A treatment revolution: current management for chronic HCV Ray Chung, M.D. Director of Hepatology and Liver Center Kevin and Polly Maroni Research Scholar Massachusetts General Hospital
Disclosures Research Grants Gilead, Abbvie, Merck, BMS, Mass Biologics
HCV: Scope of the Problem 2016 >170 million infected worldwide >3M infected in U.S. HCV mortality surpassed HIV mortality in 2006 leading indication for liver transplant worldwide leading cause of HCC in US
Targets for Direct Acting Antivirals (DAA) C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Helicase Protease Serine Protease Cofactor Needed for Replication Assembly RNA-dependent RNA polymerase NS3-4A protease inhibitors NS5A inhibitors NS5B polymerase inhibitors Nucleos(t)ide inhibitors non-nucleoside inhibitors McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
Potential Therapeutic Targets in the HCV Lifecycle Transport and release Fusion and uncoating Translation HCV RNA RNA replication NS5B polymerase inhibitors Viral assembly NS5A inhibitors Polyprotein processing NS3/4A protease inhibitors NS5B NS3 NS4B CypA NS5A NS2 NS4B NS2 NS3 HCV NS proteins NS5A NS5B NS5A inhibitors
Chronology of HCV Therapeutics 100 80 1991 1999 2001 2002 2011-13 75-90% 60 54 56% 40 34% 42% 39% 20 16% 6% 0 IFN 6 m IFN 12 m IFN/RBV 6 m IFN/RBV 12 m Peg-IFN 12 m Peg-IFN/ RBV 12 m Peg/RBV + DAA Adapted from Strader DB, et al. Hepatology. 2004;39:1147-71
Good news: SVR Reduces All- Cause and Liver-Related Mortality 530 pts with F4-6, IFN-based Rx, median F/U 8.4Y van der Meer A, JAMA, 2013
Targets for Direct Acting Antivirals (DAA) C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Helicase Protease Serine Protease Cofactor Needed for Replication Assembly RNA-dependent RNA polymerase NS3-4A protease inhibitors NS5A inhibitors NS5B polymerase inhibitors Nucleos(t)ide inhibitors non-nucleoside inhibitors McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
Characteristics of HCV DAA Classes Characteristic NS3 Protease inhibitors Nucleos(t)ide NS5B Polymerase inhibitors Nonnucleoside NS5B Polymerase inhibitors NS5A inhibitors Potency High; Variable among HCV genotypes Moderate-high; Pangenotypic Variable; Variable among HCV genotypes High; increasingly pangenotypic Barrier to Resistance Low 1a < 1b High 1a = 1b Very Low 1a < 1b Low 1a < 1b Drug Interaction Potential High Minimal Variable Low to moderate Comments 1 st gen: rash, anemia 2 nd gen: inc bilirubin (SMV) Single target Active site Allosteric; Many targets Multiple antiviral MOA
A Combination of DAAs Could Eliminate Resistant Variants Target Variant NS3 Linear NS3 Macrocyclic NS5A inhibitor NS5B nucleoside NS5B Palm NS5B Thumb V36M R S S S S S S S S NS5B Finger IFN RBV NS3 Protease T54A R S S S S S S S S R155K R R S S S S S S S A156T R R S S S S S S S D168V S R S S S S S S S NS5A L28V S S R S S S S S S Y93H S S R S S S S S S S282T S S S R S S S S S C316Y S S S S R S S S S NS5B M414T S S S S R S S S S R422K S S S S S R S S S M423T S S S S S R S S S P495S S S S S S S R S S From HCV DRAG S = Susceptible (< 4 fold shift in HCV replicon EC50) R = Resistant (>4 fold increase in EC50)
Genotype 1
The Promise of Triple Therapy Does Not Reach to All Groups Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 Pbo/PR48 SVR (%) n/n= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem et al, NEJM 2011;364:2417-27
Pooled analysis of simeprevir (PI) plus PegIFN/RBV for treatment of treatment-naïve patients with genotype 1 Simeprevir: Once daily HCV protease inhibitor Two Phase III trials (n=785) Simeprevir 150 mg or placebo for 12 wks + PegIFN/RBV for 24 or 48 weeks (RGT) FDA approved November 2013 for gt1 HCV Jacobson IM et al. The Liver Meeting 2013; Abstract 1122; FDA AVDAC 10.24.2013*; Choe SS et al The Liver Meeting Abstract 1500
Sofosbuvir (NI) + PEG/RBV: Phase 3 NEUTRINO Study (GTs 1,4,5,6) SVR12 n=327 n=292 35 56 Lawitz et al, NEJM April 23, 2013
Simeprevir + Sofosbuvir with or without RBV in gt 1 treatment-naïve and prior null responder patients: COSMOS Cohort 1 (n=80): Null responders F0-2 Cohort 2 (n=84): Naïve and null responders F3-4 100 93.3 93.3 SVR 12 96 100 SVR 12 100 93 93 93 75 79.2 75 50 50 25 25 0 No Ribavirin Ribavirin 12 weeks 24 weeks Lawitz E et al. Lancet. 2014; 384:1756-65 0 No Ribavirin Ribavirin 12 weeks 24 weeks
ION-1: Sofosbuvir + Ledipasvir (NS5A Inhibitor) Genotype 1: Treatment Naïve, n=865 Cirrhosis in 16% n=468 SVR12 (%) 99 97 98 99 209/214 211/217 212/217 215/217 12 weeks 24 weeks Afdhal N et al, N Engl J Med 2014;370:1889
ION-2: Sofosbuvir + Ledipasvir ± RBV Genotype 1 Treatment Experienced Cirrhosis in 20% n=440 SVR12 (%) 94 96 99 99 102/109 107/111 108/109 110.111 12 weeks 24 weeks Afdhal N et al, N Engl J Med 2014;370:1483
ION-3: Sofosbuvir + Ledipasvir +RBV Genotype 1 Treatment Naïve Non-Cirrhotic: 8 weeks vs 12 weeks* (n=647) 94 93 96 SVR12 (%) 202/215 201/216 208/216 Kowdley K et al, N Engl J Med 2014; 370:1879 8 weeks 12 weeks 8 wk 12 wk *posthoc analysis of relapse rates: HCV RNA <6M 2% 2% HCV RNA >6M 10% 1%
ION-2: Sofosbuvir + Ledipasvir ± RBV Genotype 1 Treatment Experienced Patients With Cirrhosis n=88 SVR12 (%) 86 82 100 100 19/22 18/22 22/22 22/22 12 weeks 24 weeks Afdhal N et al, N Engl J Med 2014;370:1483
Paritaprevir (PI)/ritonavir/Ombitasvir (NS5A) + Dasabuvir (NNI) (PrOD)+ RBV SAPPHIRE-1 Genotype 1, treatment naïve, noncirrhotic,12 weeks n=473 96 95 98 SVR12 % 455/473 307/322 148/151 PEARL III Trial, gt1b treatment naïve (n=419): PrOD+ RBV 99%, PrOD no RBV 99% Feld JJ et al, N Engl J Med 2014;370:1594-1603
Paritaprevir/r/Ombitasvir + Dasabuvir + RBV SAPPHIRE-2 Genotype 1, treatment experienced, noncirrhotic, 12 weeks n=394 96 96 97 SVR12 (%) PEARL II Trial, gt1b treatment experienced (n=179): PrOD + RBV 97%, PrOD no RBV 100% Zeuzem S et al, N Engl J Med 2014; 370:1604
Paritaprevir/r/Ombitasvir + Dasabuvir + RBV TURQUOISE-II (n=380) Gt1 compensated cirrhosis (naïve and experienced) Response by group: Prior partial: 94 v 100 Poordad F et al NEJM 2014; 370:1973
Sofosbuvir/Ledipasvir + RBV in Decompensated Cirrhosis: Preliminary Results of a Prospective, Multicenter Study n=99 Randomized to SOF + LDV + RBV (600 mg w/escalation) for 12 or 24 wks Patients with GT 1 or 4 and decompensated cirrhosis Median albumin = 2.6-3.0 g/l; Median platelets = 71-88K 12 Weeks 24 Weeks 100 87 89 87 89 90 86 80 60 40 20 0 45/52 42/47 26/30 24/27 19/22 18/20 Overall CPT B CPT C Flamm, Abst# 239, AASLD 2014
Sofosbuvir/Ledipasvir + RBV in Patients with Decompensated Cirrhosis: improved clinical status SAE = 10%-42% (only 4 considered treatment-related) 5 deaths: Septic shock (4), renal failure/cardiac arrest 4 2 0 Changes in MELD CPT B CPT C 12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=24) 5 n=5 n=5 4 2 0 n=3 n=3 CPT B 4 3 CPT B 2 1 0 5 Albumin 12 Weeks 24 Weeks 5 4 3 2 1 0 BL PT Wk4 Baseline PT Wk4 5-2 -2 4 CPT C 3 4 3-4 -4 2 1 2 1-6 -6 0 BL PT Wk4 0 Baseline PT Wk4 Flamm, Abst# 239, AASLD 2014
Sofosbuvir/Ledipasvir + RBV in Patients With Post-Transplant Recurrence: SOLAR-1 n=223 (214 reported) Randomized to SOF/LDV +RBV (600mg w/escalation) for 12 or 24 weeks Post-transplant patients with GT 1 or 4, including cirrhotics Most cirrhotic patients with MELD > 10 (60%) Median platelets = 90-108K, median albumin = 2.4-3.7 g/dl SVRT2 (%) 100 80 60 40 12 Weeks 24 Weeks 96 98 96 96 85 83 60 67 4 2 0-2 Changes in MELD (n=41) CP-B 12 Wk CP-B 24 Wk n=4 n=1 20 0 53/55 55/56 25/26 24/25 22/26 15/18 3/5 2/3 F0-F3 CPT A CPT B CPT C -4-6 Charlton M, Gastro 2015;149:649
SOF/LDV x 12 wks in HCV-HIV coinfection: ION-4 (n=335, gt1,4) Naggie S et al, NEJM 2015; 373:705-713
Genotype 2 and 3
Sofosbuvir in Treatment Naïve GT 2,3 Patients 100 FISSION Sofosbuvir 400mg + Ribavirin daily x12w 97 PEG-2a weekly + Ribavirin 800mg daily x24w SVR % 80 60 40 67 67 78 56 63 20 0 n= 253 243 70 Overall GT2 67 183 176 GT3 Lawitz E et al., NEJM 2013; 368:1878-87
Sofosbuvir/Ribavirin for Treatment-Naïve and Experienced Patients with Genotype 2 or 3: VALENCE SVR 12 G2 (blue), G3 (red) Phase 3 trial in Europe Amended to treat GT3 for 24 weeks SOF/RBV x12w (GT2, n=73) or 24W (GT3, n=250) 100 75 94 92 93 91 68 85 Cirrhosis 14 23% 50 Treatment experienced 58% Discontinuation due to AE, n=2 25 0 No cirrhosis Cirrhosis Overall Zeuzem et al, N Engl J Med 2014; 370:1993
All-Oral Combination of Daclatasvir (NS5A) and Sofosbuvir in Patients with Gt 3: ALLY-3 ALLY-3 0 Weeks 12 24 EOT SVR Treatment Naїve 19% w/ cirrhosis N=101 Daclatasvir + Sofosbuvir 99% 90% Prior Treatment 25% w/cirrhosis N=51 Daclatasvir + Sofosbuvir 99% 86% SVR F0-F3 = 96% (105/109) SVR F4 = 63% (20/32) No SAEs related to treatment, no premature D/C due to AEs Most AE mild: fatigue, headache, nausea, diarrhea Nelson, Hepatology 2015; 61:1127-35
SOF/RBV vs SOF/PEG/RBV in gt 3 and 2 : BOSON Foster G et al, Gastro 2015; 49:1462-70
BOSON: Overall SVR12 Foster G et al, Gastro 2015; 49:1462-70
Gt 3 SVR12 rates by Subgroup Foster G et al, Gastro 2015; 49:1462-70
What lies next?
Grazoprevir (PI) + Elbasvir (NS5A) for TN gt 1,4,6 (n=421) C-EDGE: Phase 3 trial Placebo crossover to GZR/EBR Stratified by cirrhosis, genotype/subtype Zeuzem S et al, Ann Intern Med 2015;163:1-13
SVR12: GZR/EBR for TN gt 1,4,6 Zeuzem S et al, Ann Intern Med 2015;163:1-13
C-EDGE: GZR/EBR for gt1,4,6 Treatment Experienced HCV
C-SURFER: GZR/EBR x 12 wks for gt 1 in CKD4-5 disease (75% on HD) n=122 TN and TE 6% cirrhotic 52% 1a, 48% 1b Roth D et al, Lancet 2015;386:1537-45
Toward a Pangenotypic regimen: SOF + Velpatasvir (NS5A) x 12 wks Feld J et al, NEJM 2015;373:2599
SOF + VEL for Genotype 3: ASTRAL-3 Foster G et al, NEJM 2015;373:2608
Summary All oral, tolerable, high efficacy regimens (>90% cure) are now SOC Several roads to the same IFN-free destination High barrier compounds desirable for simplified regimens but can be matched by combinations of DAA classes High SVR rates now possible in historically difficult populations (cirrhotics, decompensated, post-lt, HIV) We are on a path toward pangenotypic, shorter duration regimens Dec 2013 Sofosbuvir + P/R, Simeprevir + P/R for gt 1 Sofosbuvir + RBV for gt 2/3 Oct 2014 Sofosbuvir + simeprevir for gt1 Sofosbuvir/ledipasvir for gt1 Dec 2014 Paritaprevir/r/ombitasvir + dasabuvir +/- RBV for gt 1 July 2015 Daclatasvir + sofosbuvir for gt 3 2016: Grazoprevir/elbasvir +/- RBV (Jan), SOF/VEL (mid-2016)
Who should be treated and how? Genotype 1 Sofosbuvir + ledipasvir x 8-24W (TE cirrhosis) 1a: Paritaprevir/r/ombitasvir + dasabuvir + RBV x 12-24W (cirrhosis) 1b: Paritaprevir/r/ombitasvir + dasabuvir x 12W (+/- cirrhosis) Sofosbuvir + simeprevir x 12-24W (cirrhosis) Grazoprevir/elbasvir x 12W (16W + RBV for 1a/high level RAVs) Genotype 2 SOF/RBV x 12W (naïve and experienced) Extend to 16W in cirrhotics Genotype 3 Daclatasvir and Sofosbuvir x 12 wks (noncirrhotic); 24 wks + RBV (cirrhotic) PEG/RBV/SOF x 12W SOF/RBV x 24W Ideally, all treated www.hcvguidelines.org
AASLD/IDSA HCV Guidance http://www.hcvguidelines.org/