New developments in HCV research and their implications for front-line practice Dr. Curtis Cooper Associate Professor, University of Ottawa Director, Ottawa Hospital Viral Hepatitis Program June 17, 2013
New developments in HCV research and their implications for front-line practice 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, ABT Consultant /Advisor: Merck, Vertex, Roche, BI, GS Speaker: Merck, Roche, BI, BMS Government CADTH OHTN CIHR PCIRN Health Canada Ontario MOH Disclosures
Overview Overview of HCV and Current Standard of Care Future Therapies HIV-HCV co-infection issues New Treatment Guidelines Sexual Transmission of HCV Effective Service Delivery Models Other relevant topics
Therapies for Hepatitis C Virus PEG-Interferon α / Ribavirin Duration of Tx / RGT Definition of Therapeutic Success Plasma HCV RNA undetectable 6 months post therapy (Sustained Virologic Response=Cure)
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
Highlights From AASLD 2010 clinicaloptions.com/hepatitis Boceprevir and Telaprevir Boceprevir, a potent inhibitor of HCV NS3 protease Telaprevir, a potent inhibitor of HCV NS3/4A protease Dosed in combination with standard-of-care peginterferon alfa-2/ ribavirin Key Phase III Studies Boceprevir SPRINT-2: naive GT1 patients RESPOND-2: nonresponder GT1 patients Telaprevir ADVANCE: naive GT1 patients ILLUMINATE: responseguided therapy in naive GT1 patients
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 RESPOND-2: SVR Rates According to Treatment Arm and Prior Response 100 80 P <.0001 vs control (both arms) 66 69 75 4-wk PR + response-guided BOC + PR (n = 162) 4-wk PR + 44-wk BOC + PR (n = 161) 48-wk PR (n = 80) 60 40 20 59* 21 40 52 29 Overall RR RGT 15% FD 12% 0 95/ 162 107/ 161 Overall 17/ 80 23/ 30/ 7 57 58 2/29 Previous Nonresponders 72/ 105 77/ 103 15/ 51 Previous Relapsers Control 32% Bacon BR, et al. AASLD 2010. Abstract 216.
Patients (%) Highlights From AASLD 2010 clinicaloptions.com/hepatitis ADVANCE: Overall SVR and Relapse Rates 100 80 60 40 P <.0001 for both treatment arms vs control 69 75 44 8-wk TVR + PR + 16/40-wk PR (n = 364) 12-wk TVR + PR + 12/36-wk PR (n = 363) 48-wk PR (n = 361) 20 0 n = 250 271 158 SVR Jacobson IM, et al. AASLD 2010. Abstract 211.
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
SVR12 (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups Similar safety and tolerability profile in both treatment arms 100 80 87 92 68 68 65 66 78 81 TVR q8h/pr TVR BID/PR 60 59 58 40 20 0 n/ N = 92/ 106 97/ 105 141/ 208 139/ 206 37/ 57 CC CT TT IL28B GT 38/ 58 209/ 268 213/ 264 61/ 103 61/ 105 F0-2 F3/4 Liver Disease Status Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.
Summary Slide Much improved SVR rates in treatment naive and experienced populations Many are not eligible for these regimens Side effect profile remains very challenging Required intensive support and follow-up
Advances Soon to Come
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 16
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 17
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 18
SMV 150mg od x 12/52 91% meet RGT criteria for 24/52
Advanced are soon to come. Sofosbuvir Simeprevir Faldaprevir Daclatasvir HIV Experience- still deal with complex patients and toxicities
Interferon-Sparing Regimens
Sulkowski. EASL 2013
Highlights of AASLD 2012 clinicaloptions.com/hepatitis ELECTRON: Sofosbuvir, GS-5885, and RBV in Noncirrhotic Pts With GT1 HCV Interim analysis of nonrandomized phase II study with sofosbuvir (nucleoside polymerase inhibitor) ± 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* No SAEs related to study drugs; AE profile consistent with RBV toxicity profile *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 Rates With ABT-450/ RTV, ABT-267, ABT-333, and RBV SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs 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. Reproduced with permission.
HCV RNA < LLOQ TD or TND (%) HCV RNA < LLOQ TD or TND (%) Highlights of AASLD 2012 clinicaloptions.com/hepatitis Response to Daclatasvir, Asunaprevir, and BMS-791325 in Modified ITT 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 0 Wk 4 Wk 12 EOT SVR4 Wk 4 Wk 12 EOT SVR4 SVR12 Both regimens generally well tolerated, with no discontinuations due to AEs Infrequent SAEs, grade 3/4 AEs, or grade 3/4 lab abnormalities Everson GT, et al. AASLD 2012. Abstract LB-3. Reproduced with permission.
Summary Slide High SVR rates Excellent Tolerance DDI remain an issue HIV co-infection studies remain to be conducted
HIV-HCV Co-Infection Most issues the same as in HCV monoinfection Published trials with Boceprevir and Telaprevir DDI issues
HIV-HCV Guidelines
Sexual Transmission of HCV Depends on the kind of sex Currently an epidemic in MSM Treatment of Acute HCV
Treatment Models Multi-D maximizes patient care and treatment outcomes How do we get these clinics funded? How will this change over time?
Treat now or Wait? Treat those who need treatment now Consider those who are ready for treatment now You may lose the opportunity later Treatment will remain difficult to tolerate Treatment will remain expensive Who will provide the treatment?... Sending the message that HCV treatment is not important
Funding Major Issue Drug costs will dictate funding criteria Who is going to advocate?
Discussion
CATIE Forum
Reflecting on our response to HCV 1. What is the most effective treatment service delivery model for marginalized HCV clients/patients? 2. What are the challenges for ASOs and other CBOs trying to integrate HCV services into their work? 3. What new linkages could your organization make with other service providers?
Thank you Next English webinars: 1. Integrated approaches to treatment and prevention July 9, 1pm EST 2. Working from a sexual health or harm-reduction perspective: Integration of HIV, HCV, tuberculosis and other sexually transmitted and blood-borne infections (STBBIs) July 22, 1pm EST Please evaluate this webinar!