Hepatitis C: Newest Treatment Options and What To Do When We Cure It!

Hepatitis C: Newest Treatment Options and What To Do When We Cure It! Richard Kalman, MD Division of Hepatology Department of Transplantation Einstein Medical Center Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring 1

Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring Asia, Africa Have Highest HCV Burden 130 150 million infections worldwide 3 4 million new infections every year 700,000 die every year from complications related to HCV Still fewer than the 240 million infected with HBV who.gov Thomas DL. Nature Medicine. 2012 Lozano R. Lancet. 2012 2

Regional Differences in Genotype Genotype 1 (79%), the most common in the U.S. Followed by 2,3 Antiviral choice, duration and efficacy affected by HCV genotype / subtype who.gov Messina JP. Hepatology. 2015 US HCV Prevalence Difficult to Estimate 3.2 million people are chronically infected with HCV based on NHANES (1999 2002) population The number chronically infected with HCV in the US may be even higher Accounting for high risk populations not sampled in NHANES 45 60% of people with HCV are unaware of the infection 360,000 840,000 are homeless or incarcerated Armgstrong G. Ann Intern Med. 2006 cdc.gov Chak E. Liver Int. 2011 Denniston M. Ann Intern Med. 2014 3

Screening for Hepatitis C Most important risk factor is past or current injection drug use Additional risk factors include: Receiving a blood transfusion before 1992 Long term hemodialysis Being born to an HCV infected mother Incarceration Intranasal drug use Getting an unregulated tattoo, and other percutaneous exposures Heterosexual sexual transmission rare (HIV + MSM highest risk) Household transmission is possible Adults born between 1945 and 1965 ( Baby Boomers ) Account for ~70% HCV in the US 35% have F3/4 fibrosis Grade B recommendation by USPSTF in 2013 to screen this population Armgstrong G. Ann Intern Med. 2006 Yaphe S. Sex Transm Infect. 2012 McGarty LJ. Hepatology. 2012 Natural History of HCV Acute hepatitis C 55-85% Clearance of HCV RNA 15% 45% Fulminant Hepatitis < 1% Chronic infection Extrahepatic Disease 70% Chronic hepatitis Cirrhosis 20% 0.8% per year 1-4%/yr HCC Time (yr) 4-5%/yr Decompensation 10 20 30 Massoumy B. Best Pract Res Clin Gastroenterol. 2012 4

HCV Impacts Morbidity and Mortality 73.4% of HCV related deaths occur between 45 64 years of age Median age was 57 ~20 years less than average person in US HCV is the leading cause of liver transplant in US Several extra hepatic morbid conditions are also linked to HCV infection Cryoglobulinemia, vasculitis, lymphoproliferative disorders, MPGN, depression Davis GL. Gastroenterology. 2010 Smith BD. MMWR Recomm Rep. 2012 Ali A. Cleve Clin J Med. 2005 Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring 5

How Far We Have Come How Far We Have Come cdc.gov 6

How Far We Have Come Manns MP. Nature Reviews Drug Discovery. 2013 Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring 7

SVR is the Goal of Treating HCV Primary goal is virus eradication Clinical Trial definition is Sustained Virologic Response (SVR) SVR12: Undetectable HCV RNA 12 weeks after treatment (newer studies) SVR24: Undetectable HCV RNA 24 weeks after treatment (older studies) SVR associated with high likelihood long term cure In phase III Sofosbuvir trials, 7/12 pts with SVR 12 but not SVR 24 found to have reinfection Secondary goal is improving outcomes Prevent progression to cirrhosis and incidence of HCC Reduce need for liver transplantation Improve / enhance survival HCV RNA 4 years after SVR 0.9% Negative 99.1% Positive Swain MG. Gastroenterology. 2010 Sarrazin C. EASL abstract 063. 2015. Van Der Meer AJ. JAMA. 2012 SVR Associated with Improved Outcomes Lee MH. J Infect Dis. 2012 8

Treatment Options Asselah T. Liver International. 2016 Antiviral Class Characteristics NS3 Protease Inhibitors NS5B nucleoside/ tide NS5B nonnucleoside NS5A Inhibitors Antiviral effect Genotype Resistance barrier Examples +++ to ++++ 1 and 4 Moderate Simeprevir Grazoprevir ++ to ++++ 1 6 High Sofosbuvir ++ to +++ 1 Low Dasabuvir ++++ 1 6 Low Ledipasvir Elbasvir Velpatasvir 9

Current Approved HCV regimens (abbreviated) Genotype 1 SOF/LDV +/ RBV for 8 24 weeks OBV/PTV/RTV + DSV +/ RBV for 12 24 weeks GZR/EBV +/ RBV for 12 16 weeks DCV + SOF +/ RBV for 12 24 weeks SMV + SOF +/ RBV for 12 weeks SOF/VEL for 12 weeks Genotype 3 SOF/VEL for 12 weeks DCV + SOF +/ RBV 12 24 weeks SOF + RBV + PEG for 12 weeks Genotype 4 SOF/VEL for 12 weeks GZR/EBV +/ RBV for 12 16 weeks OBV(Pro)/PTV/RTV +/ RBV for 12 16 weeks SOF/LDV +/ RBV for 12 24 weeks Genotype 2 SOF/VEL for 12 weeks SOF + RBV for 12 24 weeks DCV + SOF +/ RBV 12 24 weeks SOF + RBV + PEG for 12 weeks for full guidance please refer to http://www.hcvguidelines.org Genotype 5 or 6 SOF/LDV +/ RBV 12 weeks SOF/VEL for 12 weeks SOF + RBV + PEG for 12 weeks RAVs Alter Some Treatment Regimens Resistance associated variants (RAV) occur during viral breakthrough and after treatment The approach to RAV treatment is rapidly changing NS5A reduces SVR in GZP/EBR x 12 weeks, but negated by extension to 16 18 weeks NS3 RAVS are rare, routine baseline testing not indicated but may consider if using NS3 again soon after failure 10

Not all RAVs persist after treatment After 3D regimen (OBV/PTV/RTV + DSV) not all RAVs remain NS3/4A (all) 46% at 24 weeks, 9% at 48 weeks NS5A (all) 97% at 24 weeks, 96% at 48 weeks NS5B (all) 75% at 24 weeks, 57% at 48 weeks After GZR/EBV 85% NS5A persist SOF + GZR/EBR 37% NS5A persist SOF/LDV 65% NS5A persist Krishnan P. EASL 2015. 057 Sulkowski M. Lancet. 2014 Zeuzem S. Ann Intern Med. 2015 Sarrazin C. AASLD 2014 Implications: SOF/VEL SOF/VEL has high SVR rates in GT 1 6 SOF/VEL is superior to SOF/RBV x 12 weeks for GT2 SOF/VEL is superior to SOF/RBV x 24 weeks in GT3 Baseline RAVs do not appear to influence SVR Well tolerated, good safety profile Not approved in post transplant setting Not safe in renal insufficiency 11

SOF/VEL x 12 weeks, All GTs Retrospective integrated analysis of data from 1,035 SOF/VEL patients in ASTRAL-1, -2, and -3 Patients, n (%) GT1 n=328 Baseline Demographics GT2 n=238 GT3 n=277 GT4 n=116 GT5 n=35 GT6 n=41 Total N=1035 Cirrhosis 73 (22) 29 (12) 80 (29) 27 (23) 5 (14) 6 (15) 220 (21) Platelets <100 x 10 3 /µl 21 (6) 4 (2) 25 (9) 8 (7) 1 (3) 3 (7) 62 (6) Albumin <3.5 mg/dl 6 (2) 1 (<1) 8 (3) 6 (5) 0 0 21 (2) Fibroscan 15 kpa 30 (16) 9 (7) 40 (20) 17 (19) 4 (17) 5 (19) 105 (16) HCV RNA 800,000 IU/mL 255 (78) 186 (78) 191 (69) 74 (64) 26 (74) 31 (76) 763 (74) Treatment experienced 110 (34) 44 (18) 71 (26) 52 (45) 11 (31) 3 (7) 291 (28) Black race 25 (8) 19 (8) 3 (1) 14 (12) 0 0 61 (6) Age 65 years 36 (11) 53 (22) 7 (3) 11 (10) 16 (46) 0 123 (12) BMI 35 kg/m 2 20 (6) 18 (8) 21 (8) 8 (7) 3 (9) 0 70 (7) HbA1c 6.5% 21 (6) 9 (4) 13 (5) 10 (9) 3 (9) 4 (10) 60 (6) NS5A RAVs (15% cut off) 50 (15) 146 (61) 31 (11) 69 (59) 3 (9) 19 (46) 318 (31) Agarwal K. EASL 2016. SAT 195 SOF/VEL x 12 weeks, All GTs Agarwal K. EASL 2016. SAT 195 Jacobson I. EASL 2016. SAT 168 12

AASLD Guidelines Recommended GT 1, Treatment Naïve GT1a w/o cirrhosis GT1b w/o cirrhosis GT1a w/cirrhosis GT1b w/cirrhosis SOF/LDV 12 weeks 12 weeks 12 weeks 12 weeks OBV/PTV/RTV + DSV 12 weeks (+RBV) 12 weeks 12 weeks GZR/EBV 12 weeks (if no NS5A RAV, otherwise 16 with RBV) DCV + SOF 12 weeks 12 weeks 12 weeks 12 weeks (if no NS5A RAV, otherwise 16 with RBV) 12 weeks SMV + SOF 12 weeks (if no Q80K) 12 weeks SOF/VEL 12 weeks 12 weeks 12 weeks 12 weeks for full guidance please refer to http://www.hcvguidelines.org AASLD guidelines Recommended GT 2 6, Treatment Naïve GT2 w/o cirrhosis GT2 w/ cirrhosis GT3, w/o cirrhosis GT3 w/ cirrhosis GT4 GT 5/6 SOF/VEL 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks DCV + SOF 12 weeks 24 weeks (+/ RBV) SOF/LDV 12 weeks 12 weeks GZR/EBV 12 weeks OBV/PTV/ RTV + DSV +RBV 12 weeks for full guidance please refer to http://www.hcvguidelines.org 13

Hard to Treat Populations Disappearing Decompensated cirrhosis SOF/VEL + RBV x 12 wk or SOF/VEL x 24 weeks Post liver transplant All approved combinations include ribavirin PTV increases Tacrolimus and Sirolimus levels HIV/HCV coinfection Beware DDI CKD No Sofosbuvir regimens if CrCl < 30 Can use 3D if not on HD Can use GZR/EBV regardless of HD Treatment experienced Interferon DAA DAA Failures GZP/EBR + SOF + RBV x 12 weeks (n=25) C SWIFT retreatment 100% SVR12 (including 9/9 with NS3+NS5A RAVs) OBV/PTV/r + DSV+ SOF (n=22) SVR12 21/22 overall (6/6 in cirrhosis) SOF/VEL + RBV x 24 weeks SVR12 59/65 overall in GT1 3 SOF/VEL + GS 9857(PI) x 12 weeks (n=128) SVR12 127/128 Overall in GT1 6 Lawitz E. EASL 2016. SAT 148 Poordad F. EASL 2016. SAT 156 Gane EJ EASL 2016. PS024 Lawitz E. EASL 2016.PS008 14

Acute HCV Classically advised waiting to see if patient develops persistent infection HEPNET Acute HCV study Single arm, prospective, multicenter 20 patients (no HIV, 11 GT1a) with acute HCV Known exposure < 4 mo, documented seroconversion, ALT > 10 x ULN Mean ALT 463, Mean bilirubin 24 mg/dl All 20 patients achieved SVR12 Detarding K. EASL 2016 LB08 Daily PPI Did NOT Effect SVR in Real World TRIO Cohort PPI use may decrease absorption of LDV 2,034 treated with DAA for 8, 12 or 24 weeks with our without RBV SVR rate 96% without PPI and 94% with PPI Type of PPI, dose, and duration had no effect on SVR BID PPI reduced SVR to 91.7% on univariate but not multivariate analysis Authors advise caution when using BID PPI Afdhal N. EASL 2016. LBP519 15

Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring 16

Phase 2 C Crest 1 and 2 Trial of Merck triple therapy PI/NS5A/Nuc GZR/MK 8408/MK 3682 x 8 weeks Non cirrhotic patients, GT1, 2 and 3 (combined 2 dosing groups for MK 3682) GT1 SVR24 44/47 GT2 SVR24 25/30 GT3 SVR24 40/43 50 40 30 20 10 0 44 40 25 3 5 3 GT1 GT2 GT3 SVR No SVR Gane E. EASL 2016. SAT 139 SURVEYOR 1 and 2: Phase 2, non cirrhotic for 8 (GT1/2/3) and 12 weeks (4/5/6) ABT 493 (NS3/4A PI) + ABT 530 (NS5A inhibitor) High barrier to resistance, potent against common RAVs, and <1% renal excretion Genotype 1 and 2 (Surveyor 1 and 2) SVR12 33/34 GT1 and 53/54 GT2 Genotype 4, 5 and 6 (Surveyor 1 Part 2) 100% SVR12 for all genotypes; regardless of prior treatment Hx or baseline variants Genotype 3 28/29 SVR12 including 7/29 with F3 fibrosis 60 50 40 30 20 10 0 53 33 29 GT1 GT2 GT3 SVR No SVR Gane E. EASL 2016. SAT 137 Poordad EASL 2016. SAT 157 Muir A. EASL 2016. PS098 17

RG 101 with 4 weeks of Oral DAA treatment x 4 weeks, Phase 2 study RG 101 targets mir 122 microrna abundant in the liver that HCV requires for replication Acts earlier in viral life cycle, before nonstructural proteins are even built on which traditional DAAs act N=79, 77% GT1 and 23%G4 DAA included LDV/SOF, SMV, or DCV Received 2mg/kg SQ on Day and Day 29 38 patients with 8 weeks of follow up 97% with undetectable viral load 14 patients with 12 weeks of follow up SVR12 100% Horvath G. EASL 2016. GS08 Learning Objectives Scope of HCV How far we have come Choosing individual therapy today (near) future therapies Post SVR monitoring 18

Rechecking HCV RNA After SVR After SVR24, no indication to recheck HCV RNA May reconsider if liver enzymes become abnormal or if risk of reinfection Do not repeat HCV AB Advise patients AB will remain positive in case erroneously checked by another provider A Path Divided Early (F0 F2) Fibrosis Stage Pre Treatment Advanced (F3 F4) 19

Measuring Fibrosis Post SVR With Early Fibrosis Consider annual liver tests and CBC No indication for HCC surveillance No indication for variceal surveillance Remain vigilant against other causes of chronic liver disease Risk factors for NAFLD Risk factors of alcohol mediated injury Social alcohol use may be acceptable Check Hepatitis B status Consider hemochromatosis if labs remain abnormal 20

Post SVR With Advanced Fibrosis Monitor for signs of decompensation Perform screening for varices and HCC HCC risk persists at least 8 years after SVR Some data may suggest early HCC recurrent after DAA Monitor MELD and refer to transplant center for MELD > 15 Advocate strict alcohol sobriety If risk factors for NAFLD are present, attempt BMI < 25, and tight control of DM and hyperlipidemia Aleman S. Clin Infect Dis. 2013 Reig M. Journal of Hepatol. 2016 Summary Screening at risk population, including Baby Boomers, for HCV is recommended (Grade B, USPSTF) SVR is associated with improved outcomes including reduced all cause mortality, liver cancer and cirrhosis Every GT now has multiple recommended treatment options by AASLD (aside from GT2) SOF/VEL is a powerful new agent with high SVR rates in all genotypes DAA failures have treatment options that can be used, but limited tremendously by cost of these regimens Triplet regimens will be expected next year with high SVR rates in as little as 8 weeks Post SVR monitoring relies on assessing for advanced fibrosis, performing routine cirrhotic care when indicated and limiting other risk factors for advanced fibrosis 21

Thank You! 22