Interim Analysis of a French Multicenter Compassionate Use Program Christophe Hézode 1 Victor De Ledinghen 2 Helene Fontaine 3 Fabien Zoulim 4 Pascal Lebray 5 Nathalie Boyer 6 ID: 739392
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Slide1
Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection: Interim Analysis of a French Multicenter Compassionate Use Program
Christophe Hézode,1 Victor De Ledinghen,2 Helene Fontaine,3 Fabien Zoulim,4 Pascal Lebray,5 Nathalie Boyer,6 Dominique Larrey,7 Christine Silvain,8 Danielle Botta-Fridlund,9 Vincent Leroy,10 Marc Bourliere,11 Louis d’Alteroche,12 Isabelle Hubert-Fouchard,13 Dominique Guyader,14 Isabelle Rosa,15 Eric Nguyen-Khac,16 Vincent Di Martino,17 Larysa Fedchuk,18 Raoudha Akremi,18 Yacia Bennai,18 Jean-Pierre Bronowicki,19 on behalf of Bristol-Myers Squibb1Hépato-gastro-entérologie, CHU Henri-Mondor, Créteil; 2Centre d’Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac; 3Hôpital Cochin, AP-HP, Université Paris-René Descartes, Paris; 4Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon; 5Service d’Hépatogastroentérologie, Hôpital Pitié Salpêtrière, Paris; 6AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy; 7Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, Montpellier; 8Service d’hépato-gastroentérologie et d’assistance nutritive, laboratoire inflammation tissus epithéliaux et cytokines EA 4331, CHU Poitiers, Poitiers; 9Hôpital de la Conception, Marseille; 10CHU de Grenoble, Clinique universitaire d’hépato-gastroentérologie, Grenoble; 11Hôpital Saint-Joseph, Marseille; 12CHU Trousseau, Tours; 13Service d’Hépato-Gastroentérologie, CHU Angers, Angers; 14Service des Maladies du Foie, CHU Rennes, Rennes; 15Centre Hospitalier Intercommunal, Créteil; 16Service d’Hépato-gastroentérologie, CHU Amiens Nord, Amiens; 17Service d’Hépatologie et de soins intensifs digestifs, CHRU Jean Minjoz, Besançon; 18Bristol-Myers Squibb Research and Development, Rueil-Malmaison; 19Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France
The Liver Meeting® 2015: The 66th Annual Meeting of the American Association for the Study of Liver Diseases San Francisco, CA, November 13–17, 2015Oral 206
Corresponding author:
Christophe Hézode (christophe.hezode@aphp.fr) Slide2
Patients infected with HCV genotype (GT) 3 are in urgent need of effective treatments due to the increased risk of accelerated disease progression and hepatocellular carcinoma
Daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV) is the only all-oral regimen currently recommended for alla patients with GT 3 infection by EASL1 and AASLD2 treatment guidelinesThe pangenotypic, 12-week RBV-free regimen of DCV + SOF achieved 96% SVR12 in non-cirrhotic GT 3 patients (ALLY-3)312- and 16-week GT 3 data for DCV + SOF + RBV in compensated cirrhosis or advanced fibrosis (SVR12 88% and 92%, respectively) have been presented here (ALLY-3+; Abs. LB-3)Background a Non-cirrhotic and compensated or decompensated cirrhotic, treatment-naive and-experienced, HIV/HCV coinfected, post-liver transplant.1. European Association for Study of Liver. J Hepatol 2015;63:199–236. 2. AASLD/IDSA/IAS-USA guidelines. Available at www.hcvguidelines.org. 3. Nelson DR, et al. Hepatology 2015;61:1127–1135.2Slide3
The French ATU (Temporary Authorisation for Use) program for DCV provided early, pre-market-authorization access to DCV for HCV patients with advanced liver disease and no other HCV treatment options
We report interim ATU findings on DCV + SOF ± RBV in GT 3-infected patients with advanced liver diseaseObjective3Slide4
Adult patients with:
METAVIR fibrosis F3 or abovea orIrrespective of fibrosis score: severe extrahepatic manifestations; post-liver transplant HCV recurrence, or indication for liver or kidney transplantRecommended regimen and treatment durationDCV 60 mg QD + SOF 400 mg QD for 24 weeksRBV use and/or shorter treatment duration (12 weeks) at physician’s discretionEndpointsEfficacy: SVR12b at post-treatment Week 12 (PT12)Safety: based on serious adverse events (SAEs), AEs, and treatment discontinuationPatients and Endpoints a Biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);b HCV RNA < lower limit of quantification (LLOQ), target detected (TD), or target not detected (TND).4Slide5
The
safety population comprised patients with detectable HCV RNA at baseline who had 1 subsequent visit form completedThe primary efficacy population comprised patients within the safety population who had available HCV RNA data at PT12aTreatment failure was defined as HCV RNA LLOQ at PT12 (including imputation)aDeath before PT12AE-related discontinuation without achieving SVR12Populationsa Missing PT12 data were back-imputed from PT24 if available. Where PT24 was missing, missing SVR12 visit data was imputed as a failure ( LLOQ at PT12) if HCV RNA was LLOQ at PT4. Where both PT4 and PT24 were missing, SVR12 failure was imputed if HCV RNA was LLOQ at end-of-treatment; b Total ATU population: 3886.All GT 3 Patients in ATUbN = 561Safety PopulationN = 468
Primary Efficacy PopulationN = 284
Excluded, 93
BL HCV RNA undetectable, 32
BL HCV RNA missing, 1
No visit form, 60
Excluded, 184
Follow-up < 12 weeks, 184
5Slide6
Treatment Regimens and Proportions
6a Excludes 2 patients with unknown treatment duration. Total efficacy population: 284. 58.9%(n = 166)18.8%(n = 53)DCV + SOF + RBV24 WeeksTotal: N = 282aSlide7
Baseline Characteristics7
a DCV + SOF + RBV, n = 5; b Overall totals include data for 2 patients with missing regimen details (not shown);c Advanced fibrosis defined by biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);d Cirrhosis defined by biopsy, FibroScan ( 14.6 kPa), or FibroTest ( 0.75).All percentages are of patients with available data in indicated category. Missing data due to unknown: sex (n = 5); HCV RNA (n = 1); previous HCV treatment status (n = 2); cirrhosis status (n = 2); Child–Pugh category (n = 26); fibrosis stage (n = 2); platelet count (n = 20); albumin count (n = 26). 7Parameter
DCV + SOF ± RBVa12 weeksn = 63
DCV + SOF
24 weeks
n = 166
DCV + SOF
+ RBV
24 weeks
n = 53
Overall
(N = 284)
b
Age
, median (range) years
53.4 (39–78)
55.0 (27–79)
53.2 (40–72)
54.1 (27–79)
Male
, n (%)
43 (68.3)
123 (75.0)
40 (80.0)
208 (74.6)
HCV RNA
, median (range) log
10
IU/mL
5.99 (2.40–7.83)
6.00 (3.03–7.40)
5.60 (1.60–7.25)
5.94 (1.60–7.83)
Advanced
fibrosis (F3)
,
c
n (%)
19 (30.2)
21 (12.7)
2 (3.8)
42 (14.8)
Cirrhosis
,
d
n (%)
37 (58.7)
135 (82.3)
48 (90.6)
222 (78.7)
Child–Pugh A
/ B / C
, n (%)
30 (83.3) /
3 (8.3) / 3 (8.3)
98 (85.2) /
15 (13.0) / 2
(1.7)
33 (76.7) /
9 (20.9) / 1 (2.3)
162 (82.7) /
28 (14.3) / 6 (3.1)
Platelets
< 100 ×10
9
cells/L
, n (%)
18 (32.1)
55 (35.0)
27 (55.1)
102 (38.6)
Albumin ˂ 35 g/L
, n(%)
19 (31.7)
39 (26.5)
14 (28.6)
74 (28.7)
Liver transplant recipient
, n (%)
3 (4.8)
16 (9.6)
5 (9.4)
24 (8.5)
Pre-liver or
renal transplant stage
, n (%)
4 (6.3)
16 (9.6)
5 (9.4)
25 (8.8)
Treatment-experienced
, n (%)
38 (60.3)
125 (76.2)
40 (75.5)
205 (72.7)
Coinfection
with HIV / HBV
,
n (%)
7 (11.3) / 0
31 (18.7) / 5 (3.0)
3 (5.7) / 2 (3.7)
41 (14.4) / 7 (2.5)Slide8
Baseline Characteristics8
a DCV + SOF + RBV, n = 5; b Overall totals include data for 2 patients with missing regimen details (not shown);c Advanced fibrosis defined by biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);d Cirrhosis defined by biopsy, FibroScan ( 14.6 kPa), or FibroTest ( 0.75).All percentages are of patients with available data in indicated category. Missing data due to unknown: sex (n = 5); HCV RNA (n = 1); previous HCV treatment status (n = 2); cirrhosis status (n = 2); Child–Pugh category (n = 26); fibrosis stage (n = 2); platelet count (n = 20); albumin count (n = 26). 8Parameter
DCV + SOF ± RBVa12 weeksn = 63
DCV + SOF
24 weeks
n = 166
DCV + SOF
+ RBV
24 weeks
n = 53
Overall
(N = 284)
b
Age
, median (range) years
53.4 (39–78)
55.0 (27–79)
53.2 (40–72)
54.1 (27–79)
Male
, n (%)
43 (68.3)
123 (75.0)
40 (80.0)
208 (74.6)
HCV RNA
, median (range) log
10
IU/mL
5.99 (2.40–7.83)
6.00 (3.03–7.40)
5.60 (1.60–7.25)
5.94 (1.60–7.83)
Advanced
fibrosis (F3)
,
c
n (%)
19 (30.2)
21 (12.7)
2 (3.8)
42 (14.8)
Cirrhosis
,
d
n (%)
37 (58.7)
135 (82.3)
48 (90.6)
222 (78.7)
Child–Pugh A
/ B / C
, n (%)
30 (83.3) /
3 (8.3) / 3 (8.3)
98 (85.2) /
15 (13.0) / 2
(1.7)
33 (76.7) /
9 (20.9) / 1 (2.3)
162 (82.7) /
28 (14.3) / 6 (3.1)
Platelets
< 100 ×10
9
cells/L
, n (%)
18 (32.1)
55 (35.0)
27 (55.1)
102 (38.6)
Albumin ˂ 35 g/L
, n(%)
19 (31.7)
39 (26.5)
14 (28.6)
74 (28.7)
Liver transplant recipient
, n (%)
3 (4.8)
16 (9.6)
5 (9.4)
24 (8.5)
Pre-liver or
renal transplant stage
, n (%)
4 (6.3)
16 (9.6)
5 (9.4)
25 (8.8)
Treatment-experienced
, n (%)
38 (60.3)
125 (76.2)
40 (75.5)
205 (72.7)
Coinfection
with HIV / HBV
,
n (%)
7 (11.3) / 0
31 (18.7) / 5 (3.0)
3 (5.7) / 2 (3.7)
41 (14.4) / 7 (2.5)Slide9
Baseline Characteristics9
a DCV + SOF + RBV, n = 5; b Overall totals include data for 2 patients with missing regimen details (not shown);c Advanced fibrosis defined by biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);d Cirrhosis defined by biopsy, FibroScan ( 14.6 kPa), or FibroTest ( 0.75).All percentages are of patients with available data in indicated category. Missing data due to unknown: sex (n = 5); HCV RNA (n = 1); previous HCV treatment status (n = 2); cirrhosis status (n = 2); Child–Pugh category (n = 26); fibrosis stage (n = 2); platelet count (n = 20); albumin count (n = 26). 9Parameter
DCV + SOF ± RBVa12 weeksn = 63
DCV + SOF
24 weeks
n = 166
DCV + SOF
+ RBV
24 weeks
n = 53
Overall
(N = 284)
b
Age
, median (range) years
53.4 (39–78)
55.0 (27–79)
53.2 (40–72)
54.1 (27–79)
Male
, n (%)
43 (68.3)
123 (75.0)
40 (80.0)
208 (74.6)
HCV RNA
, median (range) log
10
IU/mL
5.99 (2.40–7.83)
6.00 (3.03–7.40)
5.60 (1.60–7.25)
5.94 (1.60–7.83)
Advanced
fibrosis (F3)
,
c
n (%)
19 (30.2)
21 (12.7)
2 (3.8)
42 (14.8)
Cirrhosis
,
d
n (%)
37 (58.7)
135 (82.3)
48 (90.6)
222 (78.7)
Child–Pugh A
/ B / C
, n (%)
30 (83.3) /
3 (8.3) / 3 (8.3)
98 (85.2) /
15 (13.0) / 2
(1.7)
33 (76.7) /
9 (20.9) / 1 (2.3)
162 (82.7) /
28 (14.3) / 6 (3.1)
Platelets
< 100 ×10
9
cells/L
, n (%)
18 (32.1)
55 (35.0)
27 (55.1)
102 (38.6)
Albumin ˂ 35 g/L
, n(%)
19 (31.7)
39 (26.5)
14 (28.6)
74 (28.7)
Liver transplant recipient
, n (%)
3 (4.8)
16 (9.6)
5 (9.4)
24 (8.5)
Pre-liver or
renal transplant stage
, n (%)
4 (6.3)
16 (9.6)
5 (9.4)
25 (8.8)
Treatment-experienced
, n (%)
38 (60.3)
125 (76.2)
40 (75.5)
205 (72.7)
Coinfection
with HIV / HBV
,
n (%)
7 (11.3) / 0
31 (18.7) / 5 (3.0)
3 (5.7) / 2 (3.7)
41 (14.4) / 7 (2.5)Slide10
Overall SVR12 in GT 3 by Regimen and Duration
10475814716655435381.010088.681.1Relapse: 6 Other VF: 2
Death: 2DC due to AEs: 1
Relapse: 9
Other VF: 7
Death: 3
Relapse: 7
Other VF: 3
HCV RNA < LLOQ
TD/TND
DCV + SOF
DCV + SOF + RBV
Overall SVR12 by
regimen:
87% (194/224) for DCV + SOF; 83% (48/58) for DCV + SOF + RBV
Overall SVR12 by
treatment duration
: 83% (52/63) for 12 weeks; 87% (190/219) for 24 weeks
DC, discontinuation; Other VF, undefined virologic failure.
Data missing for 2 patients due to unknown treatment duration.Slide11
SVR12 in Patients Without Cirrhosis(70% With Advanced Fibrosis [F3])
11DCV + SOFDCV + SOF + RBV242545292911
Overall SVR12 97% (58/60)By regimen: 98% (53/54) for DCV + SOF; 83% (5/6) for DCV + SOF + RBVBy treatment duration: 96% (25/26) for 12 weeks; 97% (33/34) for 24 weeks
Data missing for 2 patients due to unknown treatment duration or cirrhosis status. Slide12
SVR12 in Patients With Cirrhosis
121161352333394844DCV + SOFDCV + SOF + RBV
Overall SVR12 82% (182/222)By regimen: 83% (139/168) for DCV + SOF; 83% (43/52) for DCV + SOF + RBVBy treatment duration: 73% (27/37) for 12 weeks; 85% (155/183) for 24 weeks
Data missing for 2 patients due to unknown treatment duration or cirrhosis status. Slide13
SVR12 by Baseline Child–Pugh Score
13a 4 patients received RBV for 12 weeks, all were Child–Pugh A, and all achieved SVR12.Missing data for 26 patients of unknown Child–Pugh score, and 2 patients of unknown treatment duration.Child–Pugh AChild–Pugh B or C2430269010012172833
7
10
1
1
12 Weeks
DCV + SOF ± RBV
a
24 Weeks
DCV + SOF
24 Weeks
DCV + SOF + RBV
Overall SVR12:
Child–Pugh A:
87% (142/163)
Child–Pugh B:
67% (18/27)
Child–Pugh C:
50% (3/6)Slide14
Safety and Tolerability: Deaths and Serious AEs
14a Respiratory distress/septic shock (n = 1), sepsis/pulmonary arterial hypertension (n = 1), septic shock (n = 1), liver decompensation (n = 1), acute kidney injury (n = 1) – all considered unrelated to treatment; multi-organ failure/hepatorenal failure of unreported causality (n = 1); unknown cause of death (n = 1); b Both received DCV + SOF + RBV. Treatment maintained for patient with hepatic encephalopathy. Treatment discontinued for patient with allergic dermatitis (achieved SVR12); c Blood/vascular disorders (n = 4); medical procedures (n = 5); general disorders (n = 3); neoplasm (n = 1); respiratory distress (n = 2); alcoholic hepatitis (n = 1); urinary retention (n = 1).n (%)Total (N = 468)
Deathsa
7 (1.5)
Serious AEs
44 (9.4)
SAEs reported as related to treatment
b
Hepatic decompensation (encephalopathy)
Other (allergic dermatitis)
2 (0.4)
1 (0.2)
1 (0.2)
SAEs unrelated to treatment
Hepatic decompensation (ascites,
digestive bleeding, encephalopathy)
Severe infection (dysentery, pneumonia, erysipelas)
Hepatocellular carcinoma
Cholangiocarcinoma
Renal impairment
Liver transplant
Other
c
42
(9.0)
8 (1.9)
6 (1.3)
7 (1.5)
1 (0.2)
2 (0.4)
1 (0.2)
17 (3.8)Slide15
Safety and Tolerability: Common AEs and AE-Related Discontinuations
15a Allergic dermatitis (n = 1); neutropenia (n = 1); unspecified medical decision (n = 1).n (%)Total (N = 468)Discontinuations for AEsa3 (0.6)Common AEs ( 3%)AstheniaSleep disorder/InsomniaHeadacheDiarrheaFatigue
49 (10.5)
30 (6.4)
26 (5.6)
18 (3.8)
15 (3.2)Slide16
Summary and Conclusions16
In this real-world setting, DCV + SOF ± RBV for 12 or 24 weeks was well tolerated and achieved high SVR12 in GT 3 patients with advanced liver disease97% in noncirrhotic patients, mostly with advanced fibrosis 87% in Child–Pugh A cirrhosis, and 82% in all cirrhosis24 weeks of DCV + SOF resulted in 86% SVR12 in cirrhotic patientsNo impact of RBV use on SVR for 24 weeks of treatment (81% SVR12 with RBV)The role of RBV in DCV + SOF treatment < 24 weeks requires randomized evaluation in a larger datasetThese results show the pangenotypic, all-oral regimen of DCV + SOF ± RBV is an effective and well-tolerated option for patients with GT 3 infection and advanced liver diseaseSlide17
Acknowledgments17
The authors thank the patients and their families for their support and dedication, and all physicians, pharmacists, and medical staff at all hospital sitesStudy management and analysis was performed by LincolnEditorial support was provided by Articulate Science and funded by Bristol-Myers Squibb