Disclosures Research Grant support to UCSF from Advanced HCV - PDF document

12/8/17 Disclosures • Research Grant support to UCSF from Advanced HCV management • AbbVie • Gilead Annie Luetkemeyer, MD • Merck Division of HIV, ID and Global Medicine • Proteus ZSFG, UCSF • NIH Overview • Renal failure • Acute HCV Renal failure • Retreatment • Resistance testing • Decompensated cirrhotics • HCV treatment for children and pregnant women 1

12/8/17 HCV can worsen renal failure (and vice versa) • Glecaprevir/pibrentasvir – Duration as per non-cirrhotic prescribing recommendations • Grazoprevir/Elbasvir x12 weeks – C-Surfer trial did not give RBV (N=111, 52% GT1a) ( Roth Lancet 2015) Tran AASLD 2017 VA evaluation of GLE/PIB in CKD What if patient can’t take HCV PI? Kramer AASLD 2017 2

12/8/17 SOF in renal failure Sofosbuvir-based regimens in ESRD • SOF not approved for use at CrCl<30 due to • Number of small studies demonstrating safety and efficacy increased metabolite of SOF-based regimens in CKD • Small studies of simprevir + SOF (regular or ½ dose) – 18 GT1 patients with GFR < 30 but not on dialysis, 12 weeks SOF/LDV without RBV – Overall high SVR, generally well tolerated • Target: SOF + RBV, SIM, PEG • NO clinically meaningful change in eGFR < 30 30-45 45-60 >60 – Similar cure rates – HOWEVER, worse anemia (RBV), progression of renal dz (? causality) Saxena Liver Int 2016 Lawitz E, et al. AASLD 2017. Abstract 1587. Sofosbuvir-based regimens in ESRD Acute HCV Considerations • Number of small studies demonstrating safety and efficacy • No indication for HCV PEP of SOF-based regimens in CKD • Consider monitoring for – 18 GT1 patients with GFR < 30 but not on dialysis, 12 weeks SOF/LDV without spontaneous clearance RBV • Consider early treatment : – HCV transmission prevention • NO clinically – Reduce risk of clinical meaningful complications (ex: already change in eGFR cirrhotic) – Concern for LTFU in 3-6 months • IF HCV RNA <LLOD, repeat at least 12 weeks later to confirm clearance Take Home: Stick with approved regimens when feasible but SOF- based regimens are an alternative, particularly if can avoid RBV Adapted from EACS Guidelines version 9.0, www.eacsguidelines.org Lawitz E, et al. AASLD 2017. Abstract 1587. 3

12/8/17 SWIFT-C • 100% SVR with 8 weeks of SOF/LDV in HIV(+) men with acute HCV • Acute HCV defined as < 24 of week of infection or reinfection after clearance, new HCV RNA+ and • ALT > 5x ULN if previously normal within 12 months • ALT>10X ULN if no ALT baseline Shortened Regimens? • Documentation of new HCV Ab(+) or RNA (+) w/in past 6 months Or treat the same as chronic HCV- now have 8 week option Naggie #196 AASLD 2017 Treating DAA failures 4

12/8/17 First steps after NS5a failure First steps after NS5a failure 2016 Message: 2016 Message: • Identify any patient related issues that • Identify any patient related issues that contributed to failure: poor adherence, contributed to failure: poor adherence, treatment interruption, drug-drug interactions, treatment interruption, drug-drug interactions, intolerance intolerance • Resistance testing: • Resistance testing: – At least NS5a & consider NS3a/4 ( HCV PI) – At least NS5a & consider NS3a/4 ( HCV PI) – Low utility to test for NS5b (nucleotide) resistance – Low utility to test for NS5b (nucleotide) resistance Improved resistance profile of “Next Generation” NS5As Principles of treating DAA failures Fold Change Genotype 1a Genotype 1b GT3a M28T Q30R L31M/V Y93H/N L31V Y93H Y93H > 100x/ > 1000x/ • Type of prior treatment important, i.e. NS5a or Ledipasvir 20x > 100x > 100x N/A > 100x > 10,000 NS3 alone , vs NS5a & NS3 together (EBR/GRZ or < 3x > 10,000x/ Ombitasvir > 1000x > 100x < 10x 20x N/A > 10,000x > 100x GLE/PIB) > 100x/ > 1,000x/ Daclatasvir > 100x > 1000x < 10x 20x >1000x • PEG/RBV +/- SOF failures treated as treatment > 1000x > 10,000x > 10x naïve, except for GT3 treated with GLE/PIB > 1000x/ Elbasvir 20x > 100x < 10x > 100x N/A > 1000x > 100x • Ribavirin & treatment extension to 24 weeks > 100x/ Velpatasvir < 10x < 3x 20x/50x < 3x < 3x >100x > 1000x generally unnecessary Pibrentasvir < 3x < 3x < 3x 7x/7x < 3x < 3x <3x • Resistance testing generally unnecessary Ruzasvir < 10x < 10x < 10x < 10x < 10x < 10x Wang C. AAC 2012. Wang C. AAC 2014. Cheng G, et al. EASL 2012. Abstract 1172. Zhao Y, et al. EASL 2012. Abstract A845. Yang G, et al. EASL 2013. Abstract 1199. Ng T, et al. CROI 2014. Abstract 639. Asante-Appiah E, et al. AASLD 2014. Abstract 1979. Ng T. THU-305 EASL 2017.Lawitz E. AAC 2016. 5

12/8/17 SOF/VEL/VOX Triple DAA therapy for re-treatment • Has become mainstay for retreatment of NS5a Regimen: SOF/VEL/VOX for 12 weeks failure as well as other DAA failures POLARIS-4 (n=182) POLARIS-1 (n=263) • NO NS5A exposure NS5A experienced 46% cirrhosis 46% cirrhosis 97% SVR vs 90% SOF/VEL 96 99 93 100 80 60 4/101 GT1a non-SVR 2 LTFU 40 1 relapse 1 BT (non-compliance) 20 0 No cirrhosis Cirrhosis All No Cirrhosis Cirrhosis SOF/VEL/VOX: 98% GT 1a ; 96% GT 1b ; 94% GT 3 SVR12: 96% GT 1a ; 100% GT 1b ; 95% GT 3 SOF/VEL: 89% GT 1a ; 95% GT 1b ; 85% GT 3 Bourliere M. NEJM 2017. Vosevi Package insert No impact of pre-treatment RASs POLARIS-1 POLARIS-4 No impact by genotype or VEL and VOX specific RASs Sarrazin C. et al. #THU-248 EASL 2017. 6

12/8/17 GLE/PIB for retreatment • Magellan-1: DAA experienced with or without cirrhosis, GT1 and 4 only, GLE/PIB x 12 or 16 weeks Non-NS5a, treatment experienced, +/- cirrhosis GT3 Cirrhotic, Treatment naïve or experienced (non-DAA failures) Poodad EASL 2017 Zeuzem AASLD 2016, Bourliere NEJM 2017, Foster NEJM 2016 Mavyret package insert Poordad EASL 2017 7

12/8/17 • PRS = Prior PEG/RBV +/- SOF • Essentially the same as treatment naïve except for GT3 patients- extend to 16 weeks Mavyret package insert Krishnan AASLD 2017 C-ISLE • Treatment experienced, cirrhotic GT3 patients • ELB/GRZ/SOF with or w/o RBV SOF/VEL/VOX & GLE/PIB failures?? Foster 2017 EASL 8

12/8/17 Lack of additional RAS selection in GLE/PIB failures failures • In 2256 Phase 2/3 participants, < 1% developed viral resistance • BUT, when patients DO fail, the patterns are complex with substantial resistance All POLARIS-1 relapses also had cirrhosis POLARIS-1 Deferred treatment Pilot-Matias T. SAT-204. EASL 2017. Sarrazin C. et al. #THU-248 EASL 2017. Bourliere AASLD 2007 SOF/VEL/VOX & GLE/PIB failures • Consider resistance testing of NS3 and NS5a • No data (yet) to guide retreatment Drug resistance testing Consider: • GLE/PIB failures-> SOF/VEL/VOX +/- RBV or GLE/PIB/SOF ( data forthcoming from Magellan- 3 ) • SOF/VEL/VOX failures-> SOF/VEL/VOX x 24 weeks + RBV • Expert consultation 9

12/8/17 When (if ever) is drug resistance testing indicated in 2017? Scenario Action GT1a, EBR/GRZ planned • NS5a RAS testing • If EBR RAS present, extend Decompensated Cirrhosis treatment to 16 week with RBV GT3, cirrhotic, SOF/VEL planned • NS5a RAS testing • If Y93H present, consider adding RBV SOF/VEL/VOX or GLE/PIB failure • ?NS5a and NS3 RAS testing to help guide therapy HCV cure reduces death • Always best to proceed in consultation with in decompensated cirrhosis hepatologist and transplant team, if applicable • Stabilize medical condition before treating • Avoid HCV protease inhibitors – levels can be markedly elevated – This includes Glecaprevir/Pibrenstasvir and Sofosbuvir/Velpatasvir/Voxilaprevir • Include low dose Ribavirin if possible – 600 mg , titrate up as tolerated DAA Genotype Considerations SOF/LDV/RBV x 12 weeks GT 1, 4 Extend therapy to 24 SOF/VEL/RBV x 12 weeks GT 1-6 weeks if cannot include RBV DCV/SOF/RBV x 12 weeks GT 1-4 10

12/8/17 Decompensated Cirrhotics: Retreatment after NS5a and/or SOF failure Pregnancy & Children HCV in pregnancy HCV in children • Risk of transmission ≈ 5% – Higher in HIV(+) women • Vaginal delivery ok, but should avoid fetal scalp monitors and forceps delivery • Breastfeeding not a risk for transmission, but nursing with bloody/cracked nipples not recommended • Rate of fibrosis progression in children is low • No approved treatment during pregnancy • Generally recommended to wait to treat until age 12 • SOF/LDV approved for ≥ 12 years – Treat HCV before seeking pregnancy if possible • GLE/PIB and SOF/VEL still only for ≥ 18 years • PK study of SOF/LDV x 12 weeks started at 24 • DAA’s under evaluation for treatment of children ages 3- weeks gestation ongoing (NCT02683005) 11 11