Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina The Top 5 Things to Remember about Treating.

Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina The Top 5 Things to Remember about Treating HCV FORMATTED: MM/DD/YY New York: New York: March 23, 2016 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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 resistance- associated viral variants

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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

of 34From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Enter Question Text 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 The AASLD/IDSA–Guidelines are:

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. When and In Whom to Initiate HCV Therapy www.hcvguidelines.org

of 34From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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. This is a trick question as they are all associated with cirrhosis

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Gold standard Invasive - Morbidity (3/1,000) - Mortality (1/10,000) Observer variability Sampling error Costly Rockey DC, et al. Hepatology. 2009;49:1017-1044. Regev A, et al. Am J Gastroenterol. 2002:2614-2618. Staging of Liver Disease: Liver Biopsy F1F2 F3F4

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Alternatives to Liver Biopsy ► Noninvasive approaches – Serum markers Standard laboratory tests: APRI ( 2), FIB-4 (>3.25) Standard laboratory tests: APRI ( 2), FIB-4 (>3.25) Commercial assays (FibroSure) (>0.8) Commercial assays (FibroSure) (>0.8) – Radiographic tests Elastography Elastography ► Limitations – Ability to distinguish F1 versus F2, etc. Better to differentiate advanced versus early fibrosis Better to differentiate advanced versus early fibrosis – Serologies impacted by inflammation – Indeterminate outcomes common Lin ZH, et al Hepatology. 2011;53:726-736. Vallet-Pichard A, et al. Hepatology. 2007;46:32-36. Myers RP, et al. Dig Dis Sci. 2003;48;146-153. Friedrich-Rust M, et al. Z Gastroenterol. 2013 Jan;51:43-54.

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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 Ultrasonic transducer sends a vibration wave into the liver Elastic shear wave propagates through the liver Elastic shear wave propagates through the liver Velocity of wave correlates with tissue stiffness Velocity of wave correlates with tissue stiffness – Test characteristics Mean AUROC for the diagnosis of: 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. 2013 Jan;51:43-54.

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. www.hcvguidelines.org. HIV/HCV Co-infection

of 34From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 5 UTR region 3 UTR region 9.6 kb RNA CANS2NS4BA NS5 BE2NS3 Polyprotein IRES-mediated translation p7C E1 E2NS2NS3NS4B 4A Polyprotein Processing NS5BNS5A CoreEnvelope glycoproteins Serine Protease Serine Protease Cofactor RNA dependent RNA polymerase NS3-4A Protease Inhibitors NS5B Polymerase Inhibitors HCV Genome Hepatitis C Virus NS5A Inhibitors Adapted from Naggie et al. J Antimicrob Chemother 2010

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Agents and Regimens Antiviral RegimenNS3NS5A Non-Nuc NS5B Nuc NS5B RBV Daclatasvir + sofosbuvir  Elbasvir/grazoprevir FDC  Ledipasvir/sofosbuvir FDC  Paritaprevir/r/ombitasvir FDC + dasabuvir (PrO+D)  1a only Simeprevir + sofosbuvir  Sofosbuvir + ribavirin  Velpatasvir/sofosbuvir* FDC  *pending FDA approval

of 34From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. The current recommended length of therapy for a treatment experienced GT-1 infected patient without cirrhosis is: 1. 6 weeks 2. 8 weeks 3. 12 weeks 4. 16 weeks 5. 24 weeks

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Recommended regimens for treatment-naïve and experienced patients with HIV/HCV genotype 1 without cirrhosis RegimenWeeksRating Daclatasvir + sofosbuvir*12I, A Elbasvir/grazoprevir (except GT1a with NS5A RAV)*12I, A Ledipasvir/sofosbuvir**12I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a12I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b12I, A Simeprevir + sofosbuvir12I, A www.hcvguidelines.org. *recommended in first wave PI failures (ELB/GRZ requires RBV) **recommended in first wave PI failures and prior SOF failure (add RBV)

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Take Home #1: Cure is same for HIV/HCV Naggie et al, NEJM 2015; Sulkowski et al, JAMA 2015; Wyles et al, NEJM 2015; Rockstroh et al, Lancet HIV 2015; Christensen et al, CROI 2016; Sulkowski et al, NEJM 2015 * *

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. ARV Interaction Score Card 2015 SimeprevirSofosbuvirLedipasvirDaclatasvirP/r/O + D Drug Interaction Substrate of CYP3A4, OATP1B1/3 Substrate of P-gp and BCRP Inhibitor/ Substrate of P-gp and BCRP Inhibitor of OATP1B1/3, BCRP, Substrate of P-gp and CYP3A4 Inhibit/Sub of UGT1A1,OATP1B1/3, BCRP, CYP3A4, CYP2C8, P-gp ATV/rNo data LDV ↑; ATV ↑DCV ↑*ATV ↑; PAR ↑ DRV/rSIM ↑; DRV ↔SOF ↑; DRV ↔LDV ↑; DRV ↔ALLY-2 ↔DRV ↓; PAR ↓ LPV/rNo data ALLY-2 ↔LPV ↔; PAR ↑ TPV/rNo data EFVSIM ↓; EFV ↔SOF ↔; EFV ↔ION-4 ↔DCV ↓*No PK data** RPVSIM ↔; RPV ↔SOF ↔; RPV ↔LDV ↔; RPV ↔ALLY-2 ↔PAR ↑; RPV ↑ ETVNo data No data*No data RALSIM ↔; RAL ↔SOF ↔; RAL ↔LDV ↔; RAL ↔ALLY-2 ↔PrOD ↔; ↑ RAL ELV/cobiNo dataCobi ↑; SOF ↑LDV ↑; SOF ↑No data DLGNo data LDV ↔; DLG ↔ALLY-2 ↔PAR ↓; DLG ↑ MVCNo data TDFSIM ↔; TFV ↔SOF ↔; TFV ↔LDV ↔; ↑TFVDCV ↔; TFV ↔PrOD ↔; TFV ↔ * Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, ** PrOD + EFV led to premature study discontinuation due to toxicities Slide courtesy of Jennifer Kiser

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Ledipasvir and TDF LDV/SOF +EFV/TDF/FTCRPV/TDF/FTC RAL + TDF/FTC ATV/r + TDF/FTC DRV/r + TDF/FTC AUC tau (ng.h/mL)3600 (4400)4286 (4780)40105460/57405490/4260 German et al, Clin Pharm 2014; German et al. CROI 2015 Abstract 82; Naggie et al. NEJM 2015

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Real World Data suggests higher relapse to LDV/SOF with PPI ► PPI use in TARGET 28% Terrault et al, AASLD 2015

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. A Clinical Caveat: LDV and Acid Suppressing Medications ► Healthy volunteer data only – Dosing recommendations is difficult for patients ► Possible relevance in HIV in particular? German et al, AASLD 2015

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. ARV Interaction Score Card 2016 Elbasvir/ Grazoprevir Velpatasvir/ Sofosbuvir Ledipasvir/ Sofosbuvir P/r/O + D Drug Interactions Substrate of CYP3A4, P- gp, OATP1B1/3; Inhibitor of BCRP, P-gp, CYP2C8, 3A4, UGT1A1 Substrate of P-gp, BCRP, OATP, CYP2B6, 2C8, 3A4; Inhibitor of P- gp, BCRP, OATP Inhibitor/ Substrate of P-gp and BCRP Inhibit/Sub of UGT1A1,OATP1B1/3, BCRP, CYP3A4, CYP2C8, P-gp ATV/rGRZ & ELB ↑, ATV ↑VEL ↑; ATV ↑LDV ↑; ATV ↑ATV ↑; PAR ↑ DRV/rGRZ & ELB ↑; DRV ↔VEL ↑; DRV ↔LDV ↑; DRV ↔DRV ↓; PAR ↓ LPV/rGRZ & ELB ↑; DRV ↔VEL ↑; LPV ↑No dataLPV ↔; PAR ↑ TPV/rNo data EFVGRZ & ELB↓, EFV ↓VEL ↓; EFV ↔ION-4 ↔No PK data** RPVGRZ & ELB ↔; RPV ↔VEL ↔; RPV ↔LDV ↔; RPV ↔PAR ↑; RPV ↑ ETVNo data RALGRZ & ELB ↔; RAL ↑VEL ↔; RAL ↔LDV ↔; RAL ↔PrOD ↔; ↑ RAL ELV/cobiNo dataVEL ↑; SOF ↑LDV ↑; SOF ↑No data DLGGRZ & ELB ↔; DLG ↑VEL ↔; DLG ↔LDV ↔; DLG ↔PAR ↓; DLG ↑ MVCNo data TDFGRZ & ELB ↔; TFV ↑VEL ↔; TFV ↑LDV ↔; ↑TFVPrOD ↔; TFV ↔ Slide courtesy of Jennifer Kiser

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. ION-3 Kowdley et al. NEJM; Wyles et al. CROI 2015 LB151 Take Home #2: Shortening therapy with current DAA increases relapse HCV MONO Tx Naïve, No cirrhosis: ION-3 HIV/HCV COINFECTION Tx Naïve : ALLY-2 (DCV/SOF) 8 weeks 20 relapse (4.5%) 12 weeks 3 relapse (1%) +RBV-RBV HCV RNA <6 million IU/mL -8 weeks 121/123 (98%) -12 weeks 129/131 (98%) SVR % 12 weeks 1 relapse (1%) 8 weeks 10 relapse (25%) 31/4180/83 SVR12, %

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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%) 24/26 HIV/HCV (92%) ► Cheaper 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% Terrault et al, AASLD 2015; Curry et al, AASLD 2015; Backus et al. AASLD 2015

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. O’brien et al, OFID 2015 Shortening therapy increases impact of baseline predictors

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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 (20%) ► TRIO – trend to lower SVR (18%) ► VA – lower SVR – lost when analysis only of 12 week duration (38% black) Terrault et al, AASLD 2015; Curry et al, AASLD 2015; Backus et al. AASLD 2015

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Recommended regimens for HIV/HCV genotype 1 and compensated cirrhosis RegimenWeeksRating Treatment Naïve or Experienced Elbasvir/grazoprevir (except GT1a with NS5A RAV)*12I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b12I, A Treatment Naïve Only Ledipasvir + sofosbuvir12I, A Treatment Experienced Only Daclatasvir + sofosbuvir ± ribavirin (only PI failures)24IIa, B Ledipasvir + sofosbuvir + ribavirin*12I, A Ledipasvir + sofosbuvir**24I, A www.hcvguidelines.org *recommended in first wave PI failures (ELB/GRZ requires RBV) **recommended in first wave PI failures and prior SOF failure (add RBV)

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Take home #3: Cirrhosis requires RBV or longer therapy for some Poordad et al. EASL 2015; Bourliere et al. Lancet ID 2015; Reddy et al. Hepatology 2015. SIRIUS: LDV/SOF+RBV X 12W or LDV/SOF X 24W in TE Cirrhosis 12 Weeks* 12 Weeks 24 Weeks 75/77 *not arm in SIRIUS – shown for historic comparison …but not all 60/60 TURQUOISE-II: P/r/O/D X12 weeks in Genotype 1b Cirrhosis

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Take Home #4: NS5A RAVs matter Fold-change 1a1b M28TQ30RL31M/VY93H/NL31VY93H/N LDV 20x>100x >100x/ >100x >1,000x/ >10,000 >100x/-- Ombitasvir >1000x>100x <3x >10,000x/ >10,000x <10x 20x/50x >100x DCV >100x>1000x >100x/ >1000x >1,000x/ >10,000x <10x 20x/50x Elbasvir 20x>100x >10x >1,000x/ >1,000x <10x >100x/-- >100x Velpatasvir <10x<3x20x/50x >100x/ >1000x <3x/-- ACH-3102 30x20x<10x>100x/>100x<3x/<3x ABT-530 <3x <10x/<10x<3x<3x/<3x MK-8408 <10x Wang C. AAC 2012. Cheng G. #1172. EASL 2012. Zhao Y. #A845 EASL 2012. Yang G. EASL 2013. Ng T. #639 CROI 2014. Asante-Appiah E. AASLD 2014.

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. What about NS5A Baseline Resistance? Nelson et al. Hepatology 2015; Zeuzem et al. Ann Int Med 2015 C-EDGE: Grazoprevir/elbasvir X 12 weeks in TN GT1 infection RAV at BLSVR12 AllSVR12 RAV <5X SVR12 RAV >5X GT1a BL RAV 12% 19/154 58% 11/19 90% 9/10 22% 2/9 No RAV 88% 135/154 99% 133/135 -- GT1b BL RAV 14% 18/130 94% 17/18 100% 1/1 94% 16/17 No RAV 86% 112/130 100% 112/112 -- ALLY-3: Daclatasvir + sofosbuvir X 12 weeks in GT3 infection

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Baseline NS5A resistance and LDV/SOF Sarrazin C. #1926 AASLD 2014. <100X >100X No RAVs

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Recommended regimens for HCV genotype 2&3 with or without CP-A cirrhosis Regimen GT2WeeksRating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir + sofosbuvir12IIa, B Sofosbuvir + RBV12I, A Treatment experienced SOF/RBV and/or cirrhosis Daclatasvir + sofosbuvir + ribavirin 16-24IIa, B Sofosbuvir + RBV*16-24IIa, B Sofosbuvir + PEG/RBV**12IIa, B/C Regimen GT3Weeks Rating Treatment naïve or Treatment experienced PEG/RBV without cirrhosis Daclatasvir + sofosbuvir12 I, A Sofosbuvir + PEG/RBV12 I, A Treatment experienced SOF/RBV* and/or cirrhosis Daclatasvir + sofosbuvir + ribavirin 24 IIa, B Sofosbuvir + PEG/RBV12 I, A

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Take Home #5: More to come for GT 2-6

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. 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

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. The real challenge…

of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA. Questions

Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina The Top 5 Things to Remember about Treating.

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Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University School of Medicine Durham, North Carolina The Top 5 Things to Remember about Treating.

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