - F4 Gt 1 partial responders to P/R, F3 - F4 Naive Gt 1 with HIV coinfection, F3 - F4 Expected SVR Priority 50 to 65% High 70 to 85% 40 to 50%

Cost Direct costs of HCV Gt1 therapy in naïves
(assuming treatment of F2 to F4) Cost - drugs -monitoring - EPO, G-CSF, blood tx, others TOTAL Expected efficacy Euros for 1 SVR PegIFN/ RBV 48 wks 8.000 1.000 ≈ 40% ≈ BOC/TPV + P/R 36-48 wks ≈ 65% ≈ Sofosbuvir + P/R 12 wks 4.000 500 >90% ≈ Simeprevir 12wks + P/R 48 wks 44.000 8.000 1.00 53.000 >90% ≈ Sofosbuvir + RBV 24 wks 6.000 ≈ 0 >70% ≈ Sofosbuvir + simeprevir  RBV 12 wks 5.000 ≈ 0 >95% ≈

Cost Direct costs of HCV Gt2 therapy in naïves
(assuming treatment of F2 to F4) Cost - drugs -monitoring -EPO, G-CSF, blood tx, others TOTAL Expected efficacy Cost (Eu) for 1 cure PegIFN/RBV 24 wks 6.000 5.000 1.000 ≈ 85% ≈ Sofosbuvir + P/R 12 wks 4.000 500 >90% ≈

Cost-Effectiveness of Sofosbuvir-Based Triple Therapy for Untreated Patients With Genotype 1 Chronic Hepatitis C In untreated Gt 1 chronic hepatitis C patients, at a willingness-to-pay threshold of Eu 25,000 per life year gained, sofosbuvir: was cost effective compared with boceprevir in all strategies with the exception of cirrhosis and IL28B CC patients was cost effective compared with telaprevir in IL28B non-CC and Gt 1a patients, but not cost-effective in IL28B CC and in cirrhosis Petta S et al. , Hepatology 2014

THERAPY OF HEPATITIS C IN 2014 : WHOM TO TREAT
OLISTIC VIEW : all infected individuals REALISTIC VIEW : treat according to RISK / BENEFIT COST / BENEFIT

L’inizio di una nuova era? University of Palermo, Italy

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