HCV Treatment of Genotype 1: Now and in the Future

Transcription

1 HCV Treatment of Genotype 1: Now and in the Future Bruce R. Bacon, MD, FACG James F. King, MD Endowed Chair in Gastroenterology Professor of Internal Medicine Co-Director of the Abdominal Transplant Program Co-Director of the Saint Louis University Liver Center Saint Louis University School of Medicine St. Louis, MO Therapies are directed against non-structural genes of hepatitis C virus NS3 /4A Inhibitors (Protease inhibitor PI) High potency Limited genotypic coverage Low barrier to resistance Paritaprevir, Simeprevir are approved NS5A Inhibitors High potency Multi-genotypic coverage Low barrier to resistance Ledipasvir, ombitasvir, daclatasvir NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pan genotypic coverage High barrier to resistance Sofosbuvir is approved NS5B Non Nucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance Dasabuvir is approved Ribavirin is a non-specific nucleoside analog used in combination with other DAAs hepatitis C therapies Page 1 of 22

2 SVR Decreases but Does Not Eliminate Risk for Liver Related Complications in those with hepatitis C Van der Meer, et al. JAMA 2012:308: AASLD-IDSA Guidance Recommended Regimens Regimen Sofosbuvir + peginterferon + ribavirin Sofosbuvir + ribavirin Sofosbuvir + ledipasvir Paritaprevir/r + dasabuvir+ombitasivr +/- ribavirin (PrOD) Simeprevir + sofosbuvir +/- ribavirin Daclatasvir+sofosbuvir Simeprevir + peginterferon + ribavirin Not Recommended Not Recommended Recommended Recommended Recommended Recommended Not Recommended Recommended Alternative Not Recommended Optimal treatment favored for most patients Optimal in a particular subset of patients in a specific category Treatment is clearly inferior or is deemed harmful. Unless otherwise indicated, such regimens should not be administered AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed Oct 6, Page 2 of 22

3 Four Variables Determine HCV Treatment Choice HCV genotype Cirrhosis status Previous HCV treatment Renal function HCV: Genotype 1A and 1B Treatment Naïve, Non-cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir (HCV RNA <6 M IU/mL) (HCV RNA >6 M IU/mL) Elbasivr/grazoprevir (1b) (-) -NS5A RAVs (1a) 8 12 ION-3 119/123 (97%) 206/216 (95%) 12 C-EDGE 133/135 (99%) 129/131 (99%) PrOD (1b) 12 PEARL III 207/209 (99.5%) PrOD +/- ribavirin (1a) 12 PEARL IV SAPPHIRE-I Simeprevir + Sofosbuvir 12 COSMOS OPTIMIST-1 Daclatasvir + Sofosbuvir 12 ALLY-2 (HIV Coinfected) 97/ (97%) 307/322 (95%) 20/21 (95%) 112/115 (97%) 70/72 (97%) NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. Page 3 of 22

4 HCV: Genotype 1A Treatment Naïve, Compensated Cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 12 ION-1 32/33 (97%) Elbasvir/grazoprevir 1a (-) NS5A RAV 12 C-EDGE 135/138 (98%) total NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016 HCV: Genotype 1B Treatment Naïve, Compensated Cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 12 ION-1 32/33 (97%) PrOD (1b) 12 TURQUISE III 27/27 (%) Elbasvir/grazoprevir 12 C-EDGE % NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016 Page 4 of 22

5 HCV: Genotype 1A/1B Treatment Experienced (PEG-RBV), Non-cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 12 ION-2 98% PrOD (1b) 12 PEARL II SAPPHIRE-II (+RBV) 91/91(%) 119/123 (97%) PrOD + ribavirin (1a) 12 SAPPHIRE-II 166/173 (96%) Simeprevir + Sofosbuvir 12 COSMOS OPTIMIST-1 20/21 (95%) 38/40 (95%) Daclatasvir + Sofosbuvir 12 ALLY-2 28/28 (%) Elbasvir + grazoprevir 12 C-EDGE 94-97% 1B and 1A (RAV-) NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. HCV: Genotype 1A Treatment Experienced (PEG/RBV) Compensated Cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 24 ION-2 SOLAR-I Sofosbuvir + ledipasvir+brv 12 ION-2 SOLAR-I Elbasvir+grazoprevir 12 C-EDGE 1A (NS5A RAV-) M28, Q30, L31, H58, Y93 22/22 (%) 74/77 (96%) 96-% 95% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. Page 5 of 22

6 HCV: Genotype 1B Treatment Experienced (PEG/RBV), Compensated Cirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 24 ION-2 SOLAR-I Sofosbuvir + ledipasvir+rbv 12 ION-2 SOLAR-I 22/22 (%) 74/77 (96%) 22/22 (%) 74/77 (96%) PrOD 12 TURQUOISE-III 33/33 (%) Elbasvir+grazoprevir 12 C-EDGE 89% (33/37) Total NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. HCV: Genotype 1 Treatment Experienced (SOV+RBV, +/-PEG) Regimen Weeks No-Cirrhosis Sofosbuvir + ledipasvir+rbv 12 50/50 (%) Cirrhosis Sofosbuvir + ledipasvir+rbv % AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. Page 6 of 22

7 HCV: Genotype 1A/1B Treatment Experienced (PI+PEG-RBV), Noncirrhotic Regimen Weeks Study Sofosbuvir + ledipasvir 12 ION-2 83/87 (95%) Daclatasvir+Sofosbuvir 12 ALLY-2 98% Elbasvir+grazoprevir 12 C-EDGE 96% 1B and 1A (RAV-) NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. HCV: Genotype 1A/1B Treatment Experienced (PI+PEG-RBV) Compensated-cirrhosis Regimen Weeks Study Sofosbuvir + ledipasvir + RBV 12 Sofosbuvir + ledipasvir 24 SIRUS 96% ION % Daclatasvir + Sofosbuvir+/- RBV Elbasvir + grazoprevir + RBV 1B and 1A (RAV-) Elbasvir + grazoprevir + RBV 1A + RAV 24 ALLY-2 12 C-EDGE 16 C-EDGE 98% 94% NOT HEAD TO HEAD TRIALS AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. Page 7 of 22

8 HCV: Genotype 1 Treatment Experienced: SMV+SOF or NS5A Experienced No Cirrhosis Deferral of treatment is recommended, pending availability of data for patients with HCV genotype 1, regardless of subtype Cirrhosis Testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended for patients with HCV genotype 1, regardless of subtype, in whom previous treatment with any HCV nonstructural protein 5A (NS5A) inhibitors has failed, and who have compensated cirrhosis, or have reasons for urgent retreatment. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed 4/ 26/2016. Study Design GT 1 Treatment-Naïve (ION-1) Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV GT 1 HCV treatment-naïve patients in Europe and USA Broad inclusion criteria Targeted 20% enrollment of patients with cirrhosis No upper age or BMI limit Platelet count 50,000/mm 3, no neutrophil minimum 865 patients randomized 1:1:1:1 across four arms Stratified by HCV subtype (1a or 1b) and cirrhosis Afdhal et al. NEJM 2014;370: Page 8 of 22

9 : Absence of Cirrhosis vs Cirrhosis GT 1 Treatment-Naïve (ION-1) Absence of Cirrhosis Cirrhosis SVR 179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV Error bars represent 95% confidence intervals. 12 Weeks 24 Weeks GT 1 Treatment-Naïve (ION-3) : 8 weeks of therapy with SOD/LDV leads to high SVR rates in non-cirrhotic naïve patients Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 LDV/SOF LDV/SOF + RBV LDV/SOF GT 1 treatment-naïve patients without cirrhosis Broad inclusion criteria No upper age or BMI limit Opiate substitution therapy allowed 647 patients randomized 1:1:1 across three arms 18 Stratified by HCV subtype (1a or 1b) Kowdley KV et al. NEJM 2014; 370: Page 9 of 22

10 (%) ION 3: With 8 or 12 Wks SOF/LDV ± RBV in Tx-Naive Non-cirrhotic Patients / / /216 SOF/LDV P =.52 P =.70 P = SOF/LDV + RBV SOF/LDV 8 Wks 12 Wks Post hoc analysis notes high SVR rates in those with HCV RNA <6 x 10 6 IU/mL Treatment Duration SOF/LDV SVR (%) with Baseline HCV RNA <6 million IU/mL 8 wks 97 (119/123) 12 wks 96 (126/131) rates did not differ by GT1a vs GT1b in any treatment arm Virologic failure: 23 relapses (11 in 8-wk SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk SOF/LDV) SAPPHIRE-I: PTV/OMB/DSB + RBV in HCV GT1 Inclusion Criteria HCV GT1 Treatment-naïve No cirrhosis No HIV or HBV Double-Blind Paritaprevir/ritonavir/ombitasvir qd + Dasabuvir bid + RBV bid (n=473) Placebo* (n=158) Open-Label Paritaprevir/ritonavir/ombitasvir qd + Dasabuvir bid + RBV bid (n=158) Week Paritaprevir/r (150/ mg) co-formulated with ombitasvir (25 mg) and administered once daily. Dasabuvir (250 mg) + RBV (weight-based dosing) administered twice daily. *After week 12, placebo patients received open-label paritaprevir/r/ombitasvir + dasabuvir + RBV for 12 weeks. Primary outcome:. Feld JJ, et al. N Engl J Med. 2014;370: Page 10 of 22

11 % SAPPHIRE-I Results: ITT Rates 96% 95% 98% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Overall GT1a GT1b Feld JJ, et al. N Engl J Med. 2014;370: Paritaprevir/ RTV Ombitasvir + Dasabuvir ± RBV in GT1 Patients Without Cirrhosis: Is RBV Necessary? (PEARL III and PEARL IV) PEARL III DAA-naive pts with GT1a HCV (N = 305) PTV/RTV/OMB + DBV + RBV (n =) PTV/RTV/OMB + DBV + placebo (n = 205) Wk 12 Wk 24, % PEARL IV DAA-naive pts with GT1b HCV (N =419) PTV/RTV/OMB + DBV + RBV (n = 210) PTV/RTV/OMB + DBV + placebo (n = Ferenci P et al. N Engl J Med 2014;370: Page 11 of 22

12 COSMOS: Study design Week Arm 1 Arm 2 Arm 3 Arm 4 SMV + SOF + RBV SMV + SOF + RBV SMV + SOF SMV + SOF Post-treatment follow-up Post-treatment follow-up Post-treatment follow-up Post-treatment follow-up Enrolment ratio 2:1:2:1 Cohort 1: Prior null responders (METAVIR F0-F2) Final Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4) Interim SVR4 SMV 150 mg QD + SOF 400 mg QD +/- RBV 0/1200 mg/day (BID) BID, twice daily; PegIFN, pegylated interferon; QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response; SVR4, sustained virologic response 4 weeks after planned treatment end;, sustained virologic response 12 weeks after planned treatment end COSMOS: SIM + SOF ± RBV in GT1, Treatment-naïve and Prior Null Responder % 90% 80% 93% % 93% 93% 94% Patients 70% 60% 50% 40% 30% 20% Relapse Non-VF 10% 0% 28/30 16/16 25/27 13/14 82/87 SIM/SOF + RBV SIM/SOF SIM/SOF + RBV SIM/SOF Overall 24 weeks 12 weeks Non-VF = non-virologic failure, patients who did not achieve for reasons other than Lawitz E, et al. Lancet. 2014;384(9956): virologic failure; ITT = intent-to-treat; RBV = ribavirin; SIM = simeprevir Page 12 of 22

13 Proportion of patients with (%) rates for patients receiving SMV + SOF for 12 and 8 weeks versus historical control rate (95% CI: 93.7; 99.9) 150/ week regimen 83 (95% CI: 76.3; 88.9) 128/155 SMV + SOF Historical control 83 8-week regimen Superior: 93.7 >87 Non superior: 76.3 >83 Kwo EASL 2015 GT 1 Treatment-Experienced (ION-2): Study Design Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor Broad inclusion criteria Targeted 20% enrollment of patients with cirrhosis No upper age or BMI limit Platelet count 50,000/mm 3, no neutrophil minimum 440 patients randomized 1:1:1:1 across four arms Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response Afdhal N, et al. N Engl J Med. 2014;370: Page 13 of 22

14 ION 2: With 12 or 24 Wks of SOF/LDV ± RBV by Cirrhosis Status 24 weeks duration for cirrhosis patients (%) No cirrhosis Cirrhosis / 87 19/ 22 LDV/SOF 89/ 89 18/ 22 LDV/SOF + RBV 86/ 87 22/ 22 LDV/SOF 12 Wks 24 Wks 88/ 89 22/ 22 LDV/SOF + RBV rates were significantly lower in cirrhotic vs noncirrhotic patients in the pooled 12-wk arms Previous treatment with protease inhibitor or did not matter Afdhal N, et al. N Engl J Med. 2014;370: SAPPHIRE-II: GT1 Treatmentexperienced Patients Double-Blind Treatment Period PTV/OMB/DSB + RBV (n=297) Placebo (n=97) Open-Label Treatment Period PTV/OMB/DSB + RBV 48-week Follow-up Week 0 Week 12 Week 24 Week 60 Week week Follow-up PTV/OMB/DSB: co-formulated Paritaprevir/r/ombitasvir, 150 mg/ mg/25 mg QD; dasabuvir, 250 mg BID RBV: mg daily according to body weight (<75 kg and 75 kg, respectively) Zeuzem S, et al. N Engl J Med. 2014;370: Primary Analysis: Page 14 of 22

15 SAPPHIRE-II Results: ITT Rates in Treatment-experienced Patients % 90% 80% 70% 96% 96% 97% 95% % 95% 60% 50% 40% 30% 20% 10% 0% Overall GT1a GT1b Prior relapse* Prior partial * ITT rates >95% in all prior peginterferon/ribavirin response groups response* Zeuzem S, et al. N Engl J Med. 2014;370: Prior null response* Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 Cirrhosis Phase 3 Study (TURQUOISE-II): Key eligibility criteria HCV genotype 1 Treatment-naïve and treatment-experienced Compensated cirrhosis (Child-Pugh score <6) HCV RNA >10K IU/mL No HIV or HBV PTV/RTV/OMB + DBV BID +RBV BID (n=208) PTV/RTV/OMB + DBV BID +RBV BID (172) Week Paritaprevir/ RTV (150/ mg) co-formulated with Ombitasvir (25 mg) and administered once-daily. Dasabuvir (250 mg) + RBV (weight-based dosing) administered twice-daily. Primary outcome:. Zeuzem S, et al. NEJM 2014;370: Page 15 of 22

16 TURQUOISE II: 12 vs 24 Wks OMV/PTV/RTV + DSV + RBV in Cirrhotics 80 Genotype 1a wks 24 wks Genotype 1b (%) / 52/ / 13/ / 10/ / 39/ / 115/ Naive Relapse Partial Null Overall Response Response 22/ 18/ Naive 14/ 10/ / 7 3/ 3 25/ 20/ Relapse Partial Null Response Response 67/ 51/ Overall Poordad F, et al. EASL Abstract O163. Poordad F, et al al. N Engl J Med. 2014;370: SIRIUS: Ledipasvir + Sofosbuvir in Compensated Cirrhosis after Failure of Triple Therapy 12 Weeks Alone Versus 24 Weeks With RBV Placebo LDV + SOF + RBV LDV + SOF Weeks 48 Genotype 1 Treatment-experienced: Did not achieve SVR after sequential PR and PR + protease inhibitor therapy, % Patients relapses relapses LDP + SOF +RBV 12 Weeks Bourliere M, et al. Hepatology. 2014;60(suppl): Abstract LB-6 LDP + SOF 24 Weeks Page 16 of 22

17 LDV/SOF + RBV in Treatment- Experienced Sofosbuvir exposed GT 1 HCV * HCV RNA <LLOQ, % Error bars represent 95% CIs. EOT, end of treatment. Wyles, AASLD, 2014, Oral #235 50/51 *One patient who relapsed had GT 3a infection 51/51 50/51 Wk 4 EOT LDV/SOF+RBV for 12 weeks achieved % SVR in GT 1 patients who failed prior SOF-based therapy ALLY-2: Overall Efficacy () DCV+SOF for 8-12 weeks HIV/HCV Naive 12 weeks Experienced 12 weeks Naive 8 weeks Patients achieving, % Naive 12 weeks Experienced 12 weeks Naive 8 weeks Page 17 of 22

18 RUBY-1: OBV/PTV/RTV + DSV ± RBV in Tx-naive, Noncirrhotic GT1 Pts With CKD Interim analysis of multicenter, open-label phase IIIb study in pts with egfr <30 ml/min (N = 20) GT1a: OBV/PTV/RTV QD + DSV BID + RBV* 200 mg QD for 12 wks GT1b: OBV/PTV/RTV QD + DSV BID for 12 wks Patient GT 1a 1a 1a 1a 1b 1a 1a 1a 1a 1a 1b 1a 1a 1a 1b 1b 1b 1b 1b 1a Renal Stage BASE (x0) W1 W2 W4 W8 W12EOT PTW4 PTW12 PTW24 HCV RNA: 25 IU/mL < 25 IU/mL Undetectable Pockros PJ, et al. EASL Abstract L01. RUBY-1: Hematologic Effect of RBV and Overall Safety RBV dose interruption in 8/13 GT1a pts (6 in first 4 wks) Mean Hb Change From Baseline (g/dl) GT1b (DAA only) GT1a (DAA + RBV) GT1b: N = GT1a: N = Pockros PJ, et al. EASL Abstract L01. No tx-related SAEs, discontinuations, or significant changes in liver or renal fxn to date Most AEs mild to moderate AEs Occurring in > 3 Pts, n GT1a: OBV/PTV/RTV + DSV + RBV (n = 13) GT1b: OBV/PTV/RT V + DSV (n = 7) Anemia 8 0 Fatigue 4 2 Diarrhea 4 1 Nausea 5 0 Page 18 of 22

19 HCV NS3/4A inhibitor mg once daily, oral Grazoprevir/Elbasvir HCV NS5A inhibitor 50 mg once daily, oral Grazoprevir (MK-5172) Elbasvir (MK-8742) Broad in vitro activity against most HCV genotypes 1-3 Retains in vitro activity against many clinically relevant RAVs 1-3 All-oral, once-daily regimen 1. Summa V, et al. Antimicrobial Agent Chemother. 2012:56; Coburn CA, et al. ChemMedChem. 2013:8; Harper S, et al. ACS Med Chem Lett. 2012:Mar 2; 3(4): C-EDGE Treatment-NaIve STUDY of a 12-week oral regimen of grazoprevir (MK-5172) / elbasvir (MK-8742) in patients with chronic HCV genotype 1, 4, or 6 infection Patients, % % 75% 50% 25% 0% 95% 299/316 All Patients 92% 99% 144/ /131 % 18/18 GT1a GT1b GT4 80% Non-virologic failure Breakthrough Relapse Zeuzem et al Annals of Internal Medicine /10 GT6 Page 19 of 22

20 EFFICACY AND SAFETY OF GRAZOPREVIR / ELBASVIR +/- RBV FOR 12 OR 16 WEEKS IN PATIENTS WITH HCV G1, G4 OR G6 INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON / RBV (C-EDGE TREATMENT-EXPERIENCED TRIAL) (%, 95% CI) Weeks 16 Weeks No 1RBV +RBV 2 No 3 RBV 4 Breakthrough Rebound Relapse LTFU/Early DC* RBV * LTFU/Early DC = Lost to follow up / Early discontinuation due to reasons other than virologic failure Kwo EASL 2015 GRAZOPREVIR PLUS ELBASVIR IN TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION AND CHRONIC KIDNEY DISEASE (C-SURFER) Patients, (%) % 115/116 Modified Full Analysis Set 94% 115/122 Full Analysis Set GZR/EBR 12 weeks Relapse 1* 1 Discontinued unrelated to Tx 0 6 MFAS = primary efficacy analysis; FAS was a secondary analysis *Noncirrhotic, interferon-intolerant patient with HCV GT1b infection relapsed at FW12 lost to follow-up (n=2), n=1 each for death, non-compliance, withdrawal by subject, and withdrawal by physician (due to violent behavior) Page 20 of 22

21 Coming Soon: Sofosbuvir/Velpatasvir SOF Nucleotide polymerase inhibitor Sofosbuvir (SOF) 1,2 Potent antiviral activity against HCV GT 1 6 Once-daily, oral, 400-mg tablet VEL NS5A inhibitor Velpatasvir (VEL; GS-5816) 3-5 Picomolar potency against GT nd -generation inhibitor with improved resistance profile SOF VEL SOF/VEL FDC Once daily, oral, FDC (400/ mg) 1. Jacobson IM, et al. N Engl J Med 2013;368: ; 2. Lawitz E, et al. N Engl J Med 2013;368: ; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. EASL 2013, poster Results: by Genotype ASTRAL-1, SOF/VEL (%) relapse 2 lost to follow-up 1 withdrew consent relapse Total 1a 1b Genotype 1death Error bars represent 95% confidence intervals. 42 Page 21 of 22

22 If you fail NS5 based therapy SOF/LDV + RBV 24 weeks No NS5A RAVS No Q80K (or other PI RAVs) SOF + SMV + RBV 24 weeks NS5A DAA failure Genotypic resistance testing + NS5A RAVs (Q30, L31, H58, Y93) SOF + SMV + RBV 24 weeks (even if Q80K) +NS5A RAVs +NS3 RAVs (R155, A156, D168) Desperation time 3D + SOF (SOF + SMV + DCV + RBV SOF/LDV + RBV Defer therapy if mild disease or Investigational Regimens Evolution of Therapy in HCV GT1 Sofosbuvir/Ledipasvir Paritaprevir/Ombitasvir/Dasabuvir/RBV Sofosbuvir/Simeprevir % % 90% 80% 75% SVR (cure) 70% 60% 50% 40% 30% 25% 40% 60% 20% 10% 0% 2% 10% 15% IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m PEG/RBV 12m PEG/R/PI 6-PEG/R/PI 6-12m 12m All oral DAA weeks Page 22 of 22