Update in the Management of Hepatitis C: What Does the Future Hold Paul Y Kwo, MD, FACG Professor of Medicine Mdi Medical ldirector, Liver Transplantation tti Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 fax 317-274-3106 3106 email pkwo@iu.edu The components of treatment in HCV infection XRBV NS5a X PEG IFN NS5b NS3 NS5b NNI Copyright 2014 American College of Gastroenterology 1
Direct-Acting Antiviral Agents (DAAs) - Key Characteristics NS3 /4A Inhibitors (Protease inhibitor PI) High potency Limited genotypic coverage Low barrier to resistance NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pan genotypic coverage High barrier to resistance NS5A Inhibitors High potency Multi-genotypic coverage Low barrier to resistance NS5B Non Nucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance Genotype 1 Treatment-Naive Patients Interferon eligible Sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) plus weekly PEG for 12 weeks regardless of subtype (1a or 1b) Alternative Regimen: simeprevir (150 mg) for 12 weeks and weight-based RBV (1000-1200 mg) plus weekly PEG for 24 weeks for genotype 1b or genotype 1a infection in without Q80 polymorphism Patients who are NOT eligible to receive IFN: Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000-1200 mg) for 12 weeks regardless of subtype (1a or1b) Daily sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) regardless of subtype Copyright 2014 American College of Gastroenterology 2
The current standard of care: Genotype 1 patients who have failed therapy Patients who failed therapy without protease inhibitor regardless of IFN eligibility Sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000-1200 mg) for 12 weeks regardless of subtype (1a or 1b) Alternative Regimen: simeprevir (150 mg) for 12 weeks and weight-based RBV (1000-1200 mg) plus weekly PEG for 48 weeks regardless of subtype (1a or 1b), no Q80K testing Alternative Regimen including those who have failed protease inhibitor: and can tolerate IFN: Sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) plus weekly PEG for 12-24 weeks regardless of subtype (1a or 1b) NEUTRINO Study: SVR12 by HCV Genotype (%) s with HCV RNA <LLOQ ( Patients 295/327 261/292 27/28 7/7 Overall GT 1 GT 4 GT 5,6 Error bars represent 95% confidence intervals. Lawitz E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1411. Copyright 2014 American College of Gastroenterology 3
COSMOS Study: Simeprevir + Sofosbuvir ± RBV in GT 1, Treatment-naïve and Prior Null Responder SVR12 Non-VF Relapse 2/30 2/27 1/14 3% 2% 3/87 2/87 SVR 93% 100% 93% 93% 94% 28/30 16/16 25/27 13/14 82/87 SMV/SOF + RBV SMV/SOF Non-VF, patients who did not achieve SVR12 for reasons other than virologic failure SMV/SOF + RBV SMV/SOF SMV/SOF±RBV 24 weeks 12 weeks Overall ITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end The components of SVR in HCV with nucleotide polymerase inhibitor + NS5a for genotype 1 NS5b NS5a Copyright 2014 American College of Gastroenterology 4
Sofosbuvir 400 mg/ledipasvir 90 mg approved for genotype 1 infection 10/10/14 Patient Population Recommended Treatment Duration Treatment-naïve with or without cirrhosis 12 weeks* Treatment-experienced** without cirrhosis 12 weeks Treatment-experienced** with cirrhosis 24 weeks *SOF/LDV for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL **Treatment-experienced patients who have failed treatment with either peginterferon alfa + ribavirin or an HCV protease inhibitor + peginterferon alfa + ribavirin. Study Design GT 1 Treatment-Naïve (ION-1) Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF SVR12 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;370:1889-98 Copyright 2014 American College of Gastroenterology 5
SVR12: 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 SVR12 LDV/SOF + RBV SVR12 LDV/SOF SVR12 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 Stratified by HCV subtype (1a or 1b) Kowdley KV et al. NEJM 2014; 370:1879-88 12 Copyright 2014 American College of Gastroenterology 6
SVR12 (%) ION 3: SVR12 With 8 or 12 Wks SOF/LDV ± RBV in Tx-Naive Non-cirrhotic Patients 100 80 60 40 P =.52 P =.70 P =.30 94 93 95 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 20 8 wks 97 (119/123) 0 202/215 201/216 206/216 12 wks 96 (126/131) SOF/LDV SOF/LDV + RBV SOF/LDV 8 Wks 12 Wks SVR12 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) GT 1 Treatment-Experienced (ION-2): Study Design Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF LDV/SOF + RBV SVR12 SVR12 LDV/SOF LDV/SOF + RBV SVR12 SVR12 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/mm3, 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;370:1483-1493. Copyright 2014 American College of Gastroenterology 7
ION 2: SVR12 With 12 or 24 Wks of SOF/LDV ± RBV by Cirrhosis Status 24 weeks duration for cirrhosis patients 100 95 86 100 99 100 99 100 100 82 SVR12 (%) 80 60 40 20 0 83/ 87 19/ 22 89/ 89 18/ 22 86/ 87 22/ 22 88/ 89 22/ 22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Wks 24 Wks No cirrhosis Cirrhosis SVR12 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;370:1483-1493. The components of SVR in HCV: High SVR rates without a nucleotide polymerase inhibitor coming soon NS3 NS5b NNI NS5a RBV Copyright 2014 American College of Gastroenterology 8
Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 (SAPPHIRE-I): Phase 3 Study Double-Blind Key eligibility criteria HCV genotype 1 Treatment-naïve No cirrhosis No HIV or HBV Double-Blind li PTV/RTV/OMB + DBV BID +RBV BID (n=473) Placebo* (n=158) Open-Label PTV/RTV/OMB + DBV BID +RBV BID (n=158) 0 12 24 Week Paritaprevir/ RTV (150/100 mg) co-formulated with Ombitasvir (25 mg) and administered once-daily daily. Dasabuvir (250 mg) + RBV (weight-based dosing) administered twice-daily. *After week 12, placebo patients received open-label Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV for 12 weeks. Primary outcome: SVR12. Feld JJ, et al. NEJM 2014; 370:1594-603 SAPPHIRE-I Results: ITT SVR12 Rates 96.2% 95.3% 98.0% SVR12, % Patients 455/473473 307/322322 148/151151 All Patients GT1a GT1b Copyright 2014 American College of Gastroenterology 9
Paritaprevir/ RTV Ombitasvir + Dasabuvir ± RBV in GT1 Patients Without Cirrhosis: Is RBV Necessary? (PEARL III and PEARL IV) Wk 12 SVR12, % Wk 24 PEARL III DAA-naive pts with GT1a HCV (N = 305) PEARL IV DAA-naive pts with GT1b HCV (N =419) PTV/RTV/OMB + DBV + RBV (n =100) PTV/RTV/OMB + DBV + placebo (n = 205) PTV/RTV/OMB + DBV + RBV (n = 210) PTV/RTV/OMB + DBV + placebo (n = 209 97 90 99.5 99 Ferenci P et al. N Engl J Med 2014;370:1983-1992. Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 non-responders (SAPPHIRE-II): Phase 3 Study Double-Blind Key eligibility criteria HCV genotype 1 Treatment nonresponder (relapse, partial or null response No cirrhosis No HIV or HBV Double-Blind PTV/RTV/OMB + DBV BID +RBV BID (n=297) Placebo* (n=97) Open-Label PTV/RTV/OMB + DBV BID +RBV BID 0 12 24 Week Paritaprevir/ RTV (150/100 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/ RTV Ombitasvir + Dasabuvir + RBV for 12 weeks. Primary outcome: SVR12. Zeuzem S, et al. NEJM 2014;370:1604-14 Copyright 2014 American College of Gastroenterology 10
SAPPHIRE-II Results: ITT SVR12 Rates >95% in All Prior Peginterferon/Ribavirin Response Groups 95.3% 100% 95.2% SVR12, % Patients 82/8686 65/65 139/146146 Prior Relapse Prior Partial Response Prior Null Response Paritaprevir/ RTV Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 Cirrhosis (TURQUOISE-II): Phase 3 Study Key eligibility criteria HCV genotype 1 Treatment-naïve and treatmentexperienced Compensated cirrhosis (Child- Pugh score <6) HCV RNA >10K IU/mL PTV/RTV/OMB + DBV BID +RBV BID (n=208) PTV/RTV/OMB + DBV BID +RBV BID (172) 0 12 24 Week No HIV or HBV Paritaprevir/ RTV (150/100 mg) co-formulated with Ombitasvir (25 mg) and administered once-daily. Dasabuvir (250 mg) + RBV (weight-based dosing) administered twice-daily. Primary outcome: SVR12. Zeuzem S, et al. NEJM 2014;370:1604-14 Copyright 2014 American College of Gastroenterology 11
TURQUOISE-II Results: ITT SVR12 Rates of 92% to 96% 92 96 P=0.089 SVR12, % Patients SVR 80% in 1a null Responders who Received 12 weeks of therapy 191/208 12 Weeks 208 165/172 172 24 Weeks The current standard of care: Genotypes 2/3 HCV genotype 2, regardless of eligibility for IFN therapy or treatment failure with PEG/RBV : Sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) for 12 weeks cirrhotics may benefit from extension to 16 weeks HCV genotype 3, regardless of eligibility for IFN therapy or treatment failure with PEG/RBV : Sofosbuvir (400 mg) and weight-based RBV (1000-1200 mg) for 24 weeks Alternative regimen: HCV genotype 2&3 PEG/RBV nonresponders: Sofosbuvir (400 mg) and weightbased RBV (1000-1200 mg) plus weekly PEG for 12 weeks in IFN eligible patients Copyright 2014 American College of Gastroenterology 12
FUSION: Sofosbuvir + RBV by Fibrosis Level in Treatment-experienced Genotype 2 100 96 100 Sof + RBV 12 Weeks Sof + RBV 16 Weeks 80 78 SVR R12 (%) 60 40 60 20 Jacobson, et al. NEJM 368:1867-1877 2013. n/n = 25/26 23/23 6/10 7/9 0 No Cirrhosis Cirrhosis RBV = ribavirin VALENCE: Sofosbuvir + RBV for 24 weeks Genotype 3 IFN naïve, ineligible or treatment failures G3 0 12 weeks 24 SOF+RBV (n=250) 93 92 Genotype 3 85 SVR 12 (%) 60 86/92 12/13 85/100 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment-experienced Zeuzem S et al N Engl J Med 2014; 370:1993-2001 Copyright 2014 American College of Gastroenterology 13
Interferon-Free, All Oral Regimens Other/Special Populations Paritapreivr/r, Ombitasvir, Dasabuvir with RBV for 24 weeks for Liver Transplant HCV Patients: Preliminary Efficacy Results s Percentage Patients 34/34 34/34 32/3333 25/2626 No patient had breakthrough One patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O114. Copyright 2014 American College of Gastroenterology 14
Virologic Response with SOF/LDV for 12 Weeks in HIV/HCV Coinfected Noncirrhotic, Treament Naïve Patients with Percentage of Patients h HCV RNA < LLOQ (ITT) ARV - 13/ 13 13/13 13/ 13 12/12 10/10 10/10 ARV + 37/37 37/37 30/30 22/22 Osinusi A et al. 49th EASL; London, England; April 9-13, 2014. Abst. O14. Summary: To be continued The next big advance is here: all oral therapies for genotype 1 that are FDA approved Sofosbuvir/ledipasvir: (no RBV) 8-12 weeks for naïve 24 weeks for non-responder cirrhotic patients Paritaprevir/Ombitasvir/dasabuvir±RBV (approval by end of 2014) 12 weeks for naïve, cirrhotic patients (with RBV) 24 weeks for Genotype 1a null responders 12 weeks no RBV for 1b non-cirrhotics Sofosbuvir/simeprevir also available, not licensed together yet Copyright 2014 American College of Gastroenterology 15
Summary: To be continued Genotype 2 has been largely solved (12-16 weeks) Genotype 3 treatment failure with cirrhosis is now the most problematic to treat Special populations are becoming not so special HIV/HCV patients Post OLT patients Access to therapies will be important The new components of treatment in HCV infection NS3 NS5b NS5a NS5b NNI Copyright 2014 American College of Gastroenterology 16
Paul Y. Kwo, MD, FACG Hepatitis C Therapy has Paralleled Helicobacter pylori Therapy HCV H pylori All Oral Therapy Duration 8-24 weeks Polymerase Inhibitor ± All Oral Therapy, single tablet Protease Inhibitor ± NS5a ± Non-nucleoside Inhibitor ± ribavirin Copyright 2014 American College of Gastroenterology 17