Disclosures. Advanced HCV management. Overview. Renal failure 1/10/2018. Research Grant support to UCSF from AbbVie Gilead Merck Proteus NIH

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

2 HCV can worsen renal failure (and vice versa) Tran AASLD 2017 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) Renal Failure What if patient can t take HCV PI? Gane AASLD

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

4 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 Documentation of new HCV Ab(+) or RNA (+) w/in past 6 months Shortened Regimens? Or treat the same as chronic HCV now have 8 week option Naggie #196 AASLD 2017 Treating DAA failures 4

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

6 SOF/VEL/VOX Has become mainstay for retreatment of NS5a failure as well as other DAA failures Triple DAA therapy for re treatment 100 POLARIS 1 (n=263) NS5A experienced 46% cirrhosis Regimen: SOF/VEL/VOX for 12 weeks POLARIS 4 (n=182) NO NS5A exposure 46% cirrhosis 97% SVR vs 90% SOF/VEL /101 GT1a non SVR 2 LTFU 1 relapse 1 BT (non compliance) 0 All No Cirrhosis Cirrhosis SVR12: 96% GT1a; 100% GT1b; 95% GT3 No cirrhosis Cirrhosis SOF/VEL/VOX: 98% GT1a; 96% GT1b; 94% GT3 SOF/VEL: 89% GT1a; 95% GT1b; 85% GT3 Bourliere M. NEJM 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

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

8 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

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

10 When (if ever) is drug resistance testing indicated in 2017? Scenario Action GT1a, EBR/GRZ planned NS5a RAS testing If EBR RAS present, extend 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 Decompensated Cirrhosis HCV cure reduces death in decompensated cirrhosis Always best to proceed in consultation with 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 DCV/SOF/RBV x 12 weeks GT 1 4 RBV 10

11 Decompensated Cirrhotics: Retreatment after NS5a and/or SOF failure Pregnancy & Children HCV in pregnancy 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 No approved treatment during pregnancy Treat HCV before seeking pregnancy if possible PK study of SOF/LDV x 12 weeks started at 24 weeks gestation ongoing (NCT ) HCV in children Rate of fibrosis progression in children is low Generally recommended to wait to treat until age 12 SOF/LDV approved for 12 years GLE/PIB and SOF/VEL still only for 18 years DAA s under evaluation for treatment of children ages

12 Conclusions Good options for renal failure, decompensated cirrhotics, and NS5a failures Drug resistance testing increasingly unnecessary We need data to inform safe and effective HCV treatment in pregnant women, children and adolescents. Thank you! GT Wks No Cirrhosis Compensated Cirrhosis egfr < 30 ml/min 8 GLE/PIB -- GLE/PIB 1 12 GZR/EBR,* SOF/LDV, SOF/VEL GLE/PIB, GZR/EBR,* SOF/LDV, SOF/VEL GZR/EBR Additional slides GLE/PIB -- GLE/PIB 12 SOF/VEL GLE/PIB, SOF/VEL -- 8 GLE/PIB -- GLE/PIB 12 SOF/VEL GLE/PIB, SOF/VEL -- 8 GLE/PIB -- GLE/PIB 4 12 GZR/EBR, SOF/LDV, SOF/VEL, GLE/PIB, GZR/EBR, SOF/LDV, SOF/VEL GZR/EBR 5, 6 8 GLE/PIB -- GLE/PIB 12 SOF/LDV, SOF/VEL GLE/PIB, SOF/LDV, SOF/VEL -- *If GT1a with BL NS5A RASs for EBR, 12 wks not recommended; can increase duration to 16 wks with RBV (alternative). Some data to support 8 wks, but 8 wks not recommended in HIV/HCV coinfection. If also cirrhotic, increase duration to 12 wks. If BL Y93H RAS present, add RBV or consider SOF/VEL/VOX. AASLD/IDSA GUIDELINES 9/

13 DAA experienced GT Wks NS3 + PegIFN/RBV Experience Non NS5A, SOF Containing Experience NS5A Experience 1 12 GLE/PIB, SOF/LDV,* SOF/VEL GLE/PIB, SOF/VEL, SOF/VEL/VOX SOF/VEL/VOX 2 12 GLE/PIB, SOF/VEL 3 12 SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX *Not recommended if also cirrhotic. For genotype 1b only. For genotype 1a only. If also cirrhotic with prior NS5A failure, add RBV Dvory Sobol AASLD 13