Newly Approved Hepatitis C Virus Drugs: Approach to Initial Therapy Kristen M. Marks, MD Assistant Professor Weill Cornell Medical College New York, New York Learning Objectives After attending this presentation, learners will be able to: Describe regimens recommended for initial treatment of HCV infection Recognize when to do testing for HCV resistance Identify the advantages and limitations of newly approved HCV treatment regimens Slide 3 of 41 How many HCV-infected patients do you personally manage? 1.None (Retired) 2.None (I don t see patients) 3.1-4 4.5-10 5.11-15 6.16-50 7.51-100 8.More than 100 Slide 4 of 41
Slide 6 of 41 IDSA/AASLD www.hcvguidelines.org EASL Newer strategy for HCV therapy: Direct acting antivirals target life cycle ---PREVIR Protease inhibitors e.g. telaprevir, boceprevir, faldaprevir, simeprevir, danoprevir, asunaprevir, paritaprevir, grazoprevir, voxilaprevir, glecaprevir ---BUVIR Polymerase inhibitors Nucleos(t)ide analogs: e.g. tegobuvir, sofosbuvir, Non-nucs: e.g. deleobuvir, dasabuvir ---ASVIR NS5A inhibitors e.g. daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir Slide 7 of 41 Currently used combinations of DAA classes NUC-SPARING HCV Renal insufficiency Drug-drug interactions Duration Affordability/Access Toxicity Resistance NUC NUC + + PI NS5A PI PI http://www.easl.eu/research/our-contributions/clinical-practiceguidelines/detail/easl-recommendations-on-treatment-of-hepatitis-c-2016 +/- RBV +/- RBV NUC + NS5A +/- RBV PI + + NS5A + NS5A + nonnuc NUC-SPARING HIV Toxicity Resistance Renal insufficiency Drug-drug interactions Affordability +/- RBV Slide 8 of 41
Slide 9 of 41 CASE 55 y.o. African American M with HCV Geno 1b and cirrhosis, HCV RNA 221,000 IU/mL HCV Hx: Treatment naïve Cirrhotic based on transient elastography measurement of 17 kpa No decompensation events EGD no varices Sono no HCC Other med hx includes: HTN, high cholesterol, renal insufficiency (CrCl25) Mild GERD on PPI qd HBV sag- cab+ sab- Q2. Which of the following regimens would NOT be recommended for this patient? (for this question disregard renal function and drug-drug interactions) Slide 10 of 41 1. Sofosbuvir/velpatasvir/voxilaprevir 2. Sofosbuvir/velpatasvir 3. Elbasvir/grazoprevir 4. Glecaprevir/pibrentasvir Slide 12 of 41 Q3. Testing for HCV resistance (RASs) would be indicated in this patient with HCV geno 1b if 1. He had failed PegIFN + RBV in the past 2. You plan to treat with 8 weeks of glecaprevir/pibrentasvir 3. You plan to treat with 12 weeks of grazoprevir/elbasvir 4. Nope! Resistance testing is not necessary here 5. Hmmm What s a RAS?
Slide 14 of 41 Q4. Which of the following regimens can be used with ANY dose of a proton pump inhibitor? 1. Sofosbuvir/velpatasvir/voxilaprevir 2. Sofosbuvir/velpatasvir 3. Elbasvir/grazoprevir 4. Glecaprevir/pibrentasvir Minimum to Know Pre-Treatment HCV genotype/subtype HCV resistance (sometimes) Stage of fibrosis Cirrhosis - yes/no If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Method? Liver biopsy Transient elastography Laboratory biomarkers Imaging Prior HCV treatment? Response? DAA used? Medications To check for drug interactions Comorbidities Renal function HIV status Patient preference Child-bearing potential of patient/partner Ribavirin is a teratogen HIV/Hepatitis C helpline 1-866-637-2342 Slide 16 of 41 Approved Drug Regimens for Initial Treatment Interferon PEG RBV SOF PegIFN RBV SOF RBV +/- SMV LDV SOF SOF DAC SOF RBV +/- PTV/r OMV DAS +/- Ribavirin ribavirin ribavirin +/-ribavirin +/-ribavirin GZR EBV VEL SOF Nucs sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir GLE PBV Slide 17 of 41 Protease inhibitors simeprevir Paritaprevir /ritonavir grazoprevir velpatasvir glecaprevir NS5A ledipasvir daclatasvir ombitasvir elbasvir pibrentasvir Non-Nucs dasabuvir G1 X X X X X X X X X G2 X X X X X G3 X X X X X G4 X X X X X X X X X
G1b vs G1a: G1b Initial Treatment Recommended Regimens Slide 18 of 41 IDSA/AASLD www.hcvguidelines.org NO CIRRHOSIS: CIRRHOSIS: Elbasvir/grazoprevir x 12 w Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 8 w Ledipasvir/sofosbuvir x 8* or 12 w Sofosbuvir/velpatasvir x 12 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Sofosbuvir/velpatasvir x 12 w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w* *8 wk not recommended for Black patients or HIVinfected (BOLDED are regimens approved since last year!) Slide 19 of 41 G1a Initial Treatment Recommended Regimens IDSA/AASLD www.hcvguidelines.org NO CIRRHOSIS: CIRRHOSIS: Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 8 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 8* or 12 w Ledipasvir/sofosbuvir x 12 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w *8 wk not recommended for Black patients or HIV-infected (BOLDED are regimens approved since last year!) Pangenotypic Glecaprevir/pibrentasvir DAA combo naive (TN, PEG/RBV, SOF) & special pops ENDURANCE (Phase 3) GT 1 no cirrhosis (8 vs 12W) GT 2 no cirrhosis (12W) GT 3 no cirrhosis (8 and 12W) GT 4-6 (12W) EXPEDITION (Phase 3) GT 1, 2, 4-6 cirrhosis GT 1-6 HIV GT 1-6 Renal impairment SURVEYOR (Phase 2) Slide 20 of 41 Co-formulated 3 pills once daily Pangenotypic Next generation Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93 A30K associated with failure in GT3 infection Negligible renal excretion Contains a protease inhibitor Has interaction with acid suppressing meds but?clinically significant GT 2, 4-6 no cirrhosis 8 weeks GT 3 cirrhosis/te 12 vs 16 W New York, New York, October 20, 2017 G/P Slides courtesy of S. Naggie 5
Slide 21 of 41 Glecaprevir/pibrentasvir: No Cirrhosis 8 (N=828) vs 12 (N=1076) weeks TN and TE PEG, RBV, SOF No DAA otherwise Relapse <1% Tx emergent RAS 100 90 80 70 60 50 40 30 99 99 99 100 99 100 8 weeks 12 weeks 97 98 100 100 100 100 100 100 20 10 Puoti et al. EASL 2017 0 All GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Glecaprevir/pibrentasvir: Cirrhosis Slide 22 of 41 12 weeks in N=146 Compensated cirrhosis TN or TE (25%) with IFN, P/R or SOF+P/R GT1a 33%, GT1b 27%, GT2 23%, GT4 11%, GT5 1%, GT6 5% 1 relapse- GT1a Forns et al. EASL 2017 Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1-6, Naïve + Rx-exp Slide 23 of 41 N=106 29% Rx-exp 18% cirrhosis 12% NS5a RAVs Of 2 relapses: 1 rx-exp, 0 cirrhosis, 0 baseline RAVS Renal fxn looked unchanged in pts on boosted TDF
Slide 24 of 41 POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs. 12- Wk SOF/VEL Not Non-inferior for DAA-naïve SOF/VEL/VOX 8 wks SOF/VEL 12 wks 8-wk SOF/VEL/VOX 100 95 98 93 98 92 99 97 97 97 100 99 97 92 98 94 100 100 100 did not meet criteria for noninferiority vs 80 12-wk SOF/VEL Treatment 60 difference: -3.4% 40 (95% CI: -6.2% to -0.6%) 20 476 432 217 228 155 170 61/ 57/ 61/ 53/ 91/ 86/ 58/ 56/ 17/ 30/ 9/ 2/ n/n = / / / / / / 63 59 63 53 92 89 63 57 18 0 30 9 2 0 501 440 233 232 169 172 0 Overall GT1 GT1a GT1b GT2 GT3 GT4 GT5 GT6 Unknown Relapse, n 21 3 16 2 14 1 2 1 2 0 0 0 2 1 1 0 0 0 LTFU, n 4 4 0 2 0 1 0 1 0 0 1 2 3 0 0 0 0 0 D/c for AE, n 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 SVR12 (%) Jacobson IM, et al. Gastroenterology. 2017. Slide credit: clinicaloptions.com Q2. Which of the following regimens would NOT be recommended for this treatment naïve G1b patient (for this question disregard renal function and drug-drug interactions) Slide 25 of 41 1. Sofosbuvir/velpatasvir/voxilaprevir 2. Sofosbuvir/velpatasvir 3. Elbasvir/grazoprevir 4. Glecaprevir/pibrentasvir Slide 27 of 41
Slide 28 of 41 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 100 90 80 70 60 50 40 30 20 10 0 100 93 136/136 14/15 8 week no cirrhosis 12 week cirhosis Rockstroh et al. EASL 2017 RAS Testing prior to Treatment NS5A RASs are relatively common (10-15%) Significance of NS5A RASs may depend on the RAV, the genotype, the regimen used and whether prior NS5A treatment In initial treatment, use resistance testing prior to: Treatment with grazoprevir/elbasvir for 1a Treatment of G3 with sofosbuvir/velpatasvir if cirrhosis Slide 29 of 41 Elbasvir/grazoprevir x12w Results Overall study 95% SVR 144/157 (92%) G1a, 129/131 (99%) G1b, 18/18 G4, 8/10 G6 68/70 (97%) with cirrhosis Slide 30 of 41 Baseline NS5A RASs & SVR
Slide 31 of 41 Q3. Testing for HCV resistance (RASs) would be indicated in this patient with HCV geno 1b if 1. He had failed PegIFN + RBV in the past 2. You plan to treat with 8 weeks of glecaprevir/pibrentasvir 3. You plan to treat with 12 weeks of grazoprevir/elbasvir 4. Nope! Resistance testing is not necessary here 5. Hmmm What s a RAS? Slide 33 of 41 v (Slide to be updated later this month with guidelines release) Glecaprevir/pibrentasvir: Renal Impairment Slide 34 of 41 GT 1-6 for 12 weeks Stage 4 or 5 CKD GFR<30 including HD 82% on HD TN or TE (42%) with IFN, P/R or SOF+P/R Including compensated cirrhosis (19%) GT1a 22%, GT1b 28%, GT2 16%, GT3 11%, GT4 19%, GT5 1, GT6 11 Gane et al. EASL 2017
Slide 35 of 41 Drug-Drug Interactions with DAAS Acid-reducing drugs Anti-epileptics Antiretrovirals Amiodarone Lipid-lowering drugs Slide 36 of 41 Q4. Which of the following regimens can be used with ANY dose of a proton pump inhibitor? 1. Sofosbuvir/velpatasvir/voxilaprevir 2. Sofosbuvir/velpatasvir 3. Elbasvir/grazoprevir 4. Glecaprevir/pibrentasvir Guidelines Recommendation about use of LDV or VEL with TDF SOF/LDV + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR SOF/VEL + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR Slide 38 of 41 SOF/LDV + TDF + cobi- or ritonavir-boosted PI Any CrCl: AVOID if possible, Consider TAF SOF/VEL + TDF + cobi- or ritonavir-boosted PI CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR or consider TAF
Slide 39 of 41 G4 INITIAL TREATMENT RECOMMENDED REGIMENS IDSA/AASLD www.hcvguidelines.org NO CIRRHOSIS: CIRRHOSIS: Elbasvir/grazoprevir x 12 w Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 8 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 12 w Ledipasvir/sofosbuvir x 12 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x Paritaprevir /ritonavir/ombitasvir + 12w dasabuvir x 12w* (BOLDED are regimens approved since last year!) G2 INITIAL TREATMENT RECOMMENDED REGIMENS Slide 40 of 41 IDSA/AASLD/IAS USA www.hcvguidelines.org NO CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 wks CIRRHOSIS: Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 wks G3 INITIAL TREATMENT RECOMMENDED REGIMENS Slide 41 of 41 IDSA/AASLD/IAS USA www.hcvguidelines.org NO CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir + daclatasvir x 12w CIRRHOSIS: Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 w* Sofosbuvir + daclatasvir +/-RBV x 24w* *RAV testing for Y93H and add RBV if present or use sofosbuvir/velpatasvir/voxilaprevir
Sofosbuvir + Daclatasvir for G3 (ALLY-3) Slide 42 of 41 Nelson, Hepatology 2015 61:1127-35. Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure 3% G/P 4 in 12W (3 relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) BL Y93H: 5/5 SVR BL dual NS3/NS5A 71-86% SVR Tx emergent RAS 50% failures with A30K BL A30K+Y93 (69-fold R) Slide 43 of 41 SURVEYOR-II G3 with Cirrhosis 48 patients received G/P +/- RBV x 12 w = 100% SVR Foster et al. EASL 2017 Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis A30K effect? Slide 44 of 41 Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure 3% G/P 4 in 12W (3 relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) Tx emergent RAS 50% failures with A30K BL 6% patients overall had a BL A30K SURVEYOR-II G3 with Cirrhosis 48 patients received G/P +/- RBV x 12 w = 100% SVR Foster et al. EASL 2017 Krishnan et al. EASL 2017 New York, New York, October 20, 2017 12
Slide 45 of 41 Sofosbuvir/velpatasvir x 12 wks for G3 (ASTRAL-2) Most of this 3% w/ failure had cirrhosis Foster, NEJM, 2015, hcvguidelines.org POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/Voxilaprevir for DAA-naive Cirrhotic GT3 Slide 46 of 41 100 80 60 40 20 n/n = 0 SVR12 (%) SOF/VEL/VOX 8 wks SOF/VEL 12 wks 95 95 96 96 96 99 97 91 100 100 106/ 105/ 72/ 76/ 34/ 29/ 80/ 76/ 23/ 23/ 110 109 75 77 35 32 84 80 23 23 Overall Treatment Treatment No BL RASs Any BL RASs Naive Experienced Both regimens: P <.001 for superiority vs prespecified 83% goal Overall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on-treatment failure No treatment-emergent RASs in SOF/VEL/VOX arm; Y93H in both VFs in SOF/VEL arm Jacobson IM, et al. Gastroenterology. 2017 Slide credit: clinicaloptions.com Algorithm HCV genotype/subtype & resistance Initial Treatment Algorithm Our case patient 1b, no need for resistance testing, start with 4 recommended regimens Slide 47 of 41 HIV status Cirrhosis - yes/no - duration If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Renal function Avoid Sof if CrCl <30 Medications Address drug interactions Ribavirin is a teratogen Patient preference (8 or 12 w, # pills, packaging) HIV neg Cirrhosis yes No 8 wk regimens Compensated so ok to use Pis CrCl <30, no regimens w/ sofosbuvir, so 2 remaining regimens Medications: PPI qd Elbasvir/grazoprevir no interaction Glecaprevir/pibrentasvir (limit dose) Pills and packaging Elbasvir/grazoprevir 1 pill/d Glecaprevir/pibrentasvir 3 pills/d (WHAT PAYER COVERS)
Slide 48 of 41 Summary : Is this as good as it gets? Remarkable advances in terms of HCV treatment tolerability & efficacy Advances in G2, G3, ESRD SVRs for HIV/HCV now mirror monoinfection Still drug interaction issues, but valuable resources to help manage RAV testing prior to initial treatment if: G1a and planned grazoprevir/elbasvir G3 & cirrhosis and planned sofosbuvir/velpatasvir Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer Post SVR continue liver disease management/hcc screening, monitor HBV reactivation, and consider HCV screening if ongoing risk Resources Slide 49 of 41 HCVguidelines.org nynjaetc.org http://www.hep-druginteractions.org THANK YOU Thank you