HCV-G3: Sofosbuvir with ledipasvir or daclatasvir? Ioannis Goulis, MD Aristotelian University of Thessaloniki XXIII International Hepatitis B & C Meeting of Athens Hadziyannis
HCV genotype 3 therapy Chronic infection with HCV genotype 3 is common around the world Recent data showed that there is an increasing prevalence in Greece Associated with an increased risk of progression to steatosis, cirrhosis and HCC compared with other HCV genotypes (including gen 1) In the past it was considered that treatment of HCV genotype 3 patients is easier compared to HCV gen 1 & 4 Raptopoulou M et al, Hippokratia 211; Kanwal F et al, Hepatology 214
Treatment of HCV patients with genotype 3 IFN and RBV free therapy options are limited Results of treatment in genotype 3 patients with the first line of the all-oral therapy not optimal Effect of fibrosis stage difficulties in cirrhosis Efforts to improve SVR results Role of Peg-IFN+RBV+DAA Choice of DAA added to SOF What we expect in the coming future
SVR 12 in GT-3 naïve pts by fibrosis level and treatment scheme FISSION & VALENCE studies 9 8 7 6 5 4 3 2 1 93 94 92 71 63 61 56 34 3 Overall No cirrhosis Cirrrhosis SOF+RBV 24 wks SOF+RBV 12 wks PEGIFN+RBV 24 wks Lawitz et al, NEJM 213, Zeuzem et al, NEJM 214
SVR12 (%) VALENCE: SOF + RBV in IFN-Naive and IFN-Experienced Pts With GT3 HCV Phase III study: SOF + RBV for 24 weeks 8 95 92 87 No cirrhosis Cirrhosis 6 62 4 2 87/ 92 12/ 13 24 wks Naive 85/ 98 29/ 47 24 wks Tx Failures Zeuzem S, et al. N Engl J Med. 214
Efforts to improve SVR rates Role of PEG-IFN in genotype 3 patients Combination with RBV in treatment naïve F-F3 patients Combination with RBV + SOF in Cirrhotic patients Treatment experienced (including SOF failures)
Virologic response (%) SVR (%) PEG-IFN + RBV therapy RVR is associated with a high SVR rate 9 8 7 6 5 4 3 71 6 38 GT-1 GT-2 GT-3 GT-4 9 8 7 6 5 4 3 Patients with RVR 88 86 86 2 16 2 1 1 RVR (week 4) GT-1 GT-2 GT-3 GT-4 Fried et al, J Hepatol 211
SOF + PegIFN + RBV in HCV GT 2 or 3 Treatment-Experienced Patients Phase 2 LONESTAR-2 Open-label, Phase 2 study of the efficacy of SOF + PegIFN+ RBV for 12 weeks in treatment-experienced patients with GT 2 or 3 GT 2/3 TE N=47 SOF + PegIFN + RBV -12 mg SVR12 Study Week 12 24 No response guided therapy Mean age (range), y 56 (39 72) Male, n (%) 32 (68) White, n (%) 45 (96) Hispanic, n (%) 21 (45) Mean BMI (range), kg/m 2 31 (21 53) IL28B CC, n (%) 17 (36) HCV GT 3, n (%) 24 (51) Mean BL HCV RNA (range), log 1 IU/mL 6 (4 7) Cirrhosis, n (%) 26 (55) Prior relapse/breakthrough, n (%) 4 (85) Lawitz E et al, Hepatology 214
SVR12 (%) SOF + PegIFN + RBV in HCV GT 3 Treatment-Experienced Pts LONESTAR-2 Virologic Response 9 8 7 6 5 4 3 2 1 83 83 83 2/24* 1/12 1/12 *2 relapses (1 with cirrhosis); 2 lost to follow-up1/12 GT 3 Overall Non-cirrhotic Cirrhotic Lawitz E et al, Hepatology 214
Patients with < LLOQ (%) SOF + PEG-IFN/RBV in previous SOF+RBV failures No Cirrhosis Cirrhosis 93 88 8 74 6 4 47 2 13/14 7/8 17/23 7/15 12 weeks SOF + PEG/RBV 24 weeks SOF+RBV Esteban et al, EASL 214
SVR12 (%) BOSON: Is SOF + PegIFN/RBV for 12 Wks Superior to SOF + RBV for 24 Wks in GT3? SOF + RBV for 24 wks SOF + pegifn/rbv for 12 wks Treatment Naive 9 96 82 91 Treatment Experienced 94 81 76 86 8 6 4 2 n/n = 65/ 72 68/ 71 18/ 22 21/ 23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis 44/ 54 49/ 52 26/ 34 3/ 35 Foster GR, et al. Gastroenterology. 215;149:1462-147.
Newer IFN-free combinations
EC5 s for NS5A inhibitors against HCV genotype 3 Drug 1a 1b 3a 4 Daclatasvir.2.4.15.12 Ledipasvir.34.4 35.11 GS-5816.11.9.12.9 MK-8742.4.3.3.3 ACH-312.2.7 <.2 <.2 IDX-719.62.24.17.2 ABT-53.2.4.2.2 Gao et al, Curr Opin Virol 213 Ng et al, CROI 214
Study AI444-4 (phase ΙΙ): DCV + SOF ± RBV in naïve patients with GT 3 Main endpoint: SVR12 after 24w of treatment n=16 7d Follow-up LI B: 7 d Lead-in SOF, then DCV+SOF Follow-up Naïve GT2/3 HCV patients (n=44) n=14 n=14 D: DCV+SOF Follow-up F: DCV+SOF+RBV Follow-up Week 24 SVR12 RBV: -12 mg/d, weight-based (GT 1); 8 mg/d (GT 2/3). GT = genotype, DCV = daclatasvir, SOF = sofosbuvir (GS-7977), RBV = ribavirin,. Sulkowski MS et al (214) N Engl J Med;37:211-21
HCV RNA <LLOQ Ασθενείς, % Main endpoint: Naïve patients with SVR12 (mitt) GT2,3 B D F Lead-in SOF+DCV (24εβδ) DCV+SOF (24εβδ) DCV+SOF+RBV (24εβδ) N = 14/16 14/14 12/14 Naïve patients GT2, GT3 Comparable SVR12 rates in subgroups according to viral genotype : 92% (24/26) GT2 89% (16/18) GT3 LLOQ = κατώτερο όριο ποςοτικοποίηςησ (25 IU/mL), SOF = sofosbuvir, DCV = daclatasvir, RBV = ribavirin, EOT = τζλοσ τησ θεραπείασ, SVR = διαρκή ιολογική ανταπόκριςη. Sulkowski MS et al (214) N Engl J Med
SVR12 (%) ALLY-3: SOF + DCV x 12 Wks in Tx-Naive and Tx- Experienced Pts With GT3 HCV N = 152 pts with GT3 HCV 66% tx naive, 34% experienced 19% of tx-naive pts and 25% of tx-experienced pts had cirrhosis 61% of tx-experienced pts relapsed on previous therapy, 14% had null response 1 SAE, grade 3/4 lab abnormalities in 2% of pts Nelson DR, et al. AASLD 214. Abstract LB-3.
ALLY-3: Results No cirrhosis Cirrhosis 8 96 63 97 58 94 69 6 4 2 Overall Tx Naive Tx Experienced Nelson DR, et al. AASLD 214. Abstract LB-3.
ALLY-3+ ALLY-3+ Study Design Phase 3b, open-label, randomized study 1:1 randomization (N = 5) Stratified by fibrosis stage (F3 or F4) DCV + SOF + RBV 12 weeks DCV + SOF + RBV 16 weeks 24-week follow-up 24-week follow-up DCV 6 mg daily N = 5 SOF 4 mg daily RBV (weight-based 12 or mg/day) Primary efficacy endpoint: SVR12 HCV RNA <LLOQ TD/TND (next observation carried backward) by Roche COBAS TaqMan v2. assay (LLOQ 25 IU/mL) Patient population Naïve 26% 4 8 12 16 2 24 28 32 36 4 Week Experienced 76% (SOF-based regimens 12%) Leroy V, et al. AASLD 215. Abstract LB-3.
HCV RNA < LLOQ TD/TND (%) ALLY-3+ SVR12: All Treated Patients 9 8 7 6 5 4 3 2 1 ITT ANALYSIS (Primary Endpoint) 9 88 92 45 5 21 24 24 26 Overall 12 Weeks 16 Weeks VBT a Relapse b 4 2 2 Death c 1 1 Leroy V, et al. AASLD 215. Abstract LB-3.
HCV RNA < LLOQ TD/TND (%) HCV RNA < LLOQ TD/TND (%) ALLY-3+ SVR12: All Treated Patients ITT ANALYSIS (Primary Endpoint) OBSERVED ANALYSIS 9 8 7 6 5 4 3 2 1 9 88 92 45 5 21 24 24 26 Overall 12 Weeks 16 Weeks 9 8 7 6 5 4 3 2 1 92 45 49 91 92 21 23 24 26 Overall 12 Weeks 16 Weeks VBT a Relapse b 4 2 2 VBT a Relapse b 4 2 2 Death c 1 1 Leroy V, et al. AASLD 215. Abstract LB-3.
HCV RNA < LLOQ TD/TND (%) SVR12: Patients with Advanced Fibrosis a ALLY-3+ 9 8 7 6 5 4 3 2 1 14 14 6 6 Overall 12 Weeks 16 Weeks 8 8 Leroy V, et al. AASLD 215. Abstract LB-3.
HCV RNA < LLOQ TD/TND (%) ALLY-3+ SVR12: Patients with Cirrhosis 9 8 7 6 5 4 3 2 1 ITT ANALYSIS 86 83 89 31 36 15 18 16 18 Overall 12 Weeks 16 Weeks VBT a Relapse b 4 2 2 Death c 1 1 Leroy V, et al. AASLD 215. Abstract LB-3.
HCV RNA < LLOQ TD/TND (%) HCV RNA < LLOQ TD/TND (%) ALLY-3+ SVR12: Patients with Cirrhosis 9 8 7 6 5 4 3 2 1 ITT ANALYSIS 86 83 89 31 36 15 18 16 18 Overall 12 Weeks 16 Weeks VBT a Relapse b 4 2 2 Death c 1 1 9 8 7 6 5 4 3 2 1 OBSERVED ANALYSIS 89 88 89 31 35 15 17 VBT Relapse 4 2 2 16 18 Overall 12 Weeks 16 Weeks Leroy V, et al. AASLD 215. Abstract LB-3.
LDV/SOF + RBV combination in treatment naïve & experienced genotype 3 patients W W12 W24 Treatment-naïve n=25 Treatment-naïve n=26 Treatment experienced n=5 LDV/SOF LDV/SOF + RBV LDV/SOF + RBV SVR12 SVR12 SVR12 Inclusion of patients with cirrhosis Broad inclusion criteria: No upper limit for age or BMI PLT>5./mm 3 Gane EJ et al, Gastroenterology 215
Results SVR 12 8 6 64 82 4 2 16/25 26/26 41*/5 Rx naïve LDV + SOF Rx naive LDV+SOF +RBV Rx experienced LDV+SOF +RBV *One patient with virologic breakthrough on treatment week 12 All the rest patients with virologic relapse Gane EJ et al, Gastroenterology 215
LDV/SOF + RBV combination in treatment experienced genotype 3 patients SVR 12 89 82 8 73 6 4 2 Total Without cirrhosis Cirrhosis One patient with virologic breakthrough on treatment week 12 All the rest patients with virologic relapse Gane EJ et al, Gastroenterology 215
SOF +DCV /LDV + RBV in patients with advanced liver disease Real-life experience
SOF+NS5A±RBV for 12 Weeks in 467 Patients with History of Decompensated Cirrhosis GT 1 N=235 GT 3 N=189 Other GTs N=43 Foster, EASL, 215, O2 Total N=467 Mean age, years (range) 56.1 (29-76) 54 (36-75) 59 (36-81) 55.6 (29-81) Male gender, n (%) 174 (74.) 131 (69.3) 32 (74.4) 337 (72.2) Treatment experienced, n (%) 17 (45.5) 88 (46.6) 25 (58.1) 22 (47.1) Liver transplanted, n (%) 27 (11.5) 15 (7.9) 5 (11.6) 47 (1.1) Past or present decompensated cirrhosis, n (%) 223 (94.9) 179 (94.7) 39 (9.7) 441 (94.4) CTP B, n (%) 161 (68.5) 121 (64.) 27 (62.8) 39 (66.2) CTP C, n (%) 19 (8.1) 24 (12.7) 3 (7.) 46 (9.9) MELD mean (range) 11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-36) Active ascites, n (%) 97 (41.3) 67 (35.4) 14 (32.6) 178 (38.1) Previous variceal bleed, n (%) 61 (26.) 55 (29.1) 11 (25.6) 127 (27.2) Active encephalopathy, n (%) 41 (17.4) 34 (18.) 5 (11.6) 8 (17.1) Treatment, n (%)* LDV/SOF+RBV SOF+DCV+RBV SOF+NS5A without RBV *Choice of therapy was at clinician's discretion 164 (35.1) 45 (9.6) 26 (5.6) 61 (13.1) 114 (24.4) 14 (3.) 27 (5.8) 13 (2.8) 3 (.6) 252 (54) 172 (36.8) 43 (9.2)
SVR12, % SVR12 in GT 1 Patients with History of Decompensated Cirrhosis 8 81 86 82 6 6 4 2 17/21 141/164 3/5 37/45 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV LDV/SOF±RBV for 12 weeks resulted in high SVR rates in GT 1 decompensated cirrhotics Foster, EASL, 215, O2
SVR12, % SVR12 in GT 3 Patients with History of Decompensated Cirrhosis 8 6 4 43 59 71 7 2 3/7 36/61 5/7 8/114 LDV/SOF LDV/SOF +RBV Majority of patients received RBV SOF+DCV SOF+DCV +RBV SVR rates were comparable to those seen in other studies of SOF+NS5A±RBV for 12 weeks in decompensated cirrhotics Foster, EASL, 215, O2
Changes in MELD Score MELD Improvement in GT 1 and 3 Patients with History of Decompensated Cirrhosis 15 1 Non-transplanted Transplanted on treatment 5 n = 131 n = 33-5 n = 53-1 -15 Number of Patients -2 Improvement of > 2 MELD scores was observed in 41% by FU Week 4 and 48% had no significant changes Foster, EASL, 215, O2
European DCV Compassionate Use Program Primary objective: To provide access to DCV to patients with life-threatening chronic HCV infection who have no other treatment options Day 1 Week 24 # Week 36 Week 48 Week 72 DCV (6 mg)* + SOF (4 mg) ± RBV # Follow-Up Additional Optional Follow-Up SVR12 Primary endpoint SVR24 * Dose adjusted for concomitant ARVs # Addition of RBV and shorter duration of HCV RNA < LLOQ, TD or TND at post treatment Week 12 treatment at the discretion of the physician (next value carried backward approach) Inclusion criteria Age 18 years with no treatment options High risk of hepatic decompensation or death within 12 months if left untreated Or urgent need of viral clearance (extrahepatic manifestations/comorbidities) Exclusion criteria Creatinine clearance 3 ml/min Pregnancy or not using contraception Welzel et al, AASLD 215
HCV RNA < LLOQ, TD or TND, % SVR12 (mitt) in Patients With Cirrhosis DCV + SOF DCV + SOF + RBV 8 88 86 85 86 8 75 89 88 8 8 6 4 2 37 42 25 29 19 19 11 13 12 15 12 14 6 8 Cirrhosisᵃ A B C < 1 1 to 15 > 15 Child-Pugh Class 2 2 17 17 8 9 16 2 15 17 4 5 MELD Score Category b 2 2 Welzel et al, AASLD 215
g/l platelets 1 9 /L IU/L mol/l Changes in Liver Disease Parameters From Baseline to Post-Treatment Week 12 4 3 75 5 25 ALT ALT Baseline Follow-up n = n = 69 125 75 5 25 Total Bilirubin Total Bilirubin Baseline Follow-up n = 75 n = 56 6 5 4 Albumin Albumin 3 2 1 Baseline Follow-up n = 87 n = 6 Data indicate median, IQR, range. 4 3 2 Platelets Platelets Baseline Follow-up n = 11 n = 7 Welzel et al, AASLD 215
What we expect in the near future
SOF/VEL STR for 12 Weeks Compared to SOF+RBV for 24 Weeks in GT 3 HCV-Infected Patients Phase 3, open-label, randomized study of SOF/VEL for 12 weeks in GT 3 Week 12 24 36 n=277 SOF/VEL SVR12 n=275 SOF + RBV SVR12 SOF/VEL 12 Weeks n=277 SOF + RBV 24 Weeks n=275 Mean age, y (range) 49 (21 76) 5 (19 74) Male, n (%) 17 (61) 174 (63) White, n (%) 25 (9) 239 (87) Mean BMI, kg/m 2 (range) 26.4 (16.6 48.2) 26.6 (16.9 56.2) Cirrhosis, n (%) 8 (29) 83 (3) Treatment experienced, n (%) 71 (26) 71 (26) IL28B CC, n (%) 15 (38) 111 (4) HCV RNA, log 1 IU/mL (SD) 6.2 (.7) 6.3 (.7) 36 Mangia, AASLD, 215, 249. Foster GR, et al. New Engl J Med. 215
SVR12 (%) SVR12 P<.1 8 95 8 6 4 11 relapse 2 other 38 relapse 1 BT 15 other 2 BT=breakthrough 264/277 221/275 SOF/VEL SOF + RBV 12 Weeks 24 Weeks Mangia, AASLD, 215, 249. Foster GR, et al. New Engl J Med. 215
SVR12 (%) SVR12 by Cirrhosis Status and 8 Treatment History SOF/VEL 98 93 91 89 95 9 73 71 SOF + RBV 58 8 6 4 2 16/163 141/156 4/43 33/45 31/34 22/31 33/37 22/38 264/277 221/275 Non-Cirrhotic Cirrhotic Non-Cirrhotic Cirrhotic Overall Treatment Naïve Treatment Experienced Mangia, AASLD, 215, 249. Foster GR, et al. New Engl J Med. 215
Adapted from the Wyles presentation at AASLD on November 17, 215 SURVEYOR-II Part 1 (GT3): Study Design SURVEYOR-II Part 1 (GT3): Study Design SURVEYOR-II is an open-label, multicenter phase 2 trial evaluating the safety and efficacy of co-administered ABT-493 and ABT-53, at varying doses, ± ribavirin (RBV), in HCV treatment-naïve or failed previous PegIFN/RBV treatment, noncirrhotic patients with HCV GT2 or GT3 infection Absence of cirrhosis Day 1 Week 12 PT Week 24 Treatment period Post-treatment (PT) period n=3 n=3 a n=31 n=3 ABT-493 3 mg + ABT-53 12 mg ABT-493 2 mg + ABT-53 12 mg ABT-493 2 mg + ABT-53 12 mg + RBV b ABT-493 2 mg + ABT-53 4 mg ClinicalTrials.gov: NCT2243293. N=121. a Includes one patient who was incorrectly assigned to treatment in the GT2 cohort. b Daily dose of mg or 12 mg RBV dosed BID based on patient body weight being <75 kg or 75 kg.
S V R 1 2, % P a t ie n t s 1 SURVEYOR-II Part 1 (GT3): ITT SVR12 Rates by Treatment (ITT) 9 3 9 3 9 4 8 3 8 6 4 2 ABT-493 + ABT-53 2 8 3 3 mg + 12 mg 2 8 3 2 mg + 12 mg 2 9 3 1 2 mg + 12 mg + RBV 2 5 3 2 mg + 4 mg Adapted from the Wyles presentation at AASLD on November 17, 215
SURVEYOR-II Part 1 (GT3): ITT SVR12 Rates by Treatment (per Protocol*) Wyles et al, AASLD 215
SVR12 (%) N = 24 Treatmentnaive GT-1, -2 and -3 Non-cirrhotic C-CREST-1 and 2 Part A: GRZ and MK-3682 in patients with chronic HCV GT-1, -2 or -3 GT-3 (n) 21 22 21 22 GZR + EBR + MK-3682 3 mg GZR + EBR + MK-3682 45 mg GZR + MK-848 +MK- 3682 3 mg GZR + MK-848 +MK- 3682 45 mg Follow-up Follow-up Follow-up Follow-up Safety (Overall population) The most frequent study drug-related AEs in > 1% of all patients were headache (23%), fatigue (2%) and nausea (13%) There were no drug-related serious adverse events, no patients discontinued due to adverse events and no patients died Week 9 8 7 6 5 4 3 2 1 8 SVR12 in GT-3 patients 9 9 19 9 21 GZR + EBR + MK-3682 3 mg 19 22 86 1 11 GZR + EBR + MK-3682 45 mg 2 95 2 21 GZR + MK-848 + MK- 3682 3 mg 91 2 22 GZR + MK-848 + MK- 3682 45 mg Gane E, et al. AASLD 215, Abstract LB-15.
SOF/VEL + GS-9857 6 and 8 weeks treatment for cirrhotic gen 3 patients W W6 W8 W18 W2 TN - cirrhosis n=18 SOF/VEL+GS-9857 SVR12 TE cirrhosis n=18 SOF/VEL+GS-9857 SVR12 Gane et al, AASLD 215
Results: SVR 12 rates 15/18 9 8 7 6 5 4 3 2 1 83 15*/18 SVR 12 19/19 TN- cirrhosis 6 weeks TE-cirrhosis 8 weeks *2 relapses; 1 withdrew consent Gane et al, AASLD 215
Conclusions (1) PEG-IFN + RBV has still a role for patients with genotype 3 Dual combination ONLY in naïve GT 3 pts with mild fibrosis and RVR PEG-IFN+RBV+SOF for 12 wks in GT-3 is an optimal choice for: Treatment naïve and experienced pts even with cirrhosis Previous failure to SOF + RBV Less expensive than all oral 2DAAs combination for 12/24 weeks
Conclusions (2) Optimal IFN free treatment schemes for treatment-naïve and experienced patients without cirrhosis: SOF/LDV + RBV for 12 weeks SOF + DCV for 12 weeks Presence of cirrhosis still an unresolved issue PEG-IFN + RBV + SOF for 12 weeks SOF + DCV + RBV for 12-16 weeks Hope from novel agents Most awaited data from SOF + VEL + GS-9857 combination