differential benefits of daas in patients with...

Differential benefits of DAAs in patients with co-morbidities

Marc Bourliere , MD G. Dusheiko, MD Hôpital Saint Joseph UCL Institute for Liver and Health Marseille, France Royal Free Hospital London UK

4th Workshop on HCV Therapy Advances Paris 12-13 December 2014

Disclosures MB and GD

– Board member for : Schering-Plough, Merck, Janssen, Gilead, Boehringer Ingelheim, BMS, Novartis, Roche, Abbott, GSK, Vertex, Idenix

– Speaker for : Roche, Schering-Plough, Merck, Janssen, Gilead, BMS, Abbvie

Populations

• End Stage renal disease patients • Patients with Bleeding disorders • Patients with psychiatric disorders

DAAs Combinations approved by EMA in2014

Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec

Telaprevir (G1)

Boceprevir (G1)

Sofosbuvir (G1,3,4,5,6)

Sofosbuvir +

RBV

G2,3, 4

Daclatasvir (G4)

2011 2012 2013 2014

IFN

-free

W

ith IF

N

Simeprevir (G1, 4)

Simeprevir

Sofosbuvir +

G1,4

Sofosbuvir

Daclatasvir +

G1,3,4

Sofosbuvir+ Ledipasvir

FDC* (HARVONI)

RBV

±

G1,3,4

Current access to second-generation DAAs in European region end 2014

*BE and NL: reimbursement approved, will be implemented in Jan 2015 BE: SMV/PR, SOF/PR, SMV-SOF; NL: SMV/PR, SOF/PR, SMV-SOF, DCV IT: SOF and SMV price agreed, pending official publication

SMV/PR

SMV/PR SOF/PR

SMV/PR SOF/PR

SMV-SOF

SOF/LDV SOF+DCV

Special access, pre-NICE

SOF-SMV SOF-DCV SOF-LDV

SOF/PR

SMV, DCV, SOF

SOF-SMV SOF-DCV

* *

*

Populations


Patient CA Male aged 62 • Chronic hepatitis C genotype 1b

– Cirrhosis – Past non responder interferon and RBV

• Hepatocellular carcinoma 2010 – October 2010 radiofrequency ablation – Transplant initially excluded alcohol history

• Marked ascites April 2011 – spironolactone

Patient CA

• Past mycetoma: TB

• 2010: – HB 12 WCC 6.4 Platelets 98 – Albumin 25 ALT 185 AST 233 Bilirubin 16 – Creatinine 93 umol/L eGFR 76 ml/min

Course

• April 2011 – Creatinine 114 eGFR 60

• October 2013 – Creatinine 161 eGFR 39 – Urine protein creatinine ratio 1,279 mg/ml

• Cryoglobulins detected • April 2014 HCV RNA 31,562 IU/ml

• Renal biopsy February 2014

– Mixed glomerulopathy with diabetic change – Immune complex glomerulopathy – Subendothelial deposits – Sub epithelial intramembranous mesangial deposits – Mesangiocapillary type glomerulopathy – Hepatitis C cryoglobulin induced

Treatment

• Gliclazide 40 mg daily • Propranolol 10 mg bd • Spironolactone 50 mg /day • Furosemide 20 mg /day

• Abstinent from alcohol since 2010

• Antiviral treatment:

– sofosbuvir 400 mg daclatasvir 60 mg ribavirin 600 bd Sept 2014

CA course

• September 2014 – Creatinine 207 – GFR Tc-99m DTPA eGFR 27 ml/min – Calculated Cockroft and Gault 39 ml/mn

• October 2014 HCV RNA not detected. – Continued sofosbuvir 400 mg/day

• November 2014 – Creatinine 255 eGFR 23 – HCV RNA undetectable

• Ribavirin stopped 27 November

• Admitted hyperkalemia • December 2014

– Creatinine 215 eGFR 28

HCV and cryoglobulinaemia • Cirrhosis, membranous glomerulonephritis, mixed essential

cryoglobulinaemia and vasculitis associated chronic hepatitis C. • HCV continuous stimulus for production of circulating immune

complexes which may form cryoprecipiates • Complement:

– cold-insoluble immune complex -mediated vasculitis – involving small blood vessels different tissues including skin, kidney, peripheral, and

central nervous system.

• B-cell clonal selection may arise as a result of antigen stimulation – May lead to malignant B-cell proliferation.

• Optimal treatment relies on reducing HCV RNA as the driver of the process?

Almehmi et al American Journal of kidney diseases 54: 7070 2009

Frequency of CD19+ B cells lower in HCV-infected patients with mixed essential cryoglobulinaemia

Holtz et al, Hepatology Volume 56 pages 1602-1610, 14 OCT 2012

http://onlinelibrary.wiley.com/doi/10.1002/hep.v56.5/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/hep.25821/full#fig4

B cell homeostasis in chronic hepatitis C virus–related mixed cryoglobulinemia is maintained through naïve B cell apoptosis

Holtz et al, Hepatology Volume 56 pages 1602-1610, 14 OCT 2012

B cell numbers paradoxically reduced in HCV-infected patients with MC HCV patients Increased sensitivity of naıve B cells to apoptosis: reduction in size of naıve B cell subset.

http://onlinelibrary.wiley.com/doi/10.1002/hep.v56.5/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/hep.25821/full#fig4

Discussion

• Use (and continued use) of sofosbuvir in patients with impaired renal function

• Worsening of renal function in patients with rapid decline in HCV RNA? – ? B cell surge with reduction in HCV RNA? – Rituximab use

• ? Contraindicated past TB

Sofosbuvir

Prodrug

uridine monophosphate

Metabolism GS-461203

uridine – triphosphate 1. Hydrolysis of the carboxyl ester moiety 2. Phosphoramidate cleavage 3. Phosphorylation by pyrimidine nucleotide biosynthesis pathway Dephosphorylation GS331007

80%, 14%, and 2.5% recovered in urine, faeces, and expired air Urine: recovered: GS331007 (78%) 3.5% as sofosbuvir.

uridine triphosphate

Hepatocyte

Sofosbuvir GS331007 Mild eGFR ≥ 50 and < 80

Moderate eGFR ≥ 30 and < 50

Severe (eGFR <

30

ESRD

Plasma half life

0.48-0.75 hrs 7.2 - 11.8 hrs

Cmax ng/ml 603 1378

AUC ng/ml 539 9369

Sofosbuvir AUC

61% 107% 171% 28% pre 60% post

GS331007 55% 88% 451%

Sofosbuvir pharmacokinetics in renal impairment

SOF + RBV in Patients with Severe Renal Impairment

Study Rationale: Prior studies in renally impaired patients without HCV demonstrated higher exposures of SOF and GS-3310071

Phase 2b, efficacy, PK, and safety of SOF + RBV in patients with HCV GT 1 and GT 3 with eGFR < 30 mL/min (Stage 4 CKD)

The cause of renal disease was not defined for participation; medical history of patients included HCV, diabetes, hypertension, and lupus nephritis

SVR12

Week 0 24

SOF 20 0 mg QD + RBV Part 1 Severe renal n=20 SOF 40 0 mg QD + RBV

SOF 20 0 mg QD + RBV

SOF 40 0 mg QD + RBV

0 24 0 24 0 24

SVR12

SVR12

SVR12

Part 2 ESRD

on dialysis

n=20

1. Cornpropst M, et al. EASL 2012, Poster 1101. Gane, AASLD, 2014, Poster #966 ClinicalTrials.gov NCT 01958281

Safety, efficacy and phramokinetics of Sofosbuvir in ESKD

• 10 patients with ESKD (eGFR < 30 ml/mn) and HCV (GT-1, 7GT-1a, 2 GT-1b and7 GT-3) without cirrhosis. 7/10 were naive ,were treated with SOF 200 mg/j and RBV 200 mg/j.

• Efficacy : – HCV RNA undetectable at w2, W4.

– SVR 12 = SVR 24 = 40 % – No relation between AUC and SVR 12

• Safety : – 20 % AE (anemia) – 4 dose reduction and 1 RBV stopped – No SOF discontinuation

➜ Despite favorable pharmacokinetics and good tolerance, efficacy is poor due to partly difficulty of managing ribavirin ?

Gane EJ et al. AASLD 2014: abstr. 966

Pharmacokinetics of sofosbuvir and his metabolite : GS-331007

SOF GS-331007

AUC appears to be equivalent for sofosbuvir and X4 for GS-331007 compared to patients with normal eGFR but without clinical impact so far.

Gane, AASLD, 2014, Poster #966

Sofosbuvir in renal impairment • Case series: • 4 male genotype 1

– 2 on dialysis – 1 Liver transplant fibrosing cholestatic hepatitis – 1 post renal transplant

• Dose: 400 mg alternate days + simeprevir 150 mg or RBV

• Three/four SVR • Treatment appeared “safe and feasible”

Bhamidimarri et al AASLD 2014

Sofosbuvir and ribavirin: Early efficacy and safety in renal transplant patients

• HCV RNA undetectable in all patient at week 8 – follow-up after the end of treatment in 3 patients – All achieve end of treatment response with no relapse so far

17 renal transplant patients with eGFR > 30 ml/mn treated by sofosbuvir 400 mg/j plus ribavirin 200 et 800 mg/j for24 weeks

➜ SOF-RBV is potent on-treatment in renal transplant patient , however calcineurin inhibitors dosage should be adapted in half of the patient and anemia is frequent requring treatment

Huard G et al. AASLD 2014; abstr. 701

Adverse events Number (%)

Anemia requiring treatment 8 (47,1 %)

Calcineurin inhibitors dose modification 8 (47,1 %)

Other serious adverse events – Pruritus – Myalgia

1 (5,9 %) 1 (5,9 %)

Premature discontinuation: anemia (1), pruritus (1), myalgia (1), patient wish (1)

4 (23,5 %) 3/4 relapses

Viral kinetics

ABT-450/, ombitasvir with or without dasabuvir in subject with renal impairment

• Phase I multicenter, single dose non fasting open label, 2 period study of 3D and 2D in patients with renal impairement compzred to subject with normal renal function.

• 24 subjects without HCV were compared according to renal function in 4 groups according to creatinine clearance: ≥ 90 ml/mn, between 60 – 89ml /mm, between 30-59 ml/mm and between 15-29 ml/mm.

➜ None of the changes in drug exposures were clinically relevant and they do not require dose adjustment. ➜ Clinical studies in HCV infected patients with renal insufficiency are planned in light of these

pharmacokinetic results

Compared with subjects with normal Renal function

Mild renal Impairment

Moderate renal impairment

Severe renal impairment

AUC ombitasvir comparable comparable comparable

AUC ABT-450 et dasabuvir 20 % 37 % 50 %

AUC ritonavir 42 % 80 % 114 %

– None of the changes in drug exposures were clinically relevant – Change in DAA exposure are not clinically relevant for safety

Khatri A et al.AASLD 2014: abstr. 238,

Daclatasvir: dose adjustment not required in subjects with renal impairment

CI = confidence interval; CrCL = creatinine clearance; AE = adverse events. Garimella T, et al. HCV/HIV Clinical Pharmacology Workshop. Poster 2014 P_43

• Compared with a normal creatinine clearance (CrCL; 90 mL/min), AUCinf estimated to increase 1.3-, 1.6- and 1.8-fold for subjects with CrCL values of 60, 30 and 15 mL/min, respectively

– Similar estimated increases in the AUCinf of unbound free DCV were also observed – Increased DCV exposure was within the exposures observed in the population PK and exposure-safety assessment, which has not shown a correlation between higher exposures

and adverse events (AEs) • DCV was generally well-tolerated in subjects with normal renal function or renal impairment of varying degree • DCV can be administered in subjects with renal impairment without dose modification

1.000

10.000

100.000

0 40 80 120 160

Individual AUCinf Fitted regression line 90% CIs

DC

V AU

Cin

f ng●

h/m

L

Creatinine clearance (mL/min)

100

1.000

10.000

0 40 80 120 160

DC

V C

max

ng/

mL

Creatinine clearance (mL/min)

Fitted regression line

Individual Cmax

90% CIs

Simeprevir: dose adjustment not required in subjects with renal impairment

• For subjects with severe renal impairment, simeprevir Cmin, Cmax, and AUC24h were about 71%, 34% and 62% higher, respectively, compared with matched healthy subjects

• No relevant differences in tmax were observed between the groups

Parameter

LS meansa

LS means ratio 90% CI Renal impaired

(test)

Healthy controls

(reference)

Cmin, ng/mL 985.5 577.5 1.71 0.65, 4.50

Cmax, ng/mL 3459 2588 1.34 0.66, 2.72

AUC24h, ng.h/mL 51710 32010 1.62 0.73, 3.59

Mediana Treatment difference median 90% CI

tmax, h 6.0 6.0 0.0 0.0, 2.0

AUC24h, area under the plasma-time curve; CI, confidence interval; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; tmax, time to reach Cmax aN: 8 for reference (healthy controls) and N: 8 for test (renal impaired)

For subjects with severe renal impairment, SMV Cmin, Cmax and AUC24h were about 71%, 34% and 62% higher, respectively, compared with matched healthy controls – For tmax, no relevant differences were observed between the groups

Populations


Safety and Efficacy of LDV/SOF + RBV in HCV GT 1 Patients with Bleeding Disorders

AEs were generally mild

Grade 3/4 laboratory abnormalities were infrequent and consistent with RBV safety profile

No safety concerns were associated with underlying bleeding disorders

14 GT 1 treatment-naïve and -experienced patients with hereditary bleeding disorders received LDV/SOF + RBV for 12 weeks 1 patient (7%) was cirrhotic

Primary Endpoint

100% of patients achieved SVR12 and demonstrated a similar safety profile to the general HCV patient population

Stedman CA, et al. APASL 2014. Poster #734; Data on file – Gilead Sciences EAME – (HCV1300047)

14/14

Populations


Simeprevir+ Sofosbuvir for GT-1 patients in special population: INSPIRE-C study

• Psychiatric population ( major depression, suicidal ideation ,bipolar , schizophrenia and psychosis)

• 60 patients ( schizophrenia 33%, major depression 25%, bipolar (33%), suicide attempt 8.3%)

• All patient except 2 complete treatment

Basu P et al AASLD 2014

SIM+SOF+RBV

SOF+RBV

SIM+SOF+ VITD

Duration of therapy 12 24 12

Mean age 53 58 58

Schizophrenia Major depression Bipolar Suicide attempt

8 8` 5 2

7 8 4 1

8 9 4 2

Prior IVDU on Methadone

15 12

13 8

15 8

GT-1a GT-1b

0 20

20 0

3 17

F0-F2 F3-F4

14 6

2 18

15 5

Populations

• End Stage renal disease patients • Patients with Bleeding disorders • Patients with psychiatric disorders • Gt-1 cirrhotic PI-failure patients

GT-1 PI-Failure what are the current options

• SOF+ PR 12 weeks • SOF + DCV 24 weeks • SOF + SIM ± RBV 12 weeks • SOF/LDV ± RBV 12 weeks

Sofosbuvir in «real life »

• Treatment regimen were done according to guidelines

➜ Demographics, clinical virological and safety data were collected

AASLD 2014 – Jensen DM et al., abstr. 45 ; Dieterich D et al., abstr. 46,

Cohort (Nb patients treated)

SOF/Peg/RBV SOF/RBV SOF/SMV SOF/SMV/RBV

Target (2 063) 384 667 784 228

Trio (995) 384 227 320

Trio cohort 1 211 patients included in 231 centers in USA

Target cohort 2 330 patients included

In 53 centers in USA , Canada and Germany

Treatment regimen


TARGET (n = 2 063)

TRIO (n = 995)

Age mean (range) 57,6 (20-83) 57 (17-86)

Male 1 300 (63,7 %) 565 (59 %)

Teatment failure 1 077 (52,2 %) 407 (43 %)

– PI failure (TVR/BOC) 193 (17,9 %) 82 (20 %)

Cirrhosis 999 (48,4 %) 291 (30 %)

– prior decompensation 375 (43,1 %) -

Liver transplantation 227 (11 %) -

HCC 211 (10,2 %) -

HIV 47 (2,3 %) -

Genotypes 1a-1b - 1 - 462 (48 %) – 179 (19 %) – 62 (6 %)

Genotype 2 - 212 (22 %)

Genotype 3 - 7 (1 %)

36

Baseline characteristics


TRIO : Real life data from USA : Sofosbuvir + PEG/RBV

SVR 12 in treatment –experienced GT-1 patients

ITT Per protocol

Failure to PEG IFN/RBV + Protease inhibitors

0

20

40

60

80

100

40 n =

%

73 %

36 37 33

67 % 78 % 73 %

SOF + PEG/RBV SOF + PEG/RBV

Failure to PEG IFN/RBV

Dieterich D et al. AASLD 2014, Abs. 46

SOF + DCV ± RBV in PI failures : AI444-040 – study design

Randomised, open-label, parallel group Phase 2 study investigating the safety and efficacy of SOF + DCV ± RBV

SOF: 400 mg QD; DCV: 60 mg QD RBV: 1000–1200 mg/day Sulkowski MS, et al. N Engl J Med 2014;370:211–21

SOF + DCV

0 24 SVR12

n=21

SOF + DCV + RBV n=20

Treatment-experienced (TVR + PR or BOC + PR),

non-cirrhotic HCV genotype 1 patients Week

Primary endpoint: SVR12

SOF + DCV ± RBV: efficacy in PI -failures

*METAVIR score derived from fibrotest (classified according to manufacturers website) Patients with F4 were required to have no evidence of cirrhosis based upon a biopsy Sulkowski MS, et al. N Engl J Med 2014;370:211–21

SOF + DCV

24 weeks

19/20

Without RBV

With RBV

SVR

12 (%

)

21/21

No cirrhotics included*


• Treatment regimen were done according to guidelines

➜ Demographics, clinical virological and safety data were collected


Cohort (Nb patients treated)

SOF/Peg/RBV SOF/RBV SOF/SMV SOF/SMV/RBV

Target (2 063) 384 667 784 228

Trio (995) 384 227 320

Trio cohort 1 211 patients included in 231 centers in USA

Target cohort 2 330 patients included

In 53 centers in USA , Canada and Germany

Treatment regimen

TRIO : Real life data from USA : Sofosbuvir + simeprevir

SVR 12 in treatment –experienced GT-1 patients

ITT Per protocol

Failure to PEG IFN/RBV + Protease inhibitors

0

20

40

60

80

100

n =

%

33 75 31 70

82 % 80 %

87 % 86 %

SMV + SOF + RBV SMV + SOF + RBV

Failure to PEG IFN/RBV

Dieterich D et al. AASLD 2014, Abs. 46

Real Life TARGET cohort

• Genotype 1 : SOF + SIM + RBV 12 weeks : • 72 patients failure to triple regimen with PI

We can do it !!

Jensen DM et al. AASLD 2014, Abs. 45

RVS4 : No cirrhosis : 85 % (17/20) Cirrhosis : 79 % (27/34)

SVR4 : available 54/69

SVR 4= 81 % (44/54)

Breakthrough 0 %

(0/54)

Relapse 19 %

(10/54)

Non response 0 %

(0/54)

Lost of follow up 0 %

(0/303)

No cirrhosis cirrhosis

SVR

12

(%)

50/52 12/14 51/51 11/13 35/36 14/14 38/38 13/13

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF

ION-2 : SOF/LDV in GT-1 treatment failures to PI

Afdhal N, et al. N Engl J Med 2014;370: 1483-93

SVR 12 according to fibrosis stage

Sofosbuvir + Ledipasvir in GT-1 with compensated cirrhosis

SVR : 96 % 20 treatment failure: 18 relapse, 1 death, 1 lost of follow up

Bourlière M et al. AASLD 2014, Abs. 82

w 0 w 12 w 36 w 24

SVR 12 LDV/SOF

SVR 12 LDV/SOF

+ RBV

SVR 12 LDV/SOF + RBV

SVR 12 LDV/SOF

118

204

133

58

SVR

12 (%

)

Overall 12 weeks 24 weeks

493/513

SVR 12

n

Sofosbuvir + Ledipasvir in GT-1 with compensated cirrhosis

Bourlière M et al. AASLD 2014, Abs. 82

Réponse Virologique Soutenue

Overall Treatment naive

Treatment failure

Overall SVR 12

Duration 12 weeks

24 weeks

Regimen LDV/SOF

LDV/SOF + RBV

Duration ± RBV

LDV/SOF 12 weeks

LDV/SOF + RBV 12 weeks

LDV/SOF 24 weeks

LDV/SOF + RBV 24 weeks

RVS12, %

96 % 98 % 95 %

95 % 97 % 94 %

98 % 99 % 98 %

95 % 96 % 95 %

97 % 99 % 96 %

92 % 96 % 90 %

96 % 98 % 96 %

98 % 97 % 98 %

100 % 100 % 100 %

Sofosbuvir/ledipasvir + RBV 12 weeks in cirrhotic GT-1 patients who failed triple therapy

with PI

• Phase 2 multicenter randomized controlled double blind study • 155 cirrhotic GT-1 patient who failed triple therapy with PI

Sofosbuvir/Ledipasvir + RBV for 12 weeks is the optimal combination in cirrhotic GT-1 patients who failed prior regimen with PR and subsequently failed to triple regimen with PI.

Bourlière M et al. AASLD 2014, Abs. LB-6

12 weeks 36 weeks 24 weeks D0

LDV/SOF + Placebo SVR 12

LDV/SOF + RBV Placebo SVR 12

n = 77

n = 78

Sofosbuvir/ledipasvir + RBV 12 weeks in cirrhotic GT-1 patients who failed triple therapy

with PI

Placebo 12 weeks → LDV/SOF + RBV

12 weeks (n = 77)

LDV/SOF + Placebo

24 weeks (n = 78)

Overall (n = 155)

Age mean, years (range) 56 (39–74) 57 (23–77) 56 (23–77)

Male, n (%) 58 (75) 56 (72) 114 (74)

Mean BMI, kg/m2 (range) 27,9 (19,6–47,1) 26,3 (19,1–39,8) 27,1 (19,1–47,1)

MELD mean (range) 7 (6-16) 7 (6-12) 7 (6-16)

Esophageal varices, n (%) 16 (21) 25 (32) 41 (26)

Platelets mean (range) 153 (54–316) 141 (59–278) 147 (54–316)

Platelets < 100 x 103/µl 14 (18) 13 (17) 27 (17)

Albumin g/dl mean (range) 3,9 (3,2–4,6) 3,9 (3,0–4,9) 3,9 (3,0–4,9)

Albumin < 35 g/l, n (%) 6 (8) 14 (17) 20 (13)

Bilirubin mg/dl mean (range) 0,8 (0,3–2,5) 0,8 (0,3–1,8) 0,8 (0,3–2,5)


Patients characteristics

Sofosbuvir/ledipasvir + RBV 12 weeks in cirrhotic GT-1 patients who failed triple therapy with PI

Placebo 12 weeks → LDV/SOF + RBV

12 weeks (n = 77)

LDV/SOF + Placebo

24 weeks (n = 78)

Overall (n = 155)

GT, n (%)

1a 48 (62) 50 (64) 98 (63)

1b 28 (36) 27 (35) 55 (36)

HCV RNA mean log10 UI/mL (range) 6,5 (5,3–7,7) 6,5 (3,9–7,5) 6,5 (3,9–7,7)

Prior PI regimen, n (%)

Telaprevir 43 (56) 49 (63) 92 (59)

Boceprevir 30 (39) 27 (35) 57 (37)

Otherrs 4 (5) 2 (3) 6 (4)

NS3/4A RAVS 58 (75) 55 (71) 113 (73)

CUPIC* participation , n (%) 25 (32) 22 (28) 47 (30)

Bourlière M et al.AASLD 2014, Abs. LB-6

Patients characteristics


75/77 74/77

LDV/SOF 24 weeks

LDV/SOF+RBV 12 weeks

3 relapses 2 relapses


Sustained Virological Response



Relapsers

Baseline

Regimen Sex

GT IL28B Prior Response Platelets (x103 μL)

Albumin (g/dL) Varices

HCV RNA (log10 IU/mL)

NS5A RAVs

LDV/SOF + RBV 12 Wk

M 1b TT Nonresponder 184 3.6 Small 6.67 No

M 1b CT Nonresponder 101 3.2 Small 6.59 No

M 1a CT Breakthrough 65 3.8 None 6.97 No

LDV/SOF 24 Wk

M 1a CT Nonresponder 111 3.9 Small 6.96 Yes

M 1b CT Nonresponder 179 4.1 NA 6.85 Yes

• NA, not assessed.

Results: HCV Sequence Analysis

92% SVR 98% SVR

n=127/130

No NS5A RAVs at Baseline With NS5A RAVs at Baseline

• There was no difference in SVR12 rates among patients with or without NS3/4A RAVs at Baseline (96% and 97% respectively)



Safety


Patients, n (%)

Placebo 12 Weeks → LDV/SOF + RBV 12 Wk

LDV/SOF 24 Wk

Placebo 12 Wk n=77

LDV/SOF+RBV 12 Wk

n=76

Overall Period n=77

First 12 Wk n=78

Overall Period n=78

Overall Safety

AEs 63 (82) 66 (87) 74 (96) 66 (85) 68 (87)

Grade 3-4 AEs 1 (1) 5 (7) 6 (8) 2 (3) 10 (13)

SAEs 1 (1) 3 (4) 4 (5) 3 (4) 8 (10)

Treatment Related SAEs 0 1 (1) 1 (1) 0 0

Treatment D/C due to AEs 1 (1) 0 1 (1) 0 0

Death 0 0 0 0 0

Grade 3-4 lab abnormalities 18 (23) 8 (11) 24 (31) 15 (19) 11 (14)

Hb <10 g/dL 1 (1) 1 (1) 2 (3) 0 1 (1)

Hb <8.5 g/dL 1 (1) 1 (1) 2 (3) 0 0


• (1) SOF/LDV ± RBV 12 weeks • (2) SOF + DCV 24 weeks • (3) SOF + SIM ± RBV 12 weeks • (4) SOF+ PR 12 weeks

differential benefits of daas in patients with...

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