CURRENT TREATMENTS. Mitchell L Shiffman, MD Director Liver Institute of Virginia. Richmond and Newport News, VA, USA

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1 CURRENT TREATMENTS FOR HCV Mitchell L Shiffman, MD Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA, USA Liver Institute of Virginia Education, Research and Treatment for Patients with Liver Disease Bon Secours Health System TREATMENT OF HCV CURRENT AND FUTURE TREATMENT Peginterferon Ribavirin Telaprevir Boceprevir INF free GT 2-3 Sofosbuvir Ribavirin Simeprevir GT 1 Sofosbuvir GT 1,4-6 Faldaprevir Daclatasvir Multi-DAA INF free GT 1 Gilead Abbott BMS BI GT 1B GT / INF free Vertex Merck Achillion 1

2 TELAPREVIR AND BOCEPREVIR TREATMENT NAIVE IM Jacobson et al. N Eng J Med 2011;364: F Poordad et al. N Engl J Med 2011;364: TELAPREVIR AND BOCEPREVIR RETREATMENT OF PEGINF FAILURES Zeuzem S, et al. N Engl J Med 2011;364: Bacon B, et al. N Engl J Med 2011;364: F Unresponsive 2

3 TELAPREVIR AND BOCEPREVIR CIRRHOSIS Cirrhosis Jacobson IM, et al. N Engl J Med 2011;364: Poordad F, et al. N Engl J Med 2011;364: FDA RECOMMENDED ALGORITHM TELAPREVIR Treatment naïve and Prior Relapse Measure HCV RNA TPV+PEGINF+RBV If ervr: PEGINF+RBV If NO ervr: PEGINF+RBV HCV RNA Hard Stop Rules <1000 <1000 UD 3

4 FDA RECOMMENDED ALGORITHM BOCEPREVIR Treatment Naïve PEGINF+RBV If ervr: BOC+PEGINF+RBV If NO ervr: BOC+PEGINF+RBV PEG + RBV Measure HCV RNA HCV RNA Hard Stop Rules <100 UD EXTENDED RVR RESPONSE GUIDED THERAPY Telaprevir Boceprevir Developed from observations made from peginterferon/ribavirin Applied to the triple therapy paradigms Patients who achieve RVR Treated for a shorter duration Achieve maximum SVR Patients with delayed virologic response Become HCV RNA negative after week 4 Require 48 weeks of treatment to reduce relapse Have lower SVR rates 4

5 TREATMENT NAÏVE - TELAPREVIR RAPID VIROLOGIC RESPONSE PEG-RBV TPV Jacobson IM, et al. N Engl J Med 2011;364: TREATMENT NAÏVE - BOCEPREVIR RAPID VIROLOGIC RESPONSE PEG-RBV BOC Poordad F, et al. N Engl J Med 2011;364:

6 MEASURING HCV RNA RVR AND STOP RULES Must use a PCR assay which can: Quantify the level of HCV RNA Differentiate UNQUANTIFIABLE from UNDETECTABLE An assay which reports that HCV RNA is UNQUANTIFIABLE without qualifying if HCV RNA is UNDETECTBALE is insufficient A value of <25 IU/ml detectable is NOT undetectable and not eligible for a shorter duration of treatment 1000 IU/ml -- STOP for -- Telaprevir 100 IU/ml -- STOP for -- Boceprevir Not Quantifiable Not Detectable MEASURING HCV RNA VR AND STOP RULES: BOCEPREVIR ALL MEET STOP RULES ALL MEET CRITERIA TO CONTINUE TREATMENT 6

7 MEASURING HCV RNA RVR AND STOP RULES: TELAPREVIR ALL MEET STOP RULES ALL MEET CRITERIA TO CONTINUE TREATMENT HEPATITIS C VIRUS THE POOL OF VIRUS Sensitive mutant Wild type Sensitive mutant Sensitive mutant Resistant mutants 7

8 CHRONIC HCV IMPACT OF VIRAL MUTATIONS Wild type viral protein Anti-viral agent enters the binding site Viral protein inhibited Sensitive mutant viral protein Anti-viral agent still able to enter binding site Viral protein inhibited Resistant mutant viral protein Anti-viral agent unable to enter binding site Viral protein not inhibited TREATMENT OF CHRONIC HCV EMERGENCE OF RESISTANCE The use of multiple agents acting at different sites Either a: A single DAA+PEGINF+ RBV in patients who are genetically sensitive to INF Multiple DAAs (2-3) with or without t RBV Will suppress the emergence of resistance and yield high rates of SVR 8

9 TREATMENT OF CHRONIC HCV MISTAKES WE MADE The majority of patients treated with boceprevir and telaprevir had: Cirrhosis Previously failed peginterferon and ribavirin Results were: Substantially less than observed in phase 3 clinical trials Adverse events were more frequent INTERFERON RESPONSIVENESS CIRRHOSIS INF Non-Responsive INF Responsive Bruno S, et al. J Hepatol 2013;58:

10 HCV TREATMENT WITH CIRRHOSIS CUPIC COHORT TRV BOC N Relapse Partial Response Null Response 39% 46% 10% 45% 42% 5% Esophageal Varices 35% 38% SVR Relapse Partial response Null Response 40% 53% 32% 29% 41% 51% 40% 11% TPV BOC SAE 49% 38% Premature DC 26% 24% Infections 26% 24% Death 2% 1.3% Decompensation 4.4% 4.4% Anemia <8.0 gm/dl 10% 10% EPO use 57% 66% Platelets <25, % 0.6% TPO use 1.7% 1.9% Fontaine H, et al. EASL 2013 HCV TREATMENT WITH CIRRHOSIS INCREASED INFECTION N/% N/% N 191 Stage 0-2 Stage 3 Stage 4 31% 19% 50% Naïve 21% Relapse 30% Non-response 49% Telaprevir Boceprevir Rutter K, et al. EASL % 50% Stop for: Futility AE Infection Risk of Infection Albumin >3.5 < 3.5 Platelets >90,000 <90,000 SVR Stage 0-2 Stage 3 Stage 4 17% 20% 8% 12% 60% 14% 24% 65% 47% 28% 10

11 LIMITATIONS OF CURRENT TREATMENT SIDE EFFECTS Telaprevir Boceprevir Anemia 38% 49% Nausea 41% 45% Vomiting 13% 17% Diarrhea 30% 25% Dysgusea 10% 39% Pruritus 47% NR Rash 36% 18% Anorectal Symptoms 11% <5% Pill Burdon (per day) 9 12 Poordad F, et al. N Engl J Med 2011;364: Jacobson IM, et al. N Engl J Med 2011;364: NEW PROTEASE INHIBITORS SIMEPREVIR AND FALDAPREVIR Simeprevir Faldaprevir Binding location Same as TPV and BOC Used for 12 weeks with PEGINF + Ribavirin RGT Genotype 1 Dosing Once daily More anemia than PEG/RBV No No Drug-Drug interactions No No Rash No Mild Additional AE No Increase Bili Manns M, et al. EASL 2013 Ferenci P, et al. EASL

12 SIMEPREVIR STUDY DESIGN PEGINF + RBV PEGINF Simeprevir 150 mg QD RBV Simeprevir 150 mg QD PEGINF RBV Manns M, et al. J Hepatol 2013;58(suppl; abstr 1413). FALDAPREVIR STUDY DESIGN PEGINF + RBV PEGINF RBV Faldaprevir 120 mg QD Faldaprevir 120 mg QD Faldaprevir 240 mg QD PEGINF RBV PEGINF RBV Sulkowski MS, et al. Hepatology 2013;57:

13 NEW PROTEASE INHIBITORS TREATMENT NAIVE With RVR RVR Manns M, et al. EASL 2013 Ferenci P, et al. EASL 2013 NEW PROTEASE INHIBITORS TREATMENT NAIVE Manns M, et al. EASL 2013 Ferenci P, et al. EASL

14 NEW PROTEASE INHIBITORS TREATMENT NAIVE Manns M, et al. EASL 2013 Ferenci P, et al. EASL 2013 SIMEPREVIR-PEGINF-RIBAVIRIN TREATMENT NAIVE Manns M, et al. EASL

15 TREATMENT OF HCV SOFOSBUVIR GT1 GT 2 and 3 Naive GT 2 and 3 Failures SOFOSBUVIR 400 mg QD PEGINF + RBV SOF + RBV PEGINF + RBV Placebo SOF + RBV SOF + RBV Lawitz E, et al. N Engl J Med 2013;368: Jacobson IM, et al. N Engl J Med 2013;368: INTERFERON INELIGIBILITY REASONS Psychiatric Disease Intolerant t to INF Autoimmune Disease Other: Diabetes Seizure disorder Retinal Disease Thyroid Disease Recent drug use Older age Thrombocytopenia Jacobson IM, et al. N Engl J Med 2013;368:

16 SOFOSBUVIR AND RIBAVIRIN SIDE EFFECTS Placebo SOF+RBV Stop due to AE 4% 2% SAE 3% 5% Fatigue 24% 44% Nausea 18% 22% Headache 20% 21% Rash 8% 9% Arthralgia 1% 8% Cough 3% 5% Anemia <10 gm/dl < 8.5 gm/dl 0% 13% 7% 1% Jacobson IM, et al. N Engl J Med 2013;368: SOFOSBUVIR-PEGINF-RIBAVIRIN GENOTYPE 1 Lawitz E, et al. N Engl J Med 2013;368:

17 SOFOSBUVIR-PEGINF-RIBAVIRIN GENOTYPE 1, 4, 5, 6 Treatment naïve All patients treated for only 12 weeks with all 3 drugs 1 pill per day All patients respond No RGT needed No resistance All failures are due to relapse SVR (%) N 327 All Patients 90% GT1 89% GT4, 5 and 6 96%, 100% No Cirrhosis i 92% Cirrhosis 80% Lawitz E, et al. N Engl J Med 2013;368: SOFOSBUVIR vs PEGINF/RIBAVIRIN GENOTYPE 2 and 3 Gane E, et al. EASL

18 SOFOSBUVIR vs PEGINF GENOTYPE 2 and 3: TX NAIVE SVR (%) SOF+RBV 12 weeks PEGINF+RBV 24 weeks 0 No Cx Cx No Cx Cx Genotype 2 Genotype 3 Lawitz E, et al. N Engl J Med 2013;368: GT 2 and 3: PRIOR PEGINF NON-SVR SOFOSBUVIR AND RIBAVIRIN Weeks of Treatment: Jacobson IM, et al. N Engl J Med 2013;368:

19 GT 2 and 3: PRIOR PEGINF NON-SVR SOFOSBUVIR AND RIBAVIRIN Weeks of Treatment: Genotype 2 Genotype 3 Jacobson IM, et al. N Engl J Med 2013;368: GENOTYPE 3 PEGINF/RBV NON-SVR SOFOSBUVIR Cirrhosis: SOFOSBUVIR+RBV Lawitz E, et al. AASLD 2013 Zeuzem S, et al. AASLD 2013 Jacobson IM, et al. N Engl J Med 2013;368: SOF+RBV + PEGINF 19

20 TREATMENT OF HCV SUMMARY Protease inhibitors Telaprevir Genotype 1 specific Boceprevir Simeprevir Faldaprevir Not generally effective against other HCV genotypes All act at the same site Virologic failure cannot be overcome with a different protease Polymerase inhibitor Sofosbuvir Effective against all genotypes Used with peginterferon and ribavirin in GT 1,4,5 and 6 Used with ribavirin in GT 2 and 3 20