Slide 1 of 42 Treating Hepatitis C Virus (HCV) Infection Susanna Naggie, MD, MHS Associate Professor of Medicine Duke Clinical Research Institute Durham, North Carolina Slide 3 of 42 Learning Objectives After attending this presentation, learners will be able to: Discuss pretreatment assessments and considerations in HIV and HCV Discuss differences in DAA approvals and recommendations Discuss ongoing challenges and unmet needs in HCV Slide 3 of 33 Pre-treatment Evaluation DAA therapies Chronic infection Acute infection ARV interactions Questions Slide 4 of 33 www.hcvguidelines.org
Slide 8 of 33 Staging of Liver Disease - Still Matters F1 F2 F3 F4 Rockey DC, et al. Hepatology. 9;49:117-144. Regev A, et al. Am J Gastroenterol. 2:2614-2618. Alternatives to Liver Biopsy Noninvasive approaches Serum markers Standard laboratory tests: APRI (<.3,>2), FIB-4 (>3.25) Commercial assays (FibroSure) (>.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 33 Lin ZH, et al Hepatology. 11;53:726-736. Vallet-PichardA, et al. Hepatology. 7;46:32-36. Myers RP, et al. Dig Dis Sci. 3;48;146-153. Friedrich-Rust M, et al. Z Gastroenterol. 13 Jan;51:43-54. Slide 1 of 33 Radiographic Assessments Newer Methods Ultrasound, CT, MRI Conventional studies are unhelpful in assessment of fibrosis unless patient has decompensated cirrhosis 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:.89 (95% CI,.88-.91) Cirrhosis:.94 (95% CI,.93-.95) Friedrich-Rust M, et al. Z Gastroenterol. 13 Jan;51:43-54.
Slide 12 of 33 5 UTR region Polyprotein C E1 E2 Hepatitis C Virus HCV Genome 3 UTR region 9.6 kb RNA IRES-mediated translation NS2 NS3 A NS4B A NS5 B Polyprotein Processing NS5B Polymerase Inhibitor: Sofosbuvir C Core E1 E2 p7 NS2 NS3 4A NS4B Envelope glycoproteins NS3-4A Protease Inhibitors: Grazoprevir* Glecaprevir* Voxilaprevir* Serine Protease Serine Protease Cofactor NS5A NS5B Adapted from Naggie et al. J Antimicrob Chemother 1 RNA dependent RNA polymerase NS5A Inhibitors: Daclatasvir Elbasvir* Ledipasvir* Velpatasvir* Pibrentasvir* When starting therapy: 1.Genotype/subtype 2.Cirrhosis yes/no? 3.Prior treatment experience? To DAA? 4.Is resistance testing required? 5.Other 1. Renal function? 2. Liver function? - Calculate Child Pugh for ALL cirrhotics 3. Drug interactions? 4. HBV status Slide 13 of 33 Recommended regimens for treatment-naïve or PEG/RBV experienced patients with HCV genotype 1 without cirrhosis Regimen Weeks Rating Elbasvir/grazoprevir (except GT1a with NS5A RAS) 12 I, A Glecaprevir/pibrentasvir 8 I, A Ledipasvir/sofosbuvir 8*-12 I, A/B Sofosbuvir/velpatasvir 12 I, A Slide 14 of 33 *treatment-naïve only with baseline HCV RNA <6 million IU/mL www.hcvguidelines.org.
Slide 15 of 33 Recommended regimens for treatment-naïve or PEG/RBV experienced patients patients with HCV genotype 1 with compensated cirrhosis Regimen Weeks Rating Elbasvir/grazoprevir (except GT1a with NS5A RAS) 12 I, A Glecaprevir/pibrentasvir 12 I, A Ledipasvir/sofosbuvir 12* I, A Sofosbuvir/velpatasvir 12 I, A *PEG/RBV failure requires addition of RBV for LDV/SOF which is an alternative www.hcvguidelines.org. Recommended regimens for treatment-naïve or PEG/RBV experienced patients patients with HCV genotype 2 with/without compensated cirrhosis Regimen Weeks Rating Glecaprevir/pibrentasvir 8/12 I, A/B Sofosbuvir/velpatasvir 12 I, A Slide 16 of 33 *PEG/RBV failure requires addition of RBV for LDV/SOF which is an alternative www.hcvguidelines.org. Recommended regimens for treatment-naïve or PEG/RBV experienced patients patients with HCV genotype 3 with/without compensated cirrhosis Regimen Initial Treatment Weeks Rating Glecaprevir/pibrentasvir 8/12 I, A/B Sofosbuvir/velpatasvir 12 I, A Regimen Retreatment PEG/RBV Weeks Rating Sofosbuvir/velpatasvir (NS5A RAS testing) 12 I, A Elbasvir/grazoprevir + sofosbuvir (cirrhosis) 12 I, B Sofosbuvir/velpatasvir/grazoprevir (cirrhosis) 12 IIb,B Slide 17 of 33 www.hcvguidelines.org.
Slide 18 of 33 Glecaprevir (NS3)/pibrentasvir (NS5A) Co-formulated 3 pills once daily Pangenotypic Next generation Active vs NS3 RAS at, 155, 168 and NS5A RAS at 28, 3, 31, 93 Negligible renal excretion Contains a protease inhibitor Has? interaction with acid suppressing medications Registration program 8 weeks in treatment naïve and PEG/RBV failures without cirrhosis 12 weeks in cirrhosis Renal impairment HIV co-infection Post-transplant Limited in DAA salvage (not in EU) Contraindicated in decompensated liver disease Sofosbuvir/velpatasvir/voxilaprevir (NS3) Single fixed dose combination daily pill Pangenotypic Next generation? Active vs NS3 RAS at, 155, 168 and NS5A RAS at 28, Q3, 31 Contains a protease inhibitor Sofosbuvir still with limited renal data Velpatasvir still with acid suppressing issue Registration program 8 weeks in treatment naïve and PEG/RBV failures DAA salvage Non-NS5A NS5A No data in HIV, transplant, renal disease Contraindicated in decompensated liver disease Slide 19 of 33 Slide 26 of 42 Glecaprevir/Pibrentasvir: no cirrhosis 8 (N=828) vs 12 (N=176) weeks TN and TE PEG, RBV, SOF No DAA otherwise Relapse <1% Tx emergent RAS TN GT3 may need 12W TE GT3 may need 16 weeks 9 7 5 3 1 8 weeks 12 weeks 99 99 99 99 98 97 All GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Slide of 33 Puoti et al. EASL 17
Slide 21 of 33 Glecaprevir/pibrentasvir: HIV GT 1-6 Primarily an 8 week study 12 weeks in 16 patients with cirrhosis TN or TE (19%) with IFN, P/R or SOF+P/R VBT on treatment GT3 with cirrhosis Rocksroh et al. EASL 17 9 7 5 3 1 8 week no cirrhosis 93 136/136 14/15 12 week cirhosis Glecaprevir/pibrentasvir: GT 3 FDA approved 16 weeks for GT3 prior treatment experience regardless of cirrhosis? role of Y93H and A3K Slide 22 of 33 Sofosbuvir/velpatasvir/voxilaprevir: 8 vs 12 weeks of SOF/VEL (TN or P/R TE) POLARIS 2 GT 1-6 w/ and w/o cirrhosis POLARIS 3 GT 3 with cirrhosis 2 relapses Pooled analysis N=611 8 weeks of therapy failed noninferiority in POLARIS-2 3.8% relapse 14 GT1a (regardless of cirrhosis, 5% QK-87 vs 94% SVR) Slide 23 of 33 9 7 5 3 1 92 Roberts et al. EASL 17; Jacobson et al. Gastro 17 97 97 98 94 94 1a 1b 2 3 4 5 6 Genotype
Slide 24 of 33 Multiple Predictors of SOF/Vel/VOX failure in GT1a 89% vs 97% in US vs EU Approach to retreatment for DAA experienced patients 1 st gen PI + P/R Non-NS5A, SOFcontaining NS5A Inhibitor Experienced 12-16 weeks regardless of cirrhosis Slide 25 of 33 Glecaprevir/Pibrentasvir: DAA failures 12 (N=44) vs 16 (N=47) weeks 24-36% cirrhosis Baseline RAS 52-55% NS5A 9-11% NS3+NS5A Overall SVR 89% vs 91% 12 weeks higher relapse with NS5A RAS Dual NS3/NS5A 55% SVR Slide 26 of 33 Poordad et al. EASL 17
Slide 27 of 33 POLARIS 1 GT 1-6 (3% GT3) 12 weeks of therapy vs placebo Including compensated cirrhosis (46%) 2.2% relapse 4 GT 3 relapse all 3a and ¾ had BL NS5A RAS No treatment emergent RAS all VF had cirrhosis (6 R, 1 VBT) Sofosbuvir/velpatasvir/voxilaprevir NS5A Inhibitor DAA -Experienced Bourliere et al. NEJM 17 Acute HCV an epidemic Slide 28 of 33 Treat early or treat as chronic? 45 SVR12 7 Rockstroh et al: N=26, HIV infected, later treatment, asymptomatic SVR12 77 3 Relapse 1 /26 Slide 29 of 33 W2 W4 W6 SVR12 Deterding et al: N=, not HIV infected, immediate treatment, primarily symptomatic
Slide 3 of 33 A5327: 8 weeks LDV/SOF in acute infection N=27 Population similar to HIV 6 week study 59% IL28B CC 6.17 log1 IU/mL ARVs 7 RTV-boosted PI (26%) 9 NNRTI (3%) 14 Integrase (52%) 22 on TDF, 9 boosted 1 on TAF, 4 ABC/3TC 9 7 5 3 1 92 82 44 W2 W4 W8 SVR12 DDI with Glecaprevir/pibrentasvir P-GP, BCRP, OATP inhibitors and weak inhibitors of P45 isoenzymes (CYP3A, 1A2) and UGT1A1 Substrates of P-GP, BCRP and glecaprevir is substrate of OATP1B1/3 Not Recommended Carbamazepine St. John s wort Rifampin Ethinyl Estradiol ARVs: EFV, ATV, DRV, LPV Statin: Atorva, Lova, Simva Cyclosporine Slide 31 of 33 Rockstroh et al. EASL 17, Kosloski et al. CROI 17 Contraindicated in Child Pugh B & C DDI with SOF/VEL/VOX P-GP, BCRP, OATP inhibitors Substrates of P-GP, BCRP and voxilaprevir is substrate of OATP1B1/3. VEL and VOX with substrate of multiple CYP isoenzymes Not Recommended Amiodarone Carbamazepine (antiepileptic) St. John s wort Rifampin ARVs: EFV, ATV, TPV Statin: Rosuva, pitava Cyclosporine Omeprazole elvitegravir/cobicistat,?drv/r Slide 32 of 33 PIs are Contraindicated in Child Pugh B & C
Slide 33 of 33 Questions