1. Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) Prepared by: Sophie Woolston, MD and David H. Spach, MD Last Updated: December 29, 2014

2. Hepatitis web study Hepatitis web study Background and Dosing O MBITASVIR -P ARITAPREVIR -R ITONAVIR + D ASABUVIR

3. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) Approval Status: FDA approval on December 19, 2014 Indication: Genotype 1 chronic HCV infection, including compensated cirrhosis Class & Mechanism - Ombitasvir (ABT-267): NS5A inhibitor - Paritaprevir (ABT-450): NS3/4A serine protease inhibitor - Ritonavir: HIV protease inhibitor used as pharmacologic booster - Dasabuvir (ABT-333): Non-nucleoside NS5B polymerase inhibitor Tablets: Ombitasvir-Paritaprevir-Ritonavir (fixed dose 12.5/75/50 mg) Dasabuvir: 250 mg Dose: 2 tablets Ombitasvir-Paritaprevir-Ritonavir once daily (am) with food plus Dasabuvir 1 tablet twice daily with food Adverse Effects (AE): fatigue, pruritus, and insomnia Cost: $83,319 for 12-week course Source: Viekira Pak Prescribing Information. AbbVie Inc.

4. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) Indications and Usage Patient PopulationsTreatment*Duration GT1a, without cirrhosis Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + Ribavirin 12 weeks GT1a, with cirrhosis Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + Ribavirin 24 weeks** GT1b, without cirrhosis Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir 12 weeks GT1b, with cirrhosis Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + Ribavirin 12 weeks *Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. **Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + ribavirin for 12 weeks may be considered for some patients based on prior treatment history Source: Viekira Pak Prescribing Information. AbbVie Inc.

5. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) Contraindications Decompensated cirrhosis Concomitantly taking medications that are: - highly dependent on CYP3A for clearance, - strong inducers of CYP3A and CYP2C8, or - strong inhibitors of CYP2C8 Known hypersensitivity to ritonavir Source: Viekira Pak Prescribing Information. AbbVie Inc.

6. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) Estimated Medication Cost for Therapy Estimated Cost of Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Duration of TreatmentEstimated Cost* 12 Weeks (without ribavirin)$83,319 24 Weeks (without ribavirin)Unknown *Estimated cost based on Wholesaler Acquisition Cost in United States

7. Hepatitis web study Hepatitis web study Source: Viekira Pak Prescribing Information. AbbVie Inc. Drugs Contraindicated for Use with Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Drug ClassDrug(s) within Class that are Contraindicated Alpha1-adrenoreceptor antagonistAlfuzosin HCL AnticonvulsantsCarbamazepine, phenytoin, phenobarbital Antihyperlipidemic agentGemfibrozil AntimycobacterialRifampin Ergot derivatives Ergotamine, dihydroergotamine, ergonovine, methylergonovine Ethinyl estradiol-containing products Ethinyl estradiol-containing medications such as combined oral contraceptives Herbal ProductSt. John’s Wort (Hypericum perforatum) HMG-CoA ReductaseLovastatin, simvastatin NeurolepticsPimozide Non-nucleoside reverse transcriptase inhibitor Efavirenz Phosphodiesterase-5 (PDE5) inhibitor Sildenafil when dosed as Revatio for the treatment of pulmonary arterial hypertension (PAH) Sedatives/hypnoticsTriazolam; Orally administered midazolam

8. Hepatitis web study Hepatitis web study Source: Viekira Pak Prescribing Information. AbbVie Inc. Drugs Contraindicated for Use with Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Drug ClassDrug(s) within Contraindicated ClassClinical Comments Alpha1-adrenoreceptor antagonist Alfuzosin HCLPotential for hypotension. Anticonvulsants Carbamazepine, phenytoin, phenobarbital Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of activity for HCV therapy Antihyperlipidemic agentGemfibrozil Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation. AntimycobacterialRifampin Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of HCV therapeutic activity. Ergot derivatives Ergotamine, dihydroergotamine, ergonovine, methylergonovine Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine. Ethinyl estradiol-containing products Ethinyl estradiol-containing medications such as combined oral contraceptives Potential for ALT elevations Herbal Product St. John’s Wort (Hypericum perforatum) Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of HCV therapeutic activity. HMG-CoA ReductaseLovastatin, simvastatinPotential for myopathy including rhabdomyolysis. NeurolepticsPimozidePotential for cardiac arrhythmias. Non-nucleoside reverse transcriptase inhibitor Efavirenz Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations. Phosphodiesterase-5 (PDE5) inhibitor Sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension (PAH) There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope. Sedatives/hypnotics Triazolam Orally administered midazolam Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with VIEKIRA PAK may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

9. Hepatitis web study Hepatitis web study SAPPHIRE-I: GT1 (a & b), Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 weeks PEARL-III: GT1b, Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 weeks PEARL-IV: GT1a, Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 weeks SAPPHIRE-II: GT1 (a & b), Treatment-Experienced, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 weeks PEARL-II: GT1b, Treatment-Experienced, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 week TURQUOISE II: GT1 (a & b), Treatment-Naïve & Experienced, with cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 or 24 weeks SAPPHIRE-I: GT1 (a & b), Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 weeks PEARL-III: GT1b, Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 weeks PEARL-IV: GT1a, Treatment-Naïve, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 weeks SAPPHIRE-II: GT1 (a & b), Treatment-Experienced, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 weeks PEARL-II: GT1b, Treatment-Experienced, without cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir +/- RBV x 12 week TURQUOISE II: GT1 (a & b), Treatment-Naïve & Experienced, with cirrhosis - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 or 24 weeks Summary of Key Phase 3 Studies Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) +/- RBV

10. Hepatitis web study Hepatitis web study Summary of Key Studies in Special Populations Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira Pak) +/- RBV TURQUOISE-I: GT1 (a & b), HIV Coinfection, Treatment Naïve/Experienced - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 or 24 weeks CORAL-I: GT1 (a & b), Post-Liver Transplantation Recipients - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 24 weeks TURQUOISE-I: GT1 (a & b), HIV Coinfection, Treatment Naïve/Experienced - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 12 or 24 weeks CORAL-I: GT1 (a & b), Post-Liver Transplantation Recipients - Ombitasvir-paritaprevir-ritonavir + dasabuvir + RBV x 24 weeks

11. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-I Phase 3 Treatment Naïve Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.

12. Hepatitis web study Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Design

13. Hepatitis web study Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Study Regimens Group A N = 473 Ombitasvir-Paritaprevir- RTV + Dasabuvir + Ribavirin Placebo SVR12 Ombitasvir-Paritaprevir- RTV + Dasabuvir + Ribavirin SVR12 Double blind Open label (data pending) Group B N = 158 Week 0361224 RTV = Ritonavir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg)

14. Hepatitis web study Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in G T1 SAPPHIRE-I Study: Baseline Characteristics Baseline Characteristic Group A (N=473) Group B (N=158) Age (years), Mean49.451.2 Male sex %57.346.2 Race (%) White Black Other 90.5 5.5 4.0 91.1 5.1 3.8 Body Mass Index (Mean)25.726.2 HCV genotype (%) 1a 1b 68.1 31.9 66.5 33.5 IL28B CC genotype, (%)30.431.6 HCV RNA, log 10 IU/ml6.406.47 Fibrosis score ≥ F223.326.6

15. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Results SAPPHIRE-I: SVR12 in Group A, by Genotype 1 Subtype Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. 455/473307/322148/151

16. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Results SAPPHIRE-I: SVR12 in Group A, Fibrosis Score Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. 352/36366/7037/40

17. Hepatitis web study Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Adverse Events During Double-Blind Phase NUTRINO: SVR 12 by Liver Disease Event Group A = 3D + RBV (N=473) Group B = Placebo (N=158) Any adverse event (%)87.573.4 Any adverse event leading to discontinuation of study drug (%) 0.6 Any serious adverse event (%)2.10 Grade 3 or 4 lab abnormality (%) Alanine aminotransferase0.94.4 Aspartate aminotransferase0.61.9 Alkaline phosphatase00 Total bilirubin2.80 Hemoglobin00 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

18. Hepatitis web study Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1 SAPPHIRE-I Study: Conclusions Conclusions: “In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT- 450/r–ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation.” Note: ABT-450/r = Paritaprevir-Ritonavir

19. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV Phase 3 Treatment Naïve Ferenci P, et al. N Engl J Med. 2014;370:1983-92.

20. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Study Design

21. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Study Regimens HCV Genotype 1a n = 100 3D + Ribavirin SVR12 n = 205 3D + Placebo SVR12 HCV Genotype 1b n = 210 3D+ Ribavirin SVR12 n = 209 3D + Placebo SVR12 Week 01224 3D = Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Drug Dosing 3D = Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)

22. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Baseline Characteristics Baseline Characteristic Genotype 1aGenotype 1b 3D + RBV (n=100) 3D (n=205) 3D + RBV (n=210) 3D (n=209) Age, years51.651.448.449.2 Male sex (%)70.062.950.541.2 BMI kg/m 2 26.926.725.826.1 Race (%) White Black Other 86.0 10.0 4.0 83.4 12.7 3.9 94.3 4.8 1.0 94.2 4.8 1.0 IL28B CC (%)31.030.721.021.1 Metavir F3 (%)16.0%18.5%10.5%9.6% HCV RNA log 10 IU/ml6.646.536.296.33 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

23. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Results Genotype 1aGenotype 1b 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir RBV = Ribavirin 97/100185/205209/210207/209

24. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Adverse Events Event GT1aGT1b 3D + RBV (n=100) 3D ( n=205) 3D + RBV (n=210 ) 3D (n=209) Any adverse event %92.082.480.067 Any serious adverse event %3.00.51.9 Common adverse events: Headache %25.028.324.323.4 Fatigue %46.035.121.423.0 Pruritus %10.05.911.95.3 Nausea %21.013.711.04.3 Insomnia %17.07.89.03.3 Diarrhea %14.016.14.36.2 Laboratory abnormalities (%): Hemoglobin < 10 g/dl4.009.00 Total bilirubin > 3x ULN3.00.55.70.5 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

25. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Adverse Events Event GT1aGT1b 3D + RBV (n=100) 3D ( n=205) 3D + RBV (n=210 ) 3D (n=209) Any adverse event %92.082.480.067 Any serious adverse event %3.00.51.9 Common adverse events: Headache %25.028.324.323.4 Fatigue %46.035.121.423.0 Pruritus %10.05.911.95.3 Nausea %21.013.711.04.3 Insomnia %17.07.89.03.3 Diarrhea %14.016.14.36.2 Laboratory abnormalities (%): Hemoglobin < 10 g/dl4.009.00 Total bilirubin > 3x ULN3.00.55.70.5 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

26. Hepatitis web study Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1 PEARL-III and PEARL-IV: Conclusions Conclusions: “Twelve weeks of treatment with ABT-450/r–ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection.” Note: ABT-450/r = Paritaprevir-Ritonavir

27. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II Phase 3 Treatment Experienced Zeuzem S, et al. N Engl J Med. 2014;370:1604-14.

28. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II: Study Design

29. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II: Regimens Active N = 297 Ombitasvir-Paritaprevir-RTV and Dasabuvir + Ribavirin Placebo SVR12 Ombitasvir-Paritaprevir-RTV and Dasabuvir + Ribavirin SVR12 Double blind Open label (data pending) Placebo N = 97 Week 0361224 RTV = Ritonavir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)

30. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir + RBV in GT1 SAPPHIRE-II Study: Baseline Characteristics Baseline Characteristic 3D + RBV (n=297) Placebo Arm (n=97) Age (years), Mean51.754.9 Male sex %56.261.9 Race (%) White Black Asian 90.6 7.4 2.0 88.7 10.3 0 Body Mass Index (Mean)26.326.4 HCV genotype (%) 1a 1b 58.2 41.4 58.8 41.2 IL28B CC genotype, (%)11.47.2 Type of Prior Response Relapse Partial Response Null Response 29.0 21.9 49.2 29.9 21.6 48.5 HCV RNA, log 10 IU/ml (mean)6.556.52 Fibrosis score F2 or F3 (%)32.033.0 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

31. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II: Results SAPPHIRE-II: Results by Genotype 1 Subtype Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. 286/297166/173119/123

32. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II: Results SAPPHIRE-II: Results by Prior Treatment Response Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. 286/29782/8665/65139/146

33. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II Study: Key Adverse Events Event 3D + RBV (n=297) Placebo (n=97) Any adverse events %91.282.5 Any serious adverse event %2.01.0 Common adverse events: Headache %36.435.1 Fatigue %33.322.7 Nausea %20.217.5 Asthenia %15.811.3 Insomnia %14.17.2 Pruritus %13.85.2 Diarrhea %13.112.4 Dyspnea %12.510.3 Cough %10.85.2 Myalgia %7.710.3 Abnormalities in laboratory values of grade 3 or 4 % Alanine aminotransferase1.73.1 Total bilirubin2.40 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

34. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1604-14. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 SAPPHIRE-II: Conclusions Conclusions: “Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response.”

35. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II Phase 3 Treatment Experienced Andreone P, et al. Gastroenterology. 2014;147:359-65.

36. Hepatitis web study Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Study Design

37. Hepatitis web study Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Regimens n = 91 Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin SVR12 n = 95 Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir SVR12 Week 02412 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)

38. Hepatitis web study Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Baseline Characteristics Baseline Characteristic3D + RBV (n=91) 3D (n=95) Age (years), Mean54.2 Male sex %49.560.0 Race (%) White Black 92.3 3.4 90.5 6.3 Body Mass Index (Mean)26.227.5 Previous Response to PEG + RBV Null responder Partial responder Relapser 35.2 28.6 36.3 34.7 28.4 36.8 IL28B Non-CC genotype, (%)89.092.6 HCV RNA, log 10 IU/ml (mean)6.566.48 Fibrosis score F3 (%)15.413.7 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

39. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Results PEARL-II: SVR 12 Rates* Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. 85/8891/91 *Primary endpoint by intention-to-treat analysis 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

40. Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Results by Prior Treatment Response PEARL-II: Results by Prior Treatment Response Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. 85/8891/9129/3132/3224/2526/2632/3233/33 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

41. Hepatitis web study Source: Andreone P, et al. Gastroenterology. 2014;147:359-65. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Treatment-Emergent Adverse Effects Event 3D + RBV (n=91) 3D (n=95) Any Treatment Emergent Adverse Effect %79.177.9 Any serious Treatment Emergent Adverse Effect %2.20 Common Treatment Emergent Adverse Events: Fatigue %31.915.8 Headache %24.223.2 Nausea %20.96.3 Insomnia %14.33.2 Pruritus %14.38.4 Diarrhea %13.212.6 Asthenia %12.17.4 Anemia %11.00 Blood bilirubin level increased %8.80 Rash %8.81.1 Laboratory abnormalities (%): Hemoglobin (< lower limit of normal at end of treatment) 42.05.5 Total bilirubin > 3x ULN8.80 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

42. Hepatitis web study Source: Andreone P, et al. Gastroenteroly. 2014;147:359-65. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1b PEARL-II: Conclusions Conclusions: “The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events.” Note: ABT-450 = Paritaprevir

43. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in GT1 TURQUOISE-II Phase 3 Treatment Naïve and Treatment Experienced Poordad F, et al. N Engl J Med. 2014;370:1973-82. Compensated Cirrhosis

44. Hepatitis web study Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Study Design

45. Hepatitis web study Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Regimens Group A N = 208 3D + Ribavirin SVR12 Group B N = 172 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg) Week 0361224

46. Hepatitis web study 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Results TURQUOISE II: SVR12 by Genotype 1 Subtype Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 191/208165/172124/140114/12167/6850/51 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

47. Hepatitis web study 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Results TURQUOISE II: SVR12 Based on Prior Treatment Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 81/8670/7428/2923/2317/1813/1365/7559/62 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

48. Hepatitis web study 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Results for GT1a TURQUOISE II: Genotype 1a SVR12 Based on Prior Treatment Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 59/6452/5614/1513/1311/1110/1040/5039/42 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

49. Hepatitis web study 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Results for GT1b TURQUOISE II: Genotype 1b SVR12 Based on Prior Treatment Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 22/2218/1814/1410/106/73/325/2520/20 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

50. Hepatitis web study Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Adverse Effects Event 3D + RBV x 12 weeks (n=208) 3D + RBV x 24 weeks (n=172) Any adverse event (%)91.890.7 Adverse event leading to stopping study drug (%)1.92.3 Any serious adverse event6.24.7 Most common adverse event Fatigue (%)32.746.5 Headache (%)27.930.8 Nausea (%)17.820.3 Pruritis (%)18.319.2 Insomnia (%)15.418.0 Diarrhea (%)14.416.9 Asthenia (%)13.912.8 Rash (%)11.114.5 Irritability (%)7.212.2 Anemia (%)7.710.5 Dyspnea (%)5.812.2 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

51. Hepatitis web study Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Adverse Effects Lab Abnormalities 3D + RBV x 12 weeks (n=208) 3D + RBV x 24 weeks (n=172) Alanine aminotransferase, grade 3 or 46 (2.9)0 Aspartate aminotransferase, grade 3 or 41 (0.5)0 Alkaline phosphatase, grade 3 or 400 Total bilirubin, grade 3 or 428 (13.5)9 (5.2) Hemoglobin Grade 1 Grade 2 Grade 3 Grade 4 103 (49.5) 12 (5.8) 2 (1.0) 1 (0.5) 97 (56.4) 18 (10.5) 1 (0.6) 0 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

52. Hepatitis web study Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82. 3D + Ribavirin in GT1 and Compensated Cirrhosis TURQUOISE-II: Conclusions Conclusions: “In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent.”

53. Hepatitis web study Hepatitis web study 3D (Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir) + RBV in GT1 TURQUOISE-I Phase 2 Treatment Naïve and Treatment Experienced Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. HIV Coinfection

54. Hepatitis web study Source: Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. 3D + Ribavirin for HCV-HIV Coinfection and GT1 TURQUOISE-I: Part 1 Study Design

55. Hepatitis web study Source: Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. 3D + Ribavirin for HCV-HIV Coinfection and GT1 TURQUOISE-I: Part 1 Study Regimens N = 31 3D + Ribavirin 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) and Dasabuvir: 250 mg twice daily Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg) 3D + Ribavirin SVR12 N = 32 Week 0361224

56. Hepatitis web study Source: Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. 3D + Ribavirin for HCV-HIV Coinfection and GT 1 TURQUOISE-I: Patient Population Baseline Characteristic 12-Week Arm (n=31) 24-Week Arm (n=32) Age (years), Mean50.9 Male sex %9491 Black Race (%)2325 Cirrhosis (%)19 HCV genotype (%) 1a 1b 87 13 91 9 HCV RNA, log 10 IU/ml (mean)6.546.60 IL28B non-CC genotype, (%)8478 Previous Response to PEG + RBV Naïve Relapse Partial response Null response 65 3 16 16 69 9 6 16 CD4 Count, cells/mm 3 (mean)633625

57. Hepatitis web study 3D + Ribavirin for HCV-HIV Coinfection and GT 1 TURQUOISE-I: Part 1 Results TURQUOISE-I: SVR Rates (to date) Source: Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin 29/31 30/3229/32

58. Hepatitis web study 3D + Ribavirin for HCV-HIV Coinfection and GT 1 TURQUOISE-I: Part 1 Results Details of Five Patients NOT Achieving SVR 12 Source: Wyles D, et al. 65 th AASLD. 2014: Abstract 1939. 29/31 30/3229/32 One patient in 12-week arm withdrew consent prior to finishing treatment; had undetectable HCV RNA at week 10 One patient in 12-week arm had virologic relapse at week 4 post treatment; had new resistant HCV variants at 3 viral targets (D168V in NS3/4A, M28T in NS5A, and S556G in NS5B) One patient in 24-week arm had virologic breakthrough during treatment; had new resistant HCV variants at 3 viral targets (R155K in NS3/4A, Q30R in NS5A, and S556G in NS5B) Two patients in 24-week arm achieved early SVR but appeared to be reinfected with GT1a isolate distinct from baseline HCV isolate; both patients had engaged in high-risk sexual activity post treatment

59. Hepatitis web study Hepatitis web study Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Phase 2 Treatment Naïve and Treatment Experienced Kwo PY, et al. N Engl J Med. 2014;371:2375-82. Liver Transplantation

60. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Study Design

61. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Regimen N = 34 3D + Ribavirin SVR12 Week 03624 3D = Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Drug Dosing Ombitasvir-Paritaprevir-Ritonavir- (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily Ribavirin (RBV): dosing managed per investigator discretion; most patients received 600-800 mg/day

62. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Baseline Characteristics Baseline Characteristic3D + Ribavirin (n=34) Age (years), Mean59.6 Male sex–no. (%)27 (79) Race–no. (%) White Black Multiple 29 (85) 4 (12) 1 (3) Body Mass Index (kg/m 2 ) Mean29.7 HCV genotype–no. (%) 1a 1b 29 (85) 5 (15) IL28B, non-CC genotype–no. (%)26 (76) HCV RNA, log 10 IU/ml6.6 Fibrosis stage (%) F0 F1 F2 6 (18) 13 (38) 15 (44) 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

63. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Results 34/34 On Treatment 33/34 After Treatment

64. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Adverse Events Adverse Event Occurring in > 15% of the 34 Patients Receiving 3D + RBV EventN (%) Any adverse event33 (97) Fatigue17 (50) Headache15 (44) Cough11 (32) Anemia10 (29) Diarrhea9 (26) Insomnia9 (26) Asthenia8 (24) Nausea8 (24) Muscle spasms7 (21) Rash7 (21) Back pain6 (18) Dizziness6 (18) Peripheral edema6 (18 Rhinorrhea6 (18) 3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin

65. Hepatitis web study Source: Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 3D + RBV in Liver Transplant Recipients with Recurrent HCV GT1 CORAL-I Trial: Conclusions Conclusions: “Treatment with the multitargeted regimen of ombitasvir- ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population.” Note: ABT-450/r = Paritaprevir-Ritonavir

66. Hepatitis web study Hepatitis web study This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online www.hepatitisc.uw.edu www.hepatitisc.uw.edu Hepatitis Web Study http://depts.washington.edu/hepstudy/ http://depts.washington.edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention. This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online www.hepatitisc.uw.edu www.hepatitisc.uw.edu Hepatitis Web Study http://depts.washington.edu/hepstudy/ http://depts.washington.edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention.