HCV Infection: EASL Clinical Practice Guidelines Francesco Negro University Hospital Geneva Switzerland

HCV Infection: EASL Clinical Practice Guidelines 2016 Francesco Negro University Hospital Geneva Switzerland

Panel Codinat: Jean-Michel Pawlotsky Panel: Alessio Aghemo David Back Geoffrey Dusheiko Xavier Fns Francesco Negro (EASL GB) Massimo Puoti Christoph Sarrazin

Goal of Therapy The goal of therapy is to cure HCV infection to prevent hepatic cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death The endpoint of therapy is undetectable in a sensitive assay (LOD <15 IU/mL) 12 weeks (SVR12) and/ 24 weeks (SVR24) after the end of treatment Undetectable HCV ce antigen 12 weeks (SVR12) and/ 24 weeks (SVR24) after the end of treatment is an alternative endpoint of therapy in patients with detectable HCV ce antigen pri to therapy if assays are not available not affdable

Relationship Between HCV Ce Ag and Levels Analytical sensitivity equivalent to 500-3000 IU/mL Rare false-negatives (ce Ag-negative, -positive) (Chevaliez et al., J Clin Virol 2014;61:145-8)

Treatment Indications

Treatment Indications All treatment-naïve and treatment-experienced patients with compensated decompensated chronic liver disease due to HCV must be considered f therapy => UNIVERSAL ACCESS TO THERAPY

Patients Who Should be Treated Without Delay Significant fibrosis cirrhosis (METAVIR sce F2, F3, F4), including decompensated cirrhosis Clinically significant extra-hepatic manifestations HCV recurrence after liver transplantation Individuals at risk of transmitting HCV Active injection drug users MSM with high-risk sexual practices Women of child-bearing age who wish to get pregnant Hemodialysis patients Prison inmates

Available therapies

DAAs Approved in 2014 Sofosbuvir All genotypes Simeprevir Gen 1, 4 Daclatasvir All genotypes

DAAs Approved in 2015 Sofosbuvir/ Ledipasvir Gen 1, 4, 5, 6 Ombitasvir/ Paritaprevir/ Ritonavir Gen 1, 4 Dasabuvir Gen 1

DAAs Approved in 2016 Sofosbuvir/ Velpatasvir All genotypes Grazoprevir/ Elbasvir Gen 1, 4

General Considerations IFN-free regimens are the best options in HCVmonoinfected and in HIV-coinfected patients without cirrhosis with compensated (Child-Pugh A) cirrhosis, because of their virological efficacy, ease of use and tolerability The same IFN-free treatment regimens can be used in HIV-coinfected patients as in patients without HIV infection, as the virological results of therapy are identical

Drug-Drug Interactions www.hep-druginteractions.g

DDIs: HIV Antiretrovirals

DDIs: Cardiovascular Drugs

IFN-Free Treatment Options Combination regimen GT1 GT2 GT3 GT4 GT5-6 SOF + RBV No Suboptimal Suboptimal No No SOF/LDV ± RBV Yes No No Yes Yes SOF/VEL ± RBV Yes Yes Yes Yes Yes OBV/PTV/r + DSV (3D) ± RBV Yes No No No No OBV/PTV/r (2D) ± RBV No No No Yes No GZR/EBR ± RBV Yes No No Yes No SOF + DCV ± RBV Yes Yes Yes Yes Yes SOF + SIM ± RBV Suboptimal No No Yes No

IFN-Free Treatment Options These options are considered equivalent f a given genotype, and their der of presentation does not indicate any superiity of preference, unless specified so By convention, the combination regimens listed start with fixed-dose, single-pill combinations (sofosbuvir-based followed by sofosbuvir-free), followed by combinations of sofosbuvir with another drug in a different pill

Characteristics that Infm Treatment Option Selection Pri treatment experience Drug-drug interactions HCV genotype/s ubtype Treatment selection PK profile of treatment Severity of liver disease Patient combidities

Genotype 1

Genotype 1a Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 8-12 wk 12 wk + RBV* 12 wk 12 wk + RBV* SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk OBV/PTV/r + DSV (3D) ± RBV 12 wk + RBV 12 wk + RBV 24 wk + RBV 24 wk + RBV GZR/EBR ± RBV >800,000 >800,000 >800,000 >800,000 SOF + DCV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* *24 wk without RBV if RBV contraindicated poly tolerated Only if presence of NS5A RASs at baseline, if resistance testing available

SOF/LDV Trials vs Real-Wld ION-3 vs Real-wld, Rx-naive, No cirrhosis, VL <6 M IU/mL (Curry et al., EASL 2016)

SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-1 Phase III, TN and TE (32%), Gt 1,2,4,5,6, 19% cirrhosis, 12 wks 99% 99% 99% 99% 100 99% 90 80 70 60 50 40 30 20 10 N=624 N=501 N=121 N=423 N=201 0 Overall No Yes Naïve Experienced Cirrhosis Treatment histy (Feld et al., N Engl J Med 2015;373:2599-607)

Genotype 1b Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 8-12 wk 12 wk 12 wk 12 wk SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk OBV/PTV/r + DSV (3D) ± RBV 8-12 wk 12 wk 12 wk 12 wk GZR/EBR ± RBV 12 wk 12 wk 12 wk 12 wk SOF + DCV ± RBV 12 wk 12 wk 12 wk 12 wk

SVR12 rate (%) 8 weeks of OBV/PTV/r + DSV in Genotype 1b Treatment-Naïves 100 97% 90 80 70 60 50 40 30 20 GARNET study Genotype 1b Treatment-naïve No cirrhosis (F0-F3) SVR: 13/15 F3 patients 10 0 N=166 (Abbvie, presented at the EASL/AASLD Special Conference on Hepatitis C)

Genotype 2 Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk SOF + DCV ± RBV 12 wk 12 wk 12 wk 12 wk

SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-2 Phase III, TN and TE (14%), Gt 2, 14% cirrhosis, 12 weeks SOF/VEL SOF/RBV 100 90 80 99% 96% 100% 93% 100% 81% 100% 100% 70 60 50 40 30 20 10 N=100 N=96 N=15 N=15 N=15 N=16 N=4 N=4 0 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Treatment-naïve Treatment-experienced (Foster et al., N Engl J Med 2015;373:2608-17)

Genotype 3 Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/VEL ± RBV 12 wk 12 wk + RBV* 12 wk + RBV* 12 wk + RBV* SOF + DCV ± RBV 12 wk 12 wk + RBV* 24 wk + RBV 24 wk + RBV *24 wk without RBV if RBV contraindicated poly tolerated Only if presence of NS5A RAS Y93H at baseline, if resistance testing available

SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-3 Phase III, TN and TE (26%), Gt 3, 30% cirrhosis, 12 weeks 100 90 98% 90% SOF/VEL 12 wk 93% SOF/RBV 24 wk 91% 89% 80 73% 71% 70 60 58% 50 40 30 20 10 N=163 N=156 N=43 N=45 N=34 N=31 N=37 N=38 0 No cirrhosis Treatment-naïve Cirrhosis No cirrhosis Cirrhosis Treatment-experienced (Foster et al., N Engl J Med 2015;373:2608-17)

Sofosbuvir + Velpatasvir ASTRAL-3 Phase III, TN and TE (26%), Gt 3, 30% cirrhosis, 12 weeks Resistance analysis (1% cutoff, deep sequencing) Total, n=274 Total, n=274 97% SVR12 84% No BL NS5A RASs n=231 16% BL NS5A RASs n=43 88% SVR12 225/231 38/43 SVR12 was 84% (21/25) in patients with Y93H (Foster et al., N Engl J Med 2015;373:2608-17)

Genotype 4 Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk OBV/PTV/r (2D) ± RBV 12 wk + RBV 12 wk + RBV 12 wk + RBV 12 wk + RBV GZR/EBR ± RBV 12 wk >800,000 12 wk >800,000 SOF + DCV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* SOF + SIM ±RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* *24 wk without RBV if RBV contraindicated poly tolerated

SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-1 Phase III, TN and TE (32%), Gt 4, 19% cirrhosis, 12 wks 100 100% 90 80 70 60 50 40 30 20 10 0 N=116 GT4 (Feld et al., N Engl J Med 2015;373:2599-607)

SVR12 rate (%) Grazoprevir + Elbasvir Integrated analysis of Phase II and III trials, Gt 4, w/o cirrhosis Treatment-naïve Treatment-experienced 100 96% 100% 93% 100% 90 80 78% 70 60 50 40 30 20 60% 10 0 N=56 N=10 N=9 N=15 No RBV 12 weeks + RBV 12 weeks No RBV 12 weeks + RBV 12 weeks N=5 N=8 No RBV 16 weeks + RBV 16 weeks (Asselah et al., AASLD 2015)

Genotype 5-6 Options Combination regimen No cirrhosis Compensated cirrhosis Rx-naïve Rx-exp d Rx-naïve Rx-exp d SOF/LDV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* SOF/VEL ± RBV 12 wk 12 wk 12 wk 12 wk SOF + DCV ± RBV 12 wk 12 wk + RBV* 12 wk 12 wk + RBV* *24 wk without RBV if RBV contraindicated poly tolerated

SVR12 rate (%) Sofosbuvir + Velpatasvir ASTRAL-1 Phase III, TN and TE (32%), Gt 1,2,4,5,6, 19% cirrhosis, 12 wks 100 90 80 97% 100% 70 60 50 40 30 20 10 0 N=35 GT5 N=41 GT6 (Feld et al., N Engl J Med 2015;373:2599-607)

Utility of HCV resistance testing pri to first-line therapy

HCV RAS Testing Pri to First-line Therapy Systematic testing f HCV resistance pri to treatment is NOT recommended. Indeed, this obligation would seriously limit access to care and treatment regimens can be optimized without this infmation Physicians who have easy access to a reliable test assessing HCV resistance to NS5A inhibits (spanning amino acids 24 to 93) can use these results to guide their decisions The test should be based on population sequencing (repting RASs as present absent ) deep sequencing with a cutoff of 15% (only RASs that are present in me than 15% of the sequences generated must be considered)

HCV Resistance Testing Pri to First-Line DAA Therapy Not available Available, reliable, interpretable, understandable* *recommended f GZR/EBR f US patients with GT1a Optimize therapy to avoid treatment failure Presence of NS5As RASs conferring high-level resistance (pop seq >15%) SOF/LDV, SOF/DCV, SOF/SIM: Add RBV in G1a-4-5-6 TE SOF/VEL: Add RBV in G3 TE patients and cirrhotics GZR/EBR: use 16 weeks with RBV in GT1a Add ribavirin and/ increase treatment duration in patients with NS5A RASs

SVR12 (%) SVR Accding to Baseline NS5A RASs GT1, SOF/LDV, guidelines-recommended With NS5A RASs No NS5A RASs Without cirrhosis With cirrhosis Rx-Naive Rx-Exp d Rx-Naive Rx-Exp d 100 98% 99% 99% 99% 90% 99% 96% 96% 100%100% 88% 100% 89% 96% 87% 100% 80 60 40 20 0 N=32 N=108 N=189 N=509 N=88 N=300 N=27 N=68 N=10 N=27 N=9 N=19 N=66 N=214 N=15 N=84 8 Wks* 12 Wks 12 Wks 12 Wks 12 Wks + RBV * < 6 million IU/mL 24 Wks 12 Wks + RBV 24 Wks (Zeuzem et al., AASLD 2015)

SVR12 rate (%) Grazoprevir/Elbasvir Pooled efficacy population-phase II and III trials, GT1a, 12 weeks, no RBV No NS5A RASs With NS5A RASs 100 99% 100% 97% 100% 97% 90 80 70 60 50 52% 40 30 29% 20 10 N=119 N=624 N=273 N=21 N=14 N=69 N=7 0 800,000 IU/mL >800,000 IU/mL Treatment-naïve (Merck, communicated to the panel) 800,000 IU/mL >800,000 IU/mL Treatment-experienced

SVR12 rate (%) Sofosbuvir/Ledipasvir FDC + RBV SOLAR-1- Genotype 1, decompensated cirrhosis LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks 100 87% 89% 87% 89% 86% 90% 80 60 40 20 0 N=52 N=47 Overall N=30 N=27 N=22 N=20 CPT B CPT C (Charlton et al., Gastroenterology 2015;149:649-59)

SOF/LDV SOF+DCV ± RBV Real-life UK EAP, Decompensated cirrhosis (CPT 7), All GTs Change in MELD sce (Foster et al., J Hepatol 2016;64:1224-31)

Patients with Decompensated Cirrhosis Without an Indication f LT Patients with decompensated cirrhosis (CPT-B CPT- C) not on the waiting list f liver transplantation and without concomitant combidities that could impact their survival should be treated urgently Protease inhibits should not be used in patients with Child-Pugh B and are contraindicated in patients with Child-Pugh C decompensated cirrhosis Frequent clinical and labaty assessment is necessary