Best Practices in Management of HCV Genotypes 1, 4, 5, and 6 in 2014 Michael W. Fried, MD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill Chapel Hill, North Carolina Supported by educational grants from multiple commercial supporters.

About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Available HCV Therapies for Genotypes 1, 4, 5, and 6 and Key Data

Antiviral Therapies for Genotype 1 Currently Available Regimen DAA Class PegIFN + RBV None PegIFN + RBV + boceprevir Protease inhibitor PegIFN + RBV + telaprevir PegIFN + RBV + simeprevir PegIFN+ RBV + sofosbuvir Nucleotide analogue NS5B polymerase inhibitor RBV + sofosbuvir* (Extended duration) Sofosbuvir + simeprevir NUC + PI (off-label) DAA, direct-acting antiviral; NUC, nucleotide analogue; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin. *Sofosbuvir + ribavirin for 24 wks can be considered in patients with genotype 1 HCV who are ineligible for interferon. AASLD/IDSA treatment recommendations. Available at: http://www.hcvguidelines.org. Accessed June 16, 2014.

Sofosbuvir + PegIFN/RBV: NEUTRINO Phase III Study Design Wk 12 24 Sofosbuvir + PegIFN/RBV (N = 327) SVR12 Open label Sofosbuvir 400 mg QD + pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day for 12 wks (no response-guided therapy) Treatment-naive, genotype 1, 4, 5, and 6 HCV-infected patients 89% of patients had genotype 1 HCV 17% of patients with cirrhosis HCV, hepatitis C virus; PegIFN, peginterferon; QD, every day; RBV, ribavirin; SVR sustained virologic response. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

NEUTRINO Study: Virologic Response Sofosbuvir + PegIFN/RBV x 12 Wks 100 90 89 80 80 60 SVR (%) 40 GT1, genotype 1; ITT, intent to treat; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. 20 ITT SVR12 GT1 Cirrhosis n = 327 n = 291 54 Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

Sofosbuvir + Low-Dose RBV NIH SPARE Study (No Interferon): Sofosbuvir + RBV in HCV GT1–Infected Pts 24 wks sofosbuvir + WB or low-dose (600 mg) RBV in treatment-naive subjects Primarily GT1a (70%), male (66%), black (83%), IL28B CT/TT (81%) Advanced liver disease 23%; median BMI ranged from 26-30; high median HCV RNA Part 1 (Stage F0-F2) Part 2 (All Stages) 100 96 90 90 EOT SVR24 88 80 68 60 48 Patients (%) BMI, body mass index; EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; NIH, National Institute of Health; RBV, ribavirin; SVR, sustained virologic response; WB, weight-based. 40 20 Sofosbuvir + WB RBV Sofosbuvir + Low-Dose RBV Sofosbuvir + WB RBV N = 10 N = 50 Osinusi A, et al. JAMA. 2013;310:804-811.

Response-Guided Treatment Simeprevir + P/R in GT1, Tx-Naive Patients: QUEST-1/2 Phase III Trial Design Response-Guided Treatment SMV 150 mg QD + P/R P/R P/R N = 521* Placebo + P/R P/R P/R N = 264† Wk 12 24 48 72 RGT in simeprevir arm: if HCV RNA < 25 IU/mL at Wk 4 and undetectable at Wk 12, complete treatment at Wk 24; otherwise, continue treatment to Wk 48 Stopping rules If HCV RNA > 1000 IU/mL Wk 4, stop SMV/placebo If HCV RNA < 2 log10 IU/mL reduction at Wk 12, or confirmed > 25 IU/mL at Wk 24 or 36, stop all treatment GT, genotype; P/R, peginterferon alfa-2a 180 µg/wk + ribavirin 1000-1200 mg/day; QD, every day; RGT, response-guided treatment; SMV, simeprevir; Tx, treatment. *QUEST-1: n = 264; QUEST-2: n = 257. †QUEST-1: n = 130; QUEST-2: n = 134. Jacobson I, et al. EASL 2013. Abstract 1425. Manns M, et al. EASL 2013. Abstract 1413.

Simeprevir + P/R: Phase III QUEST-1: Impact of Subtype & Fibrosis Stage in GT1 Overall GT1a GT1b F0-F2 F3 F4 100 90 100 83 80 78 80 71 80 58 60 60 52 60 50 49 SVR (%) 40 40 26 29 20 20 GT, genotype; P/R, peginterferon/ribavirin; SVR, sustained virologic response. Simeprevir P/R Simeprevir P/R SVR: GT1b > GT1a SVR is lowest for patients with GT1a and baseline Q80K mutation SVR: F0-F2 > F4 Jacobson I, et al. EASL 2013. Abstract 1425.

Multiple Classes of Direct-Acting Antiviral Agents 5’UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3’UTR p7 Protease Polymerase Ribavirin NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450 MK-5172 Faldaprevir Sovaprevir ACH-2684 Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir Sofosbuvir VX-135 IDX21437 ACH-3422 Dasabuvir BMS-791325 PPI-383 GS-9669 TMC647055 NUC, nucleotide analogue. *Representative list; may not be fully inclusive.

COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV: Phase IIa Study Design 4 12 24 36 48 Wk Arm 1 SMV + SOF + RBV Posttreatment follow-up Arm 2 SMV + SOF Posttreatment follow-up Enrolment ratio 2:1:2:1 Arm 3 SMV + SOF + RBV Posttreatment follow-up Arm 4 SMV + SOF Posttreatment follow-up GT, genotype; HCV, hepatitis C virus; QD, every day; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir. Cohort 1: previous null responders (METAVIR F0-F2) Cohort 2: treatment naive and previous null responders (METAVIR F3-F4) SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz, et al. EASL 2014. Abstract 165.

Combination of Sofosbuvir (NUC) and Simeprevir (PI): COSMOS Cohort 1 (F0-F2 Nulls): SVR12 (N = 80, all arms) Cohort 2 (F3-F4 Naives/Nulls): SVR12 (N = 87, all arms) SMV + SOF + RBV SMV + SOF 100 100 96.3 100 93.3 92.9 93 93 93 79.2 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 20 20 AE, adverse effects; GT, genotype; NUC, nucleotide analogue; PI, protease inhibitor; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. 19/24 14/15 26/27 13/14 28/30 16/16 25/27 13/14 24-Wk Arms 12-Wk Arms 24-Wk Arms 12-Wk Arms Relapse in 3 pts in cohort 1 and 3 pts in cohort 2; all with GT1a and GT2 with Q80K polymorphism at baseline AEs (anemia and indirect bilirubin increases) largely confined to RBV arms SVR in patients with GT1a and Q80K+ = 88% to 100% Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. EASL 2014. Abstract 165.

How to Use Current Therapies in Genotypes 1, 4, 5, and 6

AASLD/IDSA Recommendations for HCV Genotype 1 Treatment-Naive Patients Yes IFN Eligible? No Sofosbuvir 400 mg/d PEG + RBV x 12 wks Sofosbuvir 400 mg/d Simeprevir 150 mg/d ± RBV x 12 wks Alternative Regimens AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; IFN, interferon; PEG, peginterferon; RBV, ribavirin. Simeprevir 150 mg/d x 12 wks + PEG + RBV x 24 wks GT1b GT1a Q80K neg Sofosbuvir 400 mg/d + RBV x 24 wks RBV dose: 1000-1200 mg/day AASLD/IDSA treatment recommendations.

AASLD/IDSA Recommendations for HCV Genotype 1 Treatment-Experienced Pts Yes/No Prior Protease Inhibitor? No Sofosbuvir 400 mg/d x 12 wks + PEG + RBV x 12-24 wks Sofosbuvir 400 mg/d Simeprevir 150 mg/d ± RBV x 12 wks Alternative Regimens AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; PEG, peginterferon; RBV, ribavirin. Sofosbuvir 400 mg/d + RBV ± PEG x 24 wks Sofosbuvir 400 mg/d x 12 wks + PEG + RBV x 12 wks Simeprevir 150 mg/d x 12 wks + PEG + RBV x 48 wks GT1b GT1a Q80K neg RBV dose: 1000-1200 mg/day AASLD/IDSA treatment recommendations.

Sofosbuvir + PegIFN/RBV: Phase III NEUTRINO Study (GT1, 4, 5, 6) Sofosbuvir + PegIFN/RBV x 12 Wks 97 100 90 80 80 60 SVR (%) 40 GT, genotype; ITT, intent to treat; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. 20 ITT SVR12 GT4, 5, 6 Cirrhosis n = 327 n = 35 n = 54 Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

AASLD/IDSA Recommendations for HCV Genotype 4 Treatment-Naive Patients Yes IFN Eligible? No Sofosbuvir 400 mg/d + PEG + RBV x 12 wks Sofosbuvir 400 mg/d + RBV x 24 wks AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; IFN, interferon; PEG, peginterferon; RBV, ribavirin. Alternative Regimens Simeprevir 150 mg/d + PEG + RBV x 24-48 wks RBV dose: 1000-1200 mg/day AASLD/IDSA treatment recommendations.

Treatment Experienced AASLD/IDSA Recommendations for HCV Genotype 4 Treatment-Experienced Pts Genotype 4 Treatment Experienced Sofosbuvir 400 mg/d + PEG + RBV x 12 wks AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; PEG, peginterferon; RBV, ribavirin. Alternative Regimens Sofosbuvir 400 mg/d + RBV x 24 wks RBV dose: 1000-1200 mg/day AASLD/IDSA treatment recommendations.

Adverse Effects of New Therapies PegIFN/RBV: well-established AE profiles Sofosbuvir[1-3] Mild fatigue Mild headache Simeprevir[4,5] Mild, reversible hyperbilirubinemia Due to transporter inhibition and not associated with hepatotoxicity Mild photosensitivity AE, adverse effect; PegIFN/RBV, peginterferon/ribavirin. 1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Jacobson I, et al. AASLD 2013. Abstract LB-3. 3. Sofosbuvir [package insert]. 4. Fried MW, et al. Hepatology. 2013;58:1918-1929. 5. Simeprevir [package insert].

Considerations for Monitoring During Therapy Medications are costly: focus on pretreatment education to maximize adherence PegIFN/RBV + DAA regimens Addition of DAA generally does not augment AE profile Continue to monitor every 2 wks x 4, then monthly (cytopenias, depression, etc) DAA + RBV only regimens Anemia still occurs, monitor every 2 wks x 4, then monthly DAA + DAA regimens Individualized follow-up Wk 2 and Wk 4, then every 4 wks? Adherence is key to success AE, adverse effect; DAA, direct-acting antiviral; PegIFN/RBV, peginterferon/ribavirin.

Summary: How Do We Treat Patients Now? Multiple therapeutic options are available for patients with genotypes 1 and 4 with: Shorter durations of treatment Increased efficacy Fewer adverse effects Genotype 1, 4, 5, 6 DAA + pegIFN/RBV backbone still may be used in selected patients All oral regimens also available as on-label and off-label recommendations DAA, direct-acting antiviral; pegIFN/RBV, peginterferon/ribavirin.

What’s Coming Next? Investigational Therapies for Genotypes 1, 4, 5, and 6

ION-2[3] Treatment-experienced HCV GT1; 20% cirrhotics (N = 440) Phase III Studies of SOF/LDV FDC ± RBV for 12 or 24 Wks in GT1 Patients Wk 12 Wk 24 SVR12, % 99 97 98 SOF/LDV (n = 214) ION-1[1,2] Treatment-naive HCV GT1; cirrhosis in 15% to 17% per arm (N = 865) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Wk 12 Wk 24 94 96 99 SOF/LDV (n = 109) ION-2[3] Treatment-experienced HCV GT1; 20% cirrhotics (N = 440) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response. SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure 1. Mangia A, et al. EASL 2014. Abstract O164. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1983. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) ION-3: Phase III Study of SOF/LDV FDC ± RBV for 8-12 Wks in Tx-Naive Noncirrhotic GT1 Patients Wk 8 Wk 12 SVR12, % SOF/LDV (n = 215) 94 93 95 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response; Tx, treatment. Kowdley KV, et al. N Engl J Med. 2014;3701879-1888.

Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631) SAPPHIRE I & II: Phase III Studies of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Noncirrhotic GT1 Pts Wk 12 SVR12, % SAPPHIRE-I Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473) 96 Placebo (n = 158)* SAPPHIRE-II Treatment-experienced noncirrhotic pts with HCV GT1[3,4] (N = 394) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297) Placebo (n = 97) GT, genotype; HCV, hepatitis C virus; NNI, nonnucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment failure *Placebo recipients crossed over to active treatment regimen at Wk 12. 1. Feld JJ, et al. EASL 2014. Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. 3. Zeuzem S, et al. EASL 2014. Abstract O1. 4. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

TURQUOISE II: Phase III Study of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Cirrhotic GT1 Patients Wk 12 Wk 24 SVR12, % ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) DAA-naive cirrhotic pts with HCV GT1; 58% of patients were treatment experienced, and 36% were previous null responders (N = 380) 92 96 ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 172) DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; NNI, non-nucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. No significant difference in 12 vs 24 wks; high SVR in all subgroups analyzed ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

Ribavirin-Free Therapy in GT1b Wk 12 SVR12, % PEARL-II[1] ABT450/RTV/Ombitasvir + Dasabuvir (n = 95) 100 GT1b Tx Experienced ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 91) 97 PEARL-III[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 209) 99 GT1b Tx Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 210) 99 GT, genotype; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response; Tx, treatment. PEARL-IV[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 205) 90 GT1a Tx Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 100) 97 1. Andreone P, et al. Gastroenterology. 2014;[Epub ahead of print]. 2. Ferenci P, et al. N Engl J Med. 2014. 22;370:1983-1992.

C-WORTHY: MK-5172 + MK-8742 ± RBV in GT1 Patients With Cirrhosis and in Null Responders Wk 12 Wk 18 SVR4/8, % MK-5172 + MK-8742 + RBV (n = 31) 90 97 94 91 100 Treatment-naive patients with GT1 HCV and cirrhosis (N = 123) MK-5172 + MK-8742 (n = 29) MK-5172 + MK-8742 + RBV (n = 32) MK-5172 + MK-8742 (n = 31) MK-5172 + MK-8742 + RBV (n = 31) GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Patients with GT1 HCV and null response to pegIFN/RBV (N = 130) MK-5172 + MK-8742 (n = 33) MK-5172 + MK-8742 + RBV (n = 33) MK-5172 + MK-8742 (n = 32) MK-5172 100 mg once daily; MK-8742 50 mg once daily, RBV 1000-1200 mg divided twice daily. Lawitz E, et al. EASL 2014. Abstract O61.

AI443-014: Phase IIb Study of Daclatasvir + Asunaprevir + BMS-791325 in Noncirrhotic GT1 HCV Patients Stratified by GT1 subtype and biopsy-confirmed cirrhosis Wk 12 SVR12,* % Daclatasvir + Asunaprevir + BMS-791325 75 mg BID (n = 80) 89 90 Tx-naive pts with GT1 HCV (N = 166) Daclatasvir + Asunaprevir + BMS-791325 150 mg BID (n = 86) BID, twice daily; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; P/R/ peginterferon/ribavirin; SVR, sustained virologic response; Tx, treatment. Daclatasvir 30 mg BID; asunaprevir 200 mg BID *Modified ITT analysis: missing data, breakthrough, relapse, or addition of P/R equals failure. Everson GT, et al. AASLD 2013. Abstract LB-1.

Summary Multiple all-oral DAA regimens will be available over the next 12-18 mos: Dual and triple DAA regimens yield the highest SVR rates (90%+) ever described Treatment duration of 12 wks (maybe shorter) Well tolerated across all populations Importance of RBV varies with regimen and virologic characteristics Preliminary data indicate that traditionally difficult to cure populations (cirrhosis, previous PI failures) will benefit greatly from IFN/RBV-free DAA regimens DAA, direct-acting antiviral; IFN, interferon; PI, protease inhibitor; RBV, ribavirin; SVR, sustained virologic response.