3/28/2016. The Top 5 Things to Remember about Treating HCV

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1 The Top 5 Things to Remember about Treating HCV Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina FORMATTED: MM/DD/YY New York, New York: March 23, 16 Financial Relationships With Commercial Entities Dr Naggie has received research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Tacere, and Vertex Pharmaceuticals, Inc paid to her institution. She has served as a scientific advisor to AbbVie, Bristol-Myers Squibb, Merck & Co, Inc, and Gilead Sciences, Inc. (Updated 1/01/16) Divested all consulting and advisory positions (personal financial conflict) 10/01/15 due to Co-Chair position on AASLD/IDSA Guidance Slide 2 of 41 Slide 3 of 41 Learning Objectives After attending this presentation, participants will be able to: List the options for assessing liver fibrosis Describe the AASLD/IDSA Guideline recommendations for management and treatment of HCV Infection Describe the drug interactions with antiretrovirals and HCV direct acting antivirals (DAAs) Describe treatment plans for difficult to treat patients, including those with cirrhosis and NS5A drug resistanceassociated viral variants 1

Grazoprevir is a 1. NS3/4A Protease Inhibitor 2. NS5A Inhibitor 3. NS5B Non-nucleoside polymerase inhibitor 4. NS5B Nucleotide polymerase inhibitor 5.

.. Slide 4 of 41 Enter Question Text The AASLD/IDSA Guidelines are: 1. Funded by industry 2. Updated frequently as new data are released 3. I have never heard of these guidelines 4.

2 Grazoprevir is a 1. NS3/4A Protease Inhibitor 2. NS5A Inhibitor 3. NS5B Non-nucleoside polymerase inhibitor 4. NS5B Nucleotide polymerase inhibitor 5. A tropical place I would like to visit one day NS3/4A Protease Inhibitor 44% NS5A Inhibitor NS5B Non-nucleoside polymera.. % 13%12%11% NS5B Nucleotide polymerase i... A tropical place I would like to v... Slide 4 of 41 Enter Question Text The AASLD/IDSA Guidelines are: 1. Funded by industry 2. Updated frequently as new data are released 3. I have never heard of these guidelines 4. A resource for Hepatologists 5. The best thing since sliced bread Slide 5 of 41 Funded by industry 4% Updated frequently as new dat... 80% I have never heard of these gui... 10% 3% 3% A resource for Hepatologists The best thing since sliced bread When and In Whom to Initiate HCV Therapy Slide 6 of

All of the non-invasive markers below are suggestive of cirrhosis except: 1. APRI 2.1 2. FibroSure 0.85 3. Transient elastography 7.5 kpa 4. FIB-4 3.8 5.

3 All of the non-invasive markers below are suggestive of cirrhosis except: 1. APRI FibroSure Transient elastography 7.5 kpa 4. FIB This is a trick question as they are all associated with cirrhosis 10% 22% 18% APRI 2.1 FibroSure 0.85 Transient elastography 7.5 kpa FIB % This is a trick question as they... 42% Slide 7 of 41 Gold standard Invasive - Morbidity (3/1,000) - Mortality (1/10,000) Observer variability Sampling error Costly Staging of Liver Disease: Liver Biopsy F1 F2 F3 F4 Slide 8 of 41 Rockey DC, et al. Hepatology. 09;49: Regev A, et al. Am J Gastroenterol. 02: Alternatives to Liver Biopsy Noninvasive approaches Serum markers Standard laboratory tests: APRI (<0.3,>2), FIB-4 (>3.25) Commercial assays (FibroSure) (>0.8) Radiographic tests Elastography Limitations Ability to distinguish F1 versus F2, etc. Better to differentiate advanced versus early fibrosis Serologies impacted by inflammation Indeterminate outcomes common Slide 9 of 41 Lin ZH, et al Hepatology. 11;53: Vallet-Pichard A, et al. Hepatology. 07;46: Myers RP, et al. Dig Dis Sci. 03;48; Friedrich-Rust M, et al. Z Gastroenterol. 13 Jan;51:

Slide 10 of 41 Radiographic Assessments Newer Methods Ultrasound, CT, MRI Conventional studies are unhelpful in assessment of fibrosis unless patient has decompensated cirrhosis Elastography

characteristics Mean AUROC for the diagnosis of: Severe fibrosis: 0.89 (95% CI, 0.88-0.91) Cirrhosis: 0.94 (95% CI, 0.93-0.95) Friedrich-Rust M, et al. Z Gastroenterol. 13 Jan;51:43-54.

4 Slide 10 of 41 Radiographic Assessments Newer Methods Ultrasound, CT, MRI Conventional studies are unhelpful in assessment of fibrosis unless patient has decompensated cirrhosis Elastography Transient elastography Methodology Ultrasonic transducer sends a vibration wave into the liver Elastic shear wave propagates through the liver Velocity of wave correlates with tissue stiffness Test characteristics Mean AUROC for the diagnosis of: Severe fibrosis: 0.89 (95% CI, ) Cirrhosis: 0.94 (95% CI, ) Friedrich-Rust M, et al. Z Gastroenterol. 13 Jan;51: HIV/HCV Co-infection Slide 11 of 41 Hepatitis C Virus 5 UTR region HCV Genome 9.6 kb RNA 3 UTR region Polyprotein IRES-mediated translation C E1 E2 NS2 NS3 A NS4B A NS5 B Polyprotein Processing C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Envelope glycoproteins Serine Protease Serine Protease Cofactor RNA dependent RNA polymerase NS3-4A Protease Inhibitors NS5A Inhibitors NS5B Polymerase Inhibitors Slide 12 of 41 Adapted from Naggie et al. J Antimicrob Chemother 10 4

5 Agents and Regimens Antiviral Regimen NS3 NS5A Non-Nuc NS5B Nuc NS5B Daclatasvir + sofosbuvir Elbasvir/grazoprevir FDC Ledipasvir/sofosbuvir FDC Paritaprevir/r/ombitasvir FDC + dasabuvir (PrO+D) RBV 1a only Simeprevir + sofosbuvir Sofosbuvir + ribavirin Velpatasvir/sofosbuvir* FDC Slide 13 of 41 *pending FDA approval The current recommended length of therapy for a treatment experienced GT-1 infected patient without cirrhosis is: 1. 6 weeks 2. 8 weeks weeks weeks weeks 83% 1% 8% 7% 1% 6 weeks 8 weeks 12 weeks 16 weeks 24 weeks Slide 14 of 41 Slide 15 of 41 Recommended regimens for treatment-naïve and experienced patients with HIV/HCV genotype 1 without cirrhosis Regimen Weeks Rating Daclatasvir + sofosbuvir* 12 I, A Elbasvir/grazoprevir (except GT1a with NS5A RAV)* 12 I, A Ledipasvir/sofosbuvir** 12 I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a 12 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Simeprevir + sofosbuvir 12 I, A *recommended in first wave PI failures (ELB/GRZ requires RBV) **recommended in first wave PI failures and prior SOF failure (add RBV) 5

Slide courtesy of Jennifer Kiser 3/28/16 Slide 16 of 41 Take Home #1: Cure is same for HIV/HCV 100 90 80 70 60 50 40 30 10 0 97 100* 95 95 96 97 96 92* 92 89 DAC/SOF ELB/GRZ LDV/SOF PrOD GECCO

6 Slide courtesy of Jennifer Kiser 3/28/16 Slide 16 of 41 Take Home #1: Cure is same for HIV/HCV * * DAC/SOF ELB/GRZ LDV/SOF PrOD GECCO HIV/HCV HCV Naggie et al, NEJM 15; Sulkowski et al, JAMA 15; Wyles et al, NEJM 15; Rockstroh et al, Lancet HIV 15; Christensen et al, CROI 16; Sulkowski et al, NEJM 15 ARV Interaction Score Card 15 Simeprevir Sofosbuvir Ledipasvir Daclatasvir P/r/O + D Inhibitor of Inhibit/Sub of Substrate of Inhibitor/ Drug Substrate of OATP1B1/3, BCRP, UGT1A1,OATP1B1/3, CYP3A4, Substrate of P-gp Interaction P-gp and BCRP Substrate of P-gp BCRP, CYP3A4, OATP1B1/3 and BCRP and CYP3A4 CYP2C8, P-gp ATV/r No data No data LDV ; ATV DCV * ATV ; PAR DRV/r SIM ; DRV SOF ; DRV LDV ; DRV ALLY-2 DRV ; PAR LPV/r No data No data No data ALLY-2 LPV ; PAR TPV/r No data No data No data No data No data EFV SIM ; EFV SOF ; EFV ION-4 DCV * No PK data** RPV SIM ; RPV SOF ; RPV LDV ; RPV ALLY-2 PAR ; RPV ETV No data No data No data No data* No data RAL SIM ; RAL SOF ; RAL LDV ; RAL ALLY-2 PrOD ; RAL ELV/cobi No data Cobi ; SOF LDV ; SOF No data No data DLG No data No data LDV ; DLG ALLY-2 PAR ; DLG MVC No data No data No data No data No data TDF SIM ; TFV SOF ; TFV LDV ; TFV DCV ; TFV PrOD ; TFV Slide 17 of 41 * Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, ** PrOD + EFV led to premature study discontinuation due to toxicities Ledipasvir and TDF LDV/SOF + EFV/TDF/FTC RPV/TDF/FTC RAL + TDF/FTC ATV/r + TDF/FTC DRV/r + TDF/FTC Slide 18 of 41 AUC tau (ng.h/ml) 3600 (4400) 4286 (4780) / /4260 German et al, ClinPharm 14; German et al. CROI 15 Abstract 82; Naggie et al. NEJM 15 6

Slide courtesy of Jennifer Kiser 3/28/16 Real World Data suggests higher relapse to LDV/SOF with PPI PPI use in TARGET 28% Slide 19 of 41 Terrault et al, AASLD 15 A Clinical Caveat: LDV and Acid

Slide of 41 German et al, AASLD 15 Drug Interactions ARV Interaction Score Card 16 Elbasvir/ Grazoprevir Substrate of CYP3A4, P- gp, OATP1B1/3; Inhibitor of BCRP, P-gp, CYP2C8, 3A4, UGT1A1

7 Slide courtesy of Jennifer Kiser 3/28/16 Real World Data suggests higher relapse to LDV/SOF with PPI PPI use in TARGET 28% Slide 19 of 41 Terrault et al, AASLD 15 A Clinical Caveat: LDV and Acid Suppressing Medications Healthy volunteer data only Dosing recommendations is difficult for patients Possible relevance in HIV in particular? Slide of 41 German et al, AASLD 15 Drug Interactions ARV Interaction Score Card 16 Elbasvir/ Grazoprevir Substrate of CYP3A4, P- gp, OATP1B1/3; Inhibitor of BCRP, P-gp, CYP2C8, 3A4, UGT1A1 Velpatasvir/ Sofosbuvir Substrate of P-gp, BCRP, OATP, CYP2B6, 2C8, 3A4; Inhibitor of P- gp, BCRP, OATP Ledipasvir/ Sofosbuvir Inhibitor/ Substrate of P-gp and BCRP P/r/O + D Inhibit/Sub of UGT1A1,OATP1B1/3, BCRP, CYP3A4, CYP2C8, P-gp ATV/r GRZ & ELB, ATV VEL ; ATV LDV ; ATV ATV ; PAR DRV/r GRZ & ELB ; DRV VEL ; DRV LDV ; DRV DRV ; PAR LPV/r GRZ & ELB ; DRV VEL ; LPV No data LPV ; PAR TPV/r No data No data No data No data EFV GRZ & ELB, EFV VEL ; EFV ION-4 No PK data** RPV GRZ & ELB ; RPV VEL ; RPV LDV ; RPV PAR ; RPV ETV No data No data No data No data RAL GRZ & ELB ; RAL VEL ; RAL LDV ; RAL PrOD ; RAL ELV/cobi No data VEL ; SOF LDV ; SOF No data DLG GRZ & ELB ; DLG VEL ; DLG LDV ; DLG PAR ; DLG MVC No data No data No data No data Slide 21 of 41 TDF GRZ & ELB ; TFV VEL ; TFV LDV ; TFV PrOD ; TFV 7

SVR % SVR12, % 3/28/16 Slide 22 of 41 Take Home #2: Shortening therapy with current DAA increases relapse HCV MONO Tx Naïve, No cirrhosis: HIV/HCV COINFECTION ION-3 Naïve : ALLY-2 (DCV/SOF) 100 90 80

8 SVR % SVR12, % 3/28/16 Slide 22 of 41 Take Home #2: Shortening therapy with current DAA increases relapse HCV MONO Tx Naïve, No cirrhosis: HIV/HCV COINFECTION ION-3 Naïve : ALLY-2 (DCV/SOF) HCV RNA <6 million IU/mL -8 weeks 121/123 (98%) -12 weeks 129/131 (98%) -RBV +RBV 8 weeks relapse (4.5%) -RBV 12 weeks 3 relapse (1%) / /41 ION-3 Kowdley et al. NEJM; Wyles et al. CROI 15 LB151 Tx 12 weeks 8 weeks 1 relapse (1%) 10 relapse (25%) Shortening therapy increases impact of baseline predictors PRO Baseline viral load can predict decrease risk of relapse Real World Cohorts TRIO 242/254 (95%) TARGET 150/154 (97%) GECCO 175/191 (92%) Cheaper 24/26 HIV/HCV (92%) CON Baseline viral load is not the only predictor and has poor accuracy Real World Cohorts VA greater failure for 8 weeks in black veterans Only ~40% of TARGET eligible got 8 weeks under use? Good medical decision making? Failure = resistance 65% Slide 23 of 41 Terrault et al, AASLD 15; Curry et al, AASLD 15; Backus et al. AASLD 15 Shortening therapy increases impact of baseline predictors Slide 24 of 41 O brien et al, OFID 15 8

9 Gender and Race in Real World Experience Gender TARGET (43% overall) Women more likely to get 8 weeks (54% vs 41%) Women higher SVR (OR 2.0) TRIO (47% overall) Also more likely to get 8 weeks (54% vs 44%) SVR same Race TARGET no signal (%) TRIO trend to lower SVR (18%) VA lower SVR lost when analysis only of 12 week duration (38% black) Slide 25 of 41 Terrault et al, AASLD 15; Curry et al, AASLD 15; Backus et al. AASLD 15 Slide 26 of 41 Recommended regimens for HIV/HCV genotype 1 and compensated cirrhosis Regimen Weeks Rating Treatment Naïve or Experienced Elbasvir/grazoprevir (except GT1a with NS5A RAV)* 12 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Treatment Naïve Only Ledipasvir + sofosbuvir 12 I, A Treatment Experienced Only Daclatasvir + sofosbuvir ± ribavirin (only PI failures) 24 IIa, B Ledipasvir + sofosbuvir + ribavirin* 12 I, A Ledipasvir + sofosbuvir** 24 I, A *recommended in first wave PI failures (ELB/GRZ requires RBV) **recommended in first wave PI failures and prior SOF failure (add RBV) Take home #3: Cirrhosis requires RBV or longer therapy for some but not all SIRIUS: LDV/SOF+RBV X 12W or LDV/SOF X 24W in TE Cirrhosis /77 75/77 LDV/SOF LDV/SOF/RBV LDV/SOF 12 Weeks* 12 Weeks 24 Weeks TURQUOISE-II: P/r/O/D X12 weeks in Genotype 1b Cirrhosis SVR /60 60/60 60/60 60/60 RVR EOT SVR4 SVR12 *not Slide arm 27 of in 41 SIRIUS shown for historic comparison Poordad et al. EASL 15; Bourliere et al. Lancet ID 15; Reddy et al. Hepatology 15. 9

Take Home #4: NS5A RAVs matter Fold-change 1a 1b M28T Q30R L31M/V Y93H/N L31V Y93H/N >100x/ >1,000x/ LDV x >100x >100x >10,000 <3x >10,000x/ Ombitasvir >1000x >100x >100x >10,000x >100x/ >1,000x/ DCV

10 Take Home #4: NS5A RAVs matter Fold-change 1a 1b M28T Q30R L31M/V Y93H/N L31V Y93H/N >100x/ >1,000x/ LDV x >100x >100x >10,000 <3x >10,000x/ Ombitasvir >1000x >100x >100x >10,000x >100x/ >1,000x/ DCV >100x >1000x >1000x >10,000x >10x >1,000x/ Elbasvir x >100x >100x >1,000x >100x/ Velpatasvir <10x <3x x/50x >1000x >100x/-- <10x x/50x <10x x/50x <10x >100x/-- <3x/-- ACH x x <10x >100x/>100x <3x/<3x ABT-530 <3x <3x <3x <10x/<10x <3x <3x/<3x Slide 28 of 41 MK-8408 <10x <10x <10x <10x <10x <10x Wang C. AAC 12. Cheng G. #1172. EASL 12. Zhao Y. #A845 EASL 12. Yang G. EASL 13. Ng T. #639 CROI 14. Asante-Appiah E. AASLD SVR12 67 Without Cirrhosis M28V A30 Y93H Slide 29 of 41 Nelson et al. Hepatology 15; Zeuzem et al. Ann Int Med 15 What about NS5A Baseline Resistance? ALLY-3: Daclatasvir + sofosbuvir X 12 weeks in GT3 infection 25 With Cirrhosis C-EDGE: Grazoprevir/elbasvir X 12 weeks in TN GT1 infection RAV at BL SVR12 All SVR12 RAV <5X SVR12 RAV >5X GT1a BL RAV No RAV GT1b BL RAV No RAV 12% 19/154 88% 135/154 14% 18/130 86% 112/130 58% 11/19 99% 133/135 94% 17/18 100% 112/112 90% 9/10 22% 2/ % 1/1 94% 16/ Baseline NS5A resistance and LDV/SOF <100X >100X No RAVs Slide 30 of 41 Sarrazin C. #1926 AASLD

Recommended regimens for HCV genotype 2&3 with or without CP-A cirrhosis Slide 31 of 41 Regimen GT2 Weeks Rating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir +

IIa, B/C Regimen GT3 Weeks Rating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir + sofosbuvir 12 I, A Sofosbuvir + PEG/RBV 12 I, A Treatment experienced SOF/RBV*

11 Recommended regimens for HCV genotype 2&3 with or without CP-A cirrhosis Slide 31 of 41 Regimen GT2 Weeks Rating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir + sofosbuvir 12 IIa, B Sofosbuvir + RBV 12 I, A Treatment experienced SOF/RBV and/or cirrhosis Daclatasvir + sofosbuvir + ribavirin IIa, B Sofosbuvir + RBV* IIa, B Sofosbuvir + PEG/RBV** 12 IIa, B/C Regimen GT3 Weeks Rating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir + sofosbuvir 12 I, A Sofosbuvir + PEG/RBV 12 I, A Treatment experienced SOF/RBV* and/or cirrhosis Daclatasvir + sofosbuvir + ribavirin 24 IIa, B Sofosbuvir + PEG/RBV 12 I, A Take Home #5: More to come for GT 2-6 Slide 32 of 41 Take Home #0.5 staging of liver disease is required #1 Cure is same for HIV/HCV #2 Shortening therapy increases relapse and impact of baseline predictors #3 Cirrhosis requires RBV and/or extending therapy for most but not all regimens #4 NS5A RAVs matter for initial and re-treatment #5 Pangenotypic is coming Slide 33 of 41 11

12 The real challenge Slide 34 of 41 Questions Slide 35 of 41 12

10/21/2016. Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina. Learning Objectives

10/21/2016. Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina. Learning Objectives A Crash Course on the AASLD/IDSA Hepatitis C Virus Infection Treatment Guidelines: What s New Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina FORMATTED: 1/3/16