Luis A. Balart, MD. Professor of Medicine Tulane University New Orleans, Louisiana

Transcription

1 Luis A. Balart, MD Professor of Medicine Tulane University New Orleans, Louisiana

2 Faculty Disclosures Research support from Gilead Sciences, Merck, AbbVie, Tobira, Intercept, Galectin, Salix Speakers Bureau for Merck, Gilead, AbbVie Advisory Board Merck, Abbvie

3 Rising Cure Rates for Chronic HCV Cure Rate* 100% 80% 60% 40% 20% 0% IFN 16% IFN/RBV 35% PegIFN/RBV 44% Telaprevir or Boceprevir + PegIFN/RBV 70% 2 nd Gen DAAs IFN-Free Regimens >90% 3 rd Gen DAAs IFN-Free Regimens >95% *Cure rates based on data from clinical trials.

4 Anti-HCV+ (%) Prevalence of HCV Infection by Age and Gender US, Total Females Males 0 CDC, unpublished data Age (Years)

5 HIV Infected ~300,000 (30%) Incarcerated ~310,000 (15%) Veterans ~280,000 (8%) IDUs ~300,000 (80%-90%) Alcoholics ~250,000 (11%-36%) Homeless ~175,000 (22%)

6 Number of HCV Cases (millions) Estimates of People Living With Chronic HCV in the US Conservative estimate Upper limit of estimate 3.2 NHANES Estimate HCV Cases Not Included in NHANES* Estimated Total HCV Cases Chak E, et al. Liver Int. 2011

7 CDC and USPSTF Recommendations for HCV Screening Regardless of risk factors, one-time testing for HCV of adults born between ,2 Testing of persons of all ages at risk for HCV infection CDC also recommends for those identified with HCV infection 1 Brief alcohol screening and intervention as clinically indicated Referral to appropriate care and treatment services for HCV infection and related conditions Centers for Disease Control and Prevention (CDC). MMWR. 2012;61(4):1-18. Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.

8 Clinical Considerations on the Progression of HCV Infection Of every 100 persons infected with HCV, approximately 75% to 85% will develop chronic infection 60% to 70% will develop chronic liver disease 5% to 20% will develop cirrhosis in 20 to 30 years 1% to 5% will die from the consequences of chronic infection (liver cancer or cirrhosis)

9 Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US 20% 5% Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans Cirrhosis and Decompensated Cirrhosis 18% 16% 14% 12% 10% 8% 6% Decompensated Cirrhosis Cirrhosis HCC 4% 3% 2% 1% Hepatocellular Cancer (HCC) 4% % El-Serag HB. Gastroenterology. 2012;142:

10 Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to Rate per 100,000 People HIV Hepatitis C Hepatitis B Year 15,106 12,734 The number of HCV-related deaths has since continued to increase; HCV-related deaths rose to 19,659 in , Ly KN, et al. Ann Intern Med. 2012;156(4): Available at: Accessed May 10, 2016.

11 Factors Associated with Fibrosis Progression Host: Alcohol consumption Non alcoholic fatty liver disease Obesity Insulin resistance Older age at infection and male gender Organ transplant Ghany MG, et al. Hepatology. 2009;49(4):

12 Viral Factors Associated with Fibrosis Progression Genotype 3 Coinfection with HBV or HIV Ghany MG, et al. Hepatology. 2009;49(4):

13 Extrahepatic Manifestations of HCV Strongly associated Mixed cryoglobulinemia Sjögren (sicca) syndrome Lymphoproliferative disorders Porphyria cutanea tarda Neuropathy Membranoproliferative glomerulonephritis Cryoglobulinemic vasculitis Possibly associated Corneal ulcers (Mooren ulcers) Thyroid disease Lichen planus Pulmonary fibrosis Type 2 diabetes Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis) Arthralgias, myalgias, inflammatory polyarthritis Autoimmune

14 HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable disease HCV does not archive its genome What does cure mean? Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection SVR12 is almost invariably durable Ghany MG, et al. Hepatology. 2009;49(4):

15 Cure Lawitz et al studied over 5000 pts treated with DAA s 3 Year follow up SVR maintained in 99.7% 6 pts had virologic evidence of late relapse 12 pts had evidence of reinfection Lawitz et al EASL 2016.

16 Cure How long to retest? Seems reasonable to test after one year After that I do not recommend continued testing Selective testing if risk factors identified Ghany MG, et al. Hepatology. 2009;49(4):

17 HCC Lawitz et al studied over 5000 pts treated with DAA s 0.3% incidence of HCC Lawitz et al EASL 2016.

18 How to Best Stage Fibrosis Liver biopsy still the gold standard. Cost, risk Other alternatives rapidly gaining acceptance: Fibroscan, cheapest and easiest, can be done in clinic Ultrasound shear wave elastography MR elastography Ghany MG, et al. Hepatology. 2009;49(4):

19 SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis Baseline factors significantly associated with all-cause mortality: Older age GT 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use 10-year cumulative occurrence rate (%) Van der Meer A, et al. JAMA. 2012; 308: patients followed for a median of 8.4 years SVR patients All-cause mortality Liver-related mortality or liver transplant Non-SVR patients HCC Liver failure

20 0.3 SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Genotype 1 (n=12,166) SVR rate: 35% 0.3 Genotype 2 (n=2904) SVR rate: 72% 0.3 Genotype 3 (n=1794) SVR rate: 62% Cumulative Mortality (%) P<.0001 Non-SVR SVR P<.0001 Non-SVR Years Years Years SVR Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility ( ). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9: P<.0001 Non-SVR SVR

21 Global Distribution and Prevalence of HCV Genotypes: US Focus on GT 1 Messina JP, et al. Hepatology, 2015; 61:

22 Multi-targeted Approach for Treatment: Approved Protease, Polymerase and NS5A Inhibitors 5 UTR region 9.6 kb RNA 3 UTR region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Polyprotein Processing C E1 E2 Core Envelope Glycoproteins p7 NS2 Protease Simeprevir Paritaprevir Grazoprevir NS3 Serine Helicase Serine Protease Protease Cofactor NS3-4A protease inhibitors NS4A NS4B NS5A Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir NS5B RNA-dependent RNA polymerase NS5B polymerase inhibitors Adapted from McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48: nucleoside analogs Sofosbuvir non- nucleoside analogs Dasabuvir

23 Ledipasvir (LDV) (NS5A inhibitor) + sofosbuvir (SOF) (nucleotide polymerase inhibitor)

24 HCV-TARGET: Real World Data Ledipasvir/sofosuvir (LDV/SOF)+ ribavirin is approved for G1 and G4 Clinical trials demonstrated SVR rates > 95% across many patient groups but real world data are lacking Potential gaps in knowledge Frequency of 8-week treatment and efficacy in labeled population True rates of discontinuation and adverse events Baseline factors associated with SVR HCV-TARGET evaluated safety and efficacy of LDV/SOF in a real-world cohort Efficacy of 8 vs. 12 weeks treatment Impact of baseline factors on treatment outcomes Terrault N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA Nov 13-17, 2015.

25 HCV-TARGET: Status of LDV/SOF Treated Patients Terrault N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA Nov 13-17, 2015.

26 HCV-TARGET: SVR12 and Relapse Rates for LDV/SOF + RBV by Treatment Duration in HCV G1 Patients Terrault N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

27 HCV-TARGET: Baseline Predictors of SVR Among Patients Treated with LDV/SOF Nobs OR CL UCL P-val Male Age White* Genotype 1A* Albumin >=3.5g/dl* Platelet* (1000/ul) TBIL <+ 1.2mg/dl* HGB* (g/dl) HCV >=6 min* No Cirrhosis* Treatment Naive* Compensated* no PPI at baseline* Favors Failure Favors SVR *Estimated with logistic regression with the predictor of interest, adjusted for age and sex <.001 < < < Odds Ratio, 95% CL, and p-value Completed treatment as of 7/1/2015 and have available virological outcomes. Patients who discontinued due to AE or were lost to follow-up are excluded. Terrault N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

28 HCV-TARGET: Summary LDV/SOF-containing 8 and 12 week treatment regimens are highly effective across a broad spectrum of G1-infected patients and clinical practices The 8-week regimen is underutilized; greater use of this shorter treatment course should be encouraged HCV RNA measurement at week 4 not indicative of treatment failure Discontinuation rates are very low despite diverse patients and clinical settings Overall SVR rates were high, although PPI use was associated with a higher rate of virological failure This may be a potentially modifiable factor to further maximize SVR rates Terrault N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

29 TRIO: Real World Experience Academic and community treatment of a real-world, heterogeneous population Afdhal N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

30 TRIO: SVR Rates by Regimen LDV-SOF LDV-SOF +RBV SMV-SOF +/-RBV VKP +/-RBV Percent (%) Relapse 44 Death 3 LTFU 33 Relapse 0 Death 0 LTFU 1 Relapse 5 Death 0 LTFU 4 Relapse 2 Death 0 LTFU 1 20 DC 9 DC 1 DC 0 DC / /76 32/41 43/47 Afdhal N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

31 TRIO: SVR Rates Inside vs. Outside FDA Guidelines LDV-SOV +/- RBV VKP +/- RBV SMV+SOF +/- RBV Total Outside Guidelines 85% (115/135) 83% (5/6) 63% (5/8) 84% (125/149) Inside Guidelines 95% (1391/1462) 93% (38/41) 82% (27/33) 95% (1456/1563) Total 94% (1506/1597) 91% (43/47) 78% (32/41) 94% (1581/1685) *Patients outside of guidelines: GT1a on VKP without RIBV, tx failure cirrhotic patients on 12 weeks of VKP+/-RBV, LDV-SOF without RBV, or SMV+SOF+/-RBV Afdhal N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

32 TRIO: Predictors of Response Variable Full Population Distribution % (n) Treatment Failure Distribution % (n) p-value Platelets<100k/ml Platelets 1001+/ml 11% (170) 89% (1320) 40% (19) 60% (29) <0.001 Cirrhosis No Cirrhosis 31% (504) 69% (1138) 70% (35) 30% (15) <0.001 Outside FDA Guidelines Inside FDA Guidelines 10% (149) 90% (1536) 33% (17) 37% (34) <0.001 Male 58% (975) 76% (39) Female 42% (710) 24% (12) *Patients outside of guidelines: GT1a on VKP without RIBV, tx failure cirrhotic patients on 12 weeks of VKP+/-RBV, LDV-SOF without RBV, or SMV+SOF+/-RBV *2-side asympt. p-value via person Afdhal N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

33 TRIO: Conclusions Overall SVR in real world G1 HCV patients is 94% across all DAA therapies 149 patients were treated outside of FDA guidelines and saw a significantly lower SVR rate (84% SVR outside vs. 95% SVR inside) Platelets <100k/mL, cirrhosis, prescribing outside of FDA guidelines, and males all had a positive association with treatment failures Practice type, ethnicity, genotype subtype, baseline viral load, post transplant, age, treatment status, and HIV had no clear association with treatment failures Overall discontinuation rate was <1% (12/1685) Afdhal N, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

34 LDV/SOF Lessons Learned: Use Guidelines to best manage patients Stage patients with multiple testing methods Compliance is high with the new DAAs Ribavirin has a narrow role in treating HCV

35 Paritaprevir/r (protease inhibitor/ritonavir)/ombitasvir (NS5A inhibitor)/dasabuvir (non-nucleoside polymerase inhibitor) + RBV (PTV/RTV/OMV/DSV + RBV) (Now co-formulated as QD extended release tablet)

36 Integrated Efficacy: SVR12 in GT 1a Non-cirrhotic Patients Treated with PTV/RTV/OMV/DSV for 12 Weeks (+/- RBV) (SAPPHIRE-I and II, PEARL-IV) p=0.004 p= Placebo Ribavirin SVR12 (%) / / 593 All Patients Everson G, et al. Abstract #83, AASLD / / 420 Treatment Naïve 47/ 50 Relapse 36/ 36 83/ 87 Null Prior PegIFN/RBV Response Logistic regression: baseline BMI and treatment regimen (+/- RBV) were significant variables for not achieving SVR

37 Integrated Efficacy: SVR12 in GT 1a Cirrhotic Patients Treated with PTV/RTV/OMV/DSV + RBV for 12 vs 24 Weeks (TURQUOISE-II) p=0.08 p=0.73 p= weeks 24 weeks SVR12 (%) / / 121 All Patients 61/ 66 Everson G, et al. Abstract #83, AASLD / 56 Treatment Naïve 14/ 15 13/ 13 Relapse 11/ 11 10/ 10 Partial Responder 40/ 50 39/ 42 Null Responder Prior PegIFN/RBV Response Logistic regression: IL28B TT, prior null, North American region and history of IDU were significant variables for not achieving SVR

38 PTV/RTV/OMV/DSV Lessons Learned: GT 1a patients without cirrhosis modestly benefit from RBV inclusion in 12 week treatment regimen GT 1a patients with cirrhosis benefit from a 24 week treatment duration in the NULL responder group

39 SVR12 in GT 1b Non-cirrhotic Patients Treated with PTV/RTV/OMV/DSV for 12 Weeks (+/- RBV) 100 Pooled analysis of Phase 3 trials + RBV - RBV SVR12 (%) / /572 Overall Colombo M, et al. AASLD Boston. # / /361 Treatment naive* 33 /33 67 /68 Relapse 26 /26 52 /53 Partial response 32 /32 86 /90 Null response Treatment-experienced *Includes 1 treatment-naive G1b pt who was enrolled in PEARL-IV study

40 SVR12 in GT 1b Cirrhotic Patients Treated with PTV/RTV/OMV/DSV + RBV for 12 vs 24 Weeks Pooled analysis of Phase 3 trials All treated with RBV 12 Weeks 24 Weeks SVR12 (%) /68 51 /51 Overall 22 /22 18 /18 Treatment naive 14 /14 10 /10 Relapse 6 /7 3 /3 Partial response 25 /25 20 /20 Null response Colombo M, et al. AASLD Boston. #1931. Treatment-experienced

41 PTV/RTV/OMV/DSV Lessons Learned: GT 1b patients without cirrhosis do not benefit from the inclusion of RBV in the 12 week treatment regimen GT 1b patients with cirrhosis require only 12 weeks of treatment; Should they receive RBV? RBV-free therapy was not studied in the cirrhotic population The current label does not require RBV for GT1b cirrhosis 1 1. VIEKIRA PAK (R) [package insert]. North Chicago IL: AbbVie Inc; 2016.

42 SVR12 in HCV/HIV Co-infected Patients Treated with PTV/RTV/OMV/DSV + RBV for 12 vs 24 Weeks (TURQUOISE I) SVR12, % /31 12 Weeks 29/32 24 Weeks 24% black race, 19% compensated cirrhosis, 89% GT 1a, 16% null response to prior PEG/RBV therapy 2 of the failures in the 24 week arm were believed to have been reinfected with a different GT 1a isolate Sulkowski M, et al. JAMA. online February 23, doi: /jama

43 PTV/RTV/OMV/DSV : Points to Consider Four drug fixed dose combination extended-release tablet; three tablets taken orally once daily No dosage adjustment required in patients with mild, moderate or severe renal impairment Regimen is contraindicated in patients with moderate to severe hepatic impairment Drug:drug interaction: Contraindications Drugs highly dependent on CYP3A for clearance, moderate or strong inducers of CYP3A, strong inducers of CYP2C8 or strong inhibitors of CYP2C (Some examples: gemfibrozil, rifampin, St. John s Wort, lovastatin, simvastatin, efavirenz) Ethinyl estradiol-containing medications must be discontinued prior to starting therapy because of risk for elevated ALT Rosuvastatin and pravastatin: Okay to use; however, dose of rosuvastatin should not exceed 10 mg/day and pravastatin should not exceed 40 mg/day Omeprazole: Monitor patients for decreased efficacy of omeprazole and consider increasing dose (no more than 40 mg/day) in patients whose symptoms are not well controlled Viekira XR Package Insert. AbbVie Inc., North Chicago, IL. July 2016.

44 Grazoprevir (NS3/4A protease inhibitor) + elbasvir (NS5A inhibitor) ± RBV

45 SVR12: Grazoprevir/Elbasvir (GZR/EBR) for 12 Weeks in GT 1 Treatment-Naïve Patients (C-EDGE) 67% of failures due to relapse Most common adverse events were headache, fatigue, nausea and arthralgia (no difference from placebo arm) Patients, (%) / / / / 246 All Patients GT 1a GT 1b No Cirrhosis 68/ 70 Cirrhosis Zeuzem, et al. Abstract #G07, EASL. 2015; published online at Ann Intern Med ( on April

46 GZR/EBR: Patients With Severe Renal Impairment (C-SURFER) <1% of GZR and EBR is renally excreted No RBV This study evaluated GZR+EBR in HCV-infected patients with CrCl<30 ml/min, including patients on hemodialysis GT 1 treatment-naïve or treatment-experienced CKD stage 4/5 Included compensated cirrhotics Roth, et al. Abstract #LP-02, EASL 2015

47 GZR/EBR x 12 Weeks: On Treatment Virologic Response (C-SURFER) Patients (HCV RNA <LLoQ), % % 81/ % 100% 100% 99% 109/ / 119 TW2 TW4 TW12 (EOT) Efficacy is presented for the modified full analysis set population (mfas). 118/ 118 FW4 115/ 116 FW12 (SVR12) 1 noncirrhotic patient with HCV GT 1b infection relapsed at FW12 Roth D, et al. Lancet. 2015;386(10003):

48 Elbasvir/Grazoprevir and Baseline NS5A Polymorphisms in GT1a In GT1a patients, HCV NS5A amino acid polymorphisms at M28, Q30, L31, or Y93 was associated with reduced efficacy of Elbasvir/Grazoprevir for 12 weeks* *Regardless of prior treatment history or cirrhosis status Zepatier() [package insert]. Whitehouse Station, NJ Merck and Co Inc; 2016.

49 Elbasvir/Grazoprevir and Baseline NS5A Polymorphisms in GT1a In GT1a patients, testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended The presence of baseline polymorphisms requires 16 weeks of treatment Recommended Dosages and Durations for Zepatier in G1 G4 Patients Zepatier() [package insert]. Whitehouse Station, NJ Merck and Co Inc; 2016.

50 Sofosbuvir (SOF) (NS5B polymerase inhibitor) + Velpatasvir (VEL) (pan-genotypic NS5A inhibitor)

51 SOF/VEL: ASTRAL Study Program Phase 3 study which evaluated treatment with a fixed dose combination of SOF/VEL for 12 weeks Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

52 ASTRAL 1: Study Design Phase 3 study evaluated SOF/VEL for 12 weeks in patients with HCV GT 1, 2, 4, 5 or 6 infection Double blind, placebo controlled Broad inclusion criteria 5:1 randomization to SOF/VEL or placebo Stratified by genotype and cirrhosis (presence/absence) GT5 patients not randomized Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

53 ASTRAL 1: SVR 12 by Genotype Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

54 ASTRAL 1: SVR 12 by Cirrhosis or Prior Treatment Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

55 ASTRAL 1: Safety Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

56 ASTRAL 1: Conclusions Treatment with SOF/VEL for 12 weeks resulted in 99% SVR12 rate in patients with HCV GT1, 2, 4, 5 or 6 infection 1 99% SVR12 rate in patients with cirrhosis 99% SVR12 rate in patients with prior treatment failure Presence of baseline NS5A RAVs did not impact SVR12 1 Treatment with SOF/VEL for 12 weeks was well tolerated, with a safety profile similar to that of placebo treatment 1 SOF/VEL for 12 weeks provides a simple, safe and highly effective treatment for patients with HCV GT1, 2, 4, 5 or 6 1 ASTRAL 3 came to the same conclusion in GT3 patients 2 1. Feld JJ, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015; 2. Mangia A, et al. Presented at: American Association for the Study of Liver Diseases 2015 Annual Conference; San Francisco, CA. Nov 13-17, 2015.

57 GT 2 and GT 3 Patients

58 GT 3 Is Associated With a Significantly Higher Risk of Cirrhosis and HCC vs GT 1 VA HCV Clinical Case Registry ( ) 88,348 patients with genotype 1 (80%) 13,077 genotype 2 (12%) 8,337 genotype 3 (7.5%) Mean follow-up 5.4 years After adjustment for demographic, clinical and antiviral treatment factors, comparison between genotypes 3 and 1 Hazard Ratio Confidence Interval Cirrhosis HCC Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment Kanwal F, et al. Hepatology. 2014;60:

59 DCV/SOF for GT 3: SVR12 in Treatment-naïve and Treatmentexperienced patients Treated for 12 Weeks (ALLY-3) FDA Approved for GT 3 in July SVR12 (%) /101 44/51 Treatment-naive Treatment-experienced Nelson DR, et al. Hepatology. 2015; 61:

60 DCV/SOF for GT 3: SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3) SVR12 (%) Overall Tx-naive Tx-experienced No Yes No Yes Cirrhosis No Yes Nelson DR, et al. Hepatology. 2015; 61:

61 AASLD/IDSA Guidance Document on GT 2 and GT 3 Patients GT 2 Treatment Naïve and Treatment Experienced SOF/VEL for 12 weeks SOF + DCV for 12 weeks (alternative for non-cirrhotics) SOF + DCV for weeks (alternative for compensated cirrhotics) GT 3 Treatment Naïve and Treatment Experienced SOF/VEL for 12 weeks (non-cirrhotic) SOF/VEL + RBV for 12 weeks (compensated cirrhotics) DCV + SOF for 12 weeks (non-cirrhotic) DCV + SOF + RBV for 24 weeks (compensated cirrhotics) Available at Accessed October 3, 2016.

62 Louisiana Medicaid Coverage Plan A: Zepatier, Harvoni Plan B: Epclusa, Harvoni, Zepatier, Daclinza, Technovie, Olysio, Viekira Pak or XL Plan C: Zepatier, Epclusa Plan D: Epclusa, Zepatier, Sovaldi Plan E: Sovaldi, RBV, Pegasys, PegIntron

63 Pangenotypic Combination Therapies in Late-stage Development Combination Treatment Phase Manufacturer ABT-493 (NS3/4A protease inhibitor) + 3 AbbVie ABT-530 (NS5A inhibitor) Sofosbuvir (nucleotide polymerase inhibitor) + GS (NS5A inhibitor) + GS-9857 (NS3/4A protease inhibitor) 3 Gilead Grazoprevir (NS3/4A protease inhibitor), MK-3682 ( NS5B polymerase inhibitor) and elbasvir (NS5A replication complex inhibitor) 2 Merck Grazoprevir (NS3/4A protease inhibitor), MK-3682 (NS5B polymerase inhibitor) and MK-8408 (NS5A replication complex inhibitor) 2 Merck

64 Overall Conclusions Highly active area of drug development with multiple treatment options available now and more expected in the near term All oral regimens offer very favorable safety profiles and SVR rates >90% Need for baseline resistance testing remains controversial HIV/HCV infected patients recommended regimens are the same as for HCV monoinfected patients; however, extra caution needed regarding drug:drug interactions AASLD/IDSA Guidance Document Watch for updates ( Drug:drug interactions reference

65 PartingThoughts Treatment population is changing: more comorbidities, more Medicaid, more with limited coverage We need to treat more pts if we are to eradicate this disease and prevent its morbidity and mortality. Treat as infectious disease! We need less costly regimens in order to achieve this Eventually most patients can be treated with close to 100% efficacy and virtually no side effects and for shorter duration We need to look for alternative drug delivery systems h d i t ti

66 General Discussion Q&A