New Antivirals for Hep C in Context of HIV: Vosevi and Mavyret John Scott, MD, MSc, FIDSA November 16, 2017 This presentation is intended for educational use only and does not in any way constitute medical consultation or advice related to any specific patient
Disclosures Data Adjudication Cmte for Novartis
Objectives Review phase 3 studies of HCV treatment in patients coinfected with HIV with SOF/VEL/VOX (Vosevi) and Glecaprevir/Pibrentasvir (Mavyret) List common drug-drug interactions and side effects with these regimens
AASLD/IDSA HCV Guidelines SOF/VEL/VOX Not formally studied, but it is highly likely that response rates for HIV/HCV coinfected will be similar to those with just HCV infection G/P Studied in phase 3 study of 137 patients, including those with cirrhosis. High SVR.
Currently Approved FDA Antivirals for Hep C Drug Sofosbuvir/Ledipasvir (Harvoni) Ombitasvir- Paritaprevir-Ritonavir Dasabuvir (Viekira Pak) Glecaprevir/Pibrentas vir (Mavyret) Genotype s Cost (WAC) Currently Approved FDA Antivirals for Hep C Efficacy Side Effects Comment 1, 4, 5, 6 $94,500 ~95% + FDA approved for HIV+, one pill Qd 1 $83,319 ~95% +/++ Add ribavirin if GT 1a, many DDIs 1-6 $26,400 >95% + 3 pills Qd, ok in ESRD, ok with PPIs Daclatasvir (Daklinza) 1, 3 $63,000 >85% + Has activity against GT 2; use w/ SOF Elbasvir/grazoprevir (Zepatier) Sofosbuvir/velpatasvir (Epclusa) Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) 1, 4 $54,600 >95% ++ Good for ESRD, need RAS testing 1-6 $74,760 >95% + Needs low ph for absorption 1-6 $74,760 >95% ++ FDA approved for DAA failures, GT 1,3
Background
SOF/VEL/VOX in NS5a-experienced Patients POLARIS-1 Trial Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46. Slide courtesy David Spach, HCV Online Design: Randomized, placebo-controlled, phase 3 trial to evaluate the efficacy of a fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in NS5A-inhibitor-experienced patients with GT 1-6 chronic HCV infection Setting: - 108 sites in United States, Canada, New Zealand, Australia, France, Germany, and United Kingdom Entry Criteria - Age >18 years - Chronic HCV (any genotype) - HCV RNA 10,000 IU/mL at screening - Prior treatment failure with DAA that contained NS5A inhibitor - Patients with compensated cirrhosis allowed Primary End-Point: SVR12 Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46. Slide courtesy David Spach, HCV Online
Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A- Experienced GT 1-6 POLARIS-1: Study Design Week 0 12 Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46. 24 GT 1-6 with NS5A inhibitor experience* n = 415 N=263 N=152 Sofosbuvir-Velpatasvir- Voxilaprevir Placebo SVR12 SVR12 GT 1 patients randomized 2:1 ratio (active:placebo). Stratified by presence of cirrhosis (target 30%). Genotypes 2-6 were assigned to active arm (and not randomized). Placebo recipients were eligible for deferred treatment with sofosbuvir-velpatasvir-voxilaprevir Drug Dosing Sofosbuvir-Velpatasvir-Voxilaprevir (400/100/100 mg): fixed dose combination; one pill once daily Placebo: one pill once daily Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46.
Patients (%) Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A- Experienced GT 1-6 POLARIS-1: Prior NS5A Treatment 60 50 51 40 30 27 20 10 11 13 0 Ledipasvir Daclatasvir Ombitasvir Other Prior NS5A Treatment
Side Effects with SOF/VEL/VOX Adverse Event (AE) SOF-VEL-VOX (n = 263) Placebo (n = 152) Discontinuation due to AE no. (%) 1 (<1) 3 (2) Serious AEs no. (%) 5 (2) 7 (5) Deaths no. 0 0 Any AE in 5% of patients no. (%) Headache Fatigue Diarrhea Nausea 66 (25) 56 (21) 47 (18) 37 (14) 26 (17) 30 (20) 19 (12) 12 (8) Laboratory AEs Grade 3 or Above no. (%) 18 (6.9%) 22 (14.5%) One patient in active arm discontinued due to angioedema attributed to ramipril.
Patients with SVR12 (%) Sofosbuvir-Velpatasvir-Voxilaprevir in NS5A- Experienced GT 1-6 POLARIS-1: Results 100 80 96 100 100 95 91 100 100 60 40 20 0 97/101 45/45 5/5 74/78 20/22 1/1 6/6 1a 1b 2 3 4 5 6 Genotype POLARIS-1: SVR12 Results by Genotype
Sofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 POLARIS-4: Study Study Design Week 0 12 24 Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46, Slides courtesy David Spach, MD. GT 1-6 with prior DAA experience (no NS5A inhibitor) n = 333 N=182 N=151 Sofosbuvir-Velpatasvir- Voxilaprevir Sofosbuvir-Velpatasvir SVR12 SVR12 GT 1, 2, 3 patients randomized 1:1. Stratified by presence of cirrhosis. Genotypes 4 were assigned to active arm (and not randomized). No GT 5, 6 patients were enrolled. Drug Dosing Sofosbuvir-Velpatasvir-Voxilaprevir (400/100/100 mg): fixed dose combination; one pill once daily Sofosbuvir-Velpatasvir (400/100 mg): fixed dose combination; one pill once daily Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46, Slides courtesy David Spach, MD.
Patients (%) Sofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-3 POLARIS-4: Prior HCV Treatment 100 80 60 69 40 20 0 11 14 4 2 SOF Other SOF+SMV Other Other Slide courtesy David Spach, MD. HCV Online
Patients (%) SVR12 Sofosbuvir-Velpatasvir-Voxilaprevir in DAA- Experienced GT 1-6 100 80 POLARIS-4: Overall SVR12 by Treatment Arm 97 90 60 40 20 0 177/182 SOF-VEL-VOX 136/151 SOF-VEL P<0.001 for superiority compared with prespecified 85% performance goal for SOF-VEL-VOX Source: Bourlière M, et al. N Engl J Med. 2017;376:2134-46. Slide courtesy David Spach, MD
SOF/VEL/VOX: Drug Interactions with ARVs VOX is a substrate for OATP, P-gp, BRCP, CYP3A, CYP1A2, CYP2C8; inhibitor of OATP, P-gp, BRCP Do NOT use with ATZ/r VOX levels boosted with TAF/FTC/ELV/COBI; TDF/FTC; DAR/r so monitor of hepatic toxicity Monitor Cr, PO4, u/a with TDF-VEL These ARVs are fine: DOL, RAL, FTC, RPV EFZ is not recommended because it significantly lowers VEL levels Liverpool HCV Drug Interaction Database
Glecaprevir/Pibrentasvir (Mavyret) Glecaprevir/Pibrentasvir (Mavyret)
Glecaprevir-Pibrentasvir (Mavyret) Indications: Treatment-Naïve Patients Glecaprevir-Pibrentasvir in HCV Treatment-Naïve Patients HCV Genotype No Cirrhosis Treatment Duration Compensated Cirrhosis (Child-Pugh Class A) Genotype 1 8 weeks 12 weeks Genotype 2 8 weeks 12 weeks Genotype 3 8 weeks 12 weeks Genotype 4 8 weeks 12 weeks Genotype 5 8 weeks 12 weeks Genotype 6 8 weeks 12 weeks Source: Mavyret Prescribing Information. AbbVie. Slide courtesy David Spach,MD
Glecaprevir-Pibrentasvir (Mavyret) Indications: Treatment Experienced-Patients Glecaprevir-Pibrentasvir in HCV Treatment-Experienced Patients HCV Genotype 1 Patients Previously Treated With a Regimen Containing: An NS5A inhibitor 1 without prior treatment with an NS3/4A protease inhibitor An NS3/4A PI 2 without prior treatment with an NS5A inhibitor No Cirrhosis Treatment Duration Compensated Cirrhosis (Child-Pugh Class A) 16 weeks 16 weeks 12 weeks 12 weeks 1, 2, 4, 5, or 6 PEG + RIB +/- sofosbuvir (NS5B inhibitor) 3 8 weeks 12 weeks 3 PEG + RIB +/- sofosbuvir (NS5B inhibitor) 3 16 weeks 16 weeks 1 In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin. 2 In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin 3 Prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor. Source: Mavyret Prescribing Information. AbbVie.
Glecaprevir-Pibrentasvir in HIV-HCV Coinfected Patients EXPEDITION-2: Study Design Week 0 8 12 20 24 GT 1-6 Non-Cirrhotic n = 137 GLE-PIB SVR12 GT 1-6 Cirrhotic n = 16 GLE-PIB SVR12 Abbreviations: GLE-PIB= Glecaprevir-pibrentasvir Drug Dosing Glecaprevir-pibrentasvir (100/40 mg) fixed-dose combination: three pills (300/120 mg) once daily Source: Rockstroh J, et al. IAS 2017. Abstract 918. Slide courtesy David Spach
Glecaprevir-Pibrentasvir in HIV-HCV Coinfected Patients EXPEDITION-2: Baseline Characteristics Baseline Characteristic Treatment-experienced, n (%) IFN-based, n/n (%) SOF-based, n/n (%) IDU within 12 months, n (%) On opiate substitution therapy, n (%) N(t)RTI backbone, n (%) Tenofovir disoproxil fumarate Tenofovir alafenamide Abacavir ART anchor agent, n (%) Raltegravir Dolutegravir Rilpivirine Elvitegravir/cobicistat GLE-PIB 8 weeks (n = 137) 26 (19) 23 (17) 3 (2) 12 (9) 11 (8) 74 (54) 6 (4) 49 (36) 39 (29) 62 (45) 27 (20) 1 (<1) GLE-PIB 12 weeks (n = 16) 2 (13) 2 (13) 0 1 (6) 2 (13) 13 (81) 0 3 (19) ART naïve, n (%) 9 (7) 0 6 (38) 5 (31) 5 (31) 0 CD4 cell count, median (range), cells/mm 3 588 (154-2103) 545 (222-1806)
Patients (%) SVR12 Glecaprevir-Pibrentasvir in HIV-HCV Coinfected Patients EXPEDITION-2: Results 100 98.0 99.0 80 60 40 1 Virologic breakthrough 1 DC on day 23 1 Lost to follow-up 20 0 150/153 ITT 150/151 mitt ITT = Intent-to-treat; mitt = modified intent-to-treat One GT3 patient with cirrhosis and 85% compliance had on-treatment virologic failure Source: Rockstroh J, et al. IAS 2017. Abstract 918.
Glecaprevir/Pibrentasivr: Drug Interactions with ARVs Do not use with EFZ, ritonavir boosted PIs TAF/FTC/EVL/COBI increases G/P levels so monitor LFTs carefully AASLD HCV Guidelines
Conclusions SOF/VEL/VOX is best option for SOF or NS5a failures Beware DDIs and diarrhea G/P is good option for treatment naïve pts, pts with ESRD, using PPIs Do not use w/ EFZ or PIs Both new antivirals should not be used in Class B cirrhotics 1. Eley T, et al. [abstract]. Global Antiviral Journal 2014;10 (suppl 1):54-5.