Clinical Management: Treatment of HCV Mono-infection Curtis Cooper, MD, FRCPC Associate Professor-University of Ottawa The Ottawa Hospital- Infections Diseases Viral Hepatitis Program- Director
Industry Investigator: Merck, Vertex, Roche, BI, Janssen, GS, BMS, Abbvie, Idenix Consultant /Advisor: Merck, Vertex, Roche, BI, GS, Abbvie Speaker: Merck, Roche, BI, BMS Government OHTN CIHR Health Canada Ontario MOH CADTH Disclosures
Overview Current & Emerging Therapies Best Practices & Clinical Practice Guidelines
Therapies for Hepatitis C Virus PEG-IFN α / RBV +/- Protease Inhibitor Duration of Tx / RGT Definition of Therapeutic Success Plasma HCV RNA undetectable 6 months post therapy (Sustained Virologic Response=Cure)
Patients (%) Patients (%) Highlights From AASLD 2010 clinicaloptions.com/hepatitis SPRINT-2: Response Rates According to Race 4-wk PR + response-guided BOC + PR 4-wk PR + 44 weeks BOC + PR 48-wk PR 100 Nonblack Patients 100 Black Patients 80 60 40 P <.0001 67 68 40 80 60 40 P =.044 P =.004 53 42 20 0 23 23 20 17 9 8 12 14 n = 211 213 125 21 18 37 22 29 12 3 6 2 0 SVR Relapse SVR Relapse Poordad F, et al. AASLD 2010. Abstract LB-4.
SVR (%) Highlights From AASLD 2010 clinicaloptions.com/hepatitis PROVE 3: SVR Rates According to Prior Response 100 80 12-wk TVR + PR + 12-wk PR (n = 115) 24-wk TVR + PR + 24-wk PR (n = 113) 24-wk TVR + P (n = 111) 48-wk PR (n = 114) 69 76 60 40 51* 53* 39 38 42 57 62 36 40 20 24 14 11 9 20 0 Overall Prior Nonresponders *P <.001 vs control. P =.02 vs control. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. Prior Relapsers Prior Breakthrough
Advances Soon to Come
Direct Acting Antivirals capsid envelope protein Protease / Helicase RNA-dependent RNA Polymerase c22 33c c-100 5 3 cor e E1 E2 NS 2 NS 3 NS 4 NS5a / NS5b hypervariable region
Direct Acting Antiviral Drug (DAA) Combinations
Sofosbuvir (SOF, GS-7977) HCV-specific nucleotide polymerase inhibitor (chain terminator) Potent pan-genotypic antiviral activity against HCV GT1 6 High barrier to resistance Once-daily, oral, 400-mg tablet Favorable clinical pharmacology profile No food effect No significant drug interactions Generally safe and well-tolerated in clinical studies to date (> 2,000 patients) No safety signal in preclinical/clinical studies 10
Patients with HCV RNA <LLOQ (%) Phase 3: NEUTRINO GT 1, 4, 5, 6 Treatment-Naïve SVR12 by HCV Genotype 295/327 261/292 27/28 7/7 Overall GT 1 GT 4 GT 5,6 Open label, single arm study of PegIFN-Ribavirin-SOF x 12/52 Error bars represent 95% confidence intervals Lawitz E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #1411 11
Patients with HCV RNA <LLOQ (%) Phase 3: FISSION GT 2, 3 Treatment-Naïve Primary Endpoint and Virologic Response 231/251 76/241 249/250 158/236 242/244 207/224 NA Week 2 Week 4 Week 12 Week 24 On treatment 188/190 170/253 162/243 Week 12 Post-treatment Study met primary endpoint of non-inferiority (P<0.001) Relapse accounted for nearly all virologic failures There was 1 instance of virologic breakthrough from a patient who had suspected non-adherence based on undetectable drug plasma levels No S282T mutations observed by population or deep sequencing (1% cutoff) Error bars represent 95% confidence intervals Gane E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #5 12
SMV 150mg od x 12/52 91% meet RGT criteria for 24/52
Advances soon to come. Sofosbuvir Simeprevir Faldaprevir Still dealing with complex patients, complex IFN-based regimens and toxicities
Interferon-Sparing Regimens
COSMOS- AASLD 2013
Highlights of AASLD 2012 clinicaloptions.com/hepatitis ELECTRON: SOF-Ledipasvir-RBV -Noncirrhotic, GT1 Interim analysis of nonrandomized phase II study with sofosbuvir ± GS-5885 (NS5A inhibitor) Wk 12 Patients, % EOT SVR4 SVR12 Treatment naive (n = 25) Null responders (n = 10) SOF + RBV SOF + RBV 100 88 84 100 10 10 Treatment naive (n = 25) Null responders (n = 9) SOF + GS-5885 + RBV SOF + GS-5885 + RBV 100 100 100 100* *Data reported for 3 pts only. Data collection ongoing. Gane EJ, et al. AASLD 2012. Abstract 229.
SVR12 (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis AVIATOR: SVR12 ABT-450/r-ABT-267-ABT-333-RBV Treatment-Naive Patients Null Responders 100 80 60 86 84 96 96 82 79 100 100 100 98 100 100 88 88 100 100 96 96 100 81 100 85 83 81 89 89 100 100 Observed data (above bar) ITT (within bar) 40 20 0 n = 56 24 29 12 52 27 52 25 54 25 26 18 28 17 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV 8 wks 12 wks 12 wks Kowdley KV, et al. AASLD 2012. Abstract LB-1.
HCV RNA < LLOQ TD or TND (%) HCV RNA < LLOQ TD or TND (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis Daclatasvir-Asunaprevir-BMS-791325 (mitt Analysis) HCV RNA < LLOQ TD or TND Missing data 24-Wk Treatment (n = 16) 12-Wk Treatment (n = 16) 100 100 94 94 94 100 100 88 100 94 94 80 80 60 60 40 40 20 20 0 Wk 4 Wk 12 EOT SVR4 0 Wk 4 Wk 12 EOT SVR4 SVR12 Everson GT, et al. AASLD 2012. Abstract LB-3.
IFN-Sparing, All Oral Regimens High SVR rates Shorter Duration Excellent Tolerance Funding Issues
HCV Guidelines
Discussion