w24 ≥ 18 years chronic hcv infection genotype 1 treatment naïve early fibrosis to compensated...

W24

≥ 18 yearsChronic HCV infection

Genotype 1Treatment naïveEarly fibrosis to

compensated cirrhosisNo HBV or

HIV co-infection

N = 10 SOF + weight-based RBV

SOF + weight-based RBV

SOF + low-dose RBV

Part 2All stage of fibrosis

N = 25

N = 25SOF 400 mg : 1 pill qd RBV weight-based : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)RBV low-dose : 600 mg/day

Part 1Early or moderate fibrosis

Randomisation1 : 1

Open-label

Objective– Primary endpoint : SVR24 (HCV RNA < 12 IU/ml), by per-protocol analysis

(patients with > 8 weeks of treatment)– Modelling viral kinetics, pharmacokinetics and pharmacodynamics (20 patients)

NIH SPARE Oisinusi A. JAMA 2013;310:804-11

Design

NIH SPARE Study: SOF + RBV in genotype 1 with advanced liver disease


Part 1 Part 2



SOF + low dose RBV

N 10 25 25

Age, years 54 54 55

Female 60% 24% 44%

White / Black 10% / 90% 20% 72% 8% / 92%

Genotype 1a / 1b 60% / 40% 80/ 20% 64% / 36%

HCV RNA, log10 IU/ml 6.8 6.2 6.1

IL 28B CC 33% 16% 16%

Knodell score 0-1 / 3-4 90% / 10% 76% / 24% 72% / 28%

Discontinuation, N 1 2 3


Baseline characteristics and disposition, median or %

SOF + weight-based RBV SOF + low-dose RBV

25

50

100

75

71(49-87)

%

48(28-69)

75

N 24 22

50

Perprotocol

ITT Genotype 1b

68(46-85)

55(32-76)

4044

Genotype 1a

25 925 520 17

Perprotocol

ITT



SVR24 (HCV RNA < 25 IU/ml) in Part 2, % (95% CI)

0

Odds ratio 95% CI p

Men vs women 6.1 1.2 - 31.6 0.03

BMI > 30 vs ≤ 30 kg/m2 0.33 0.1 – 1.2 0.08

Knodell score 3-4 vs 0-1 4.3 1.1 – 16.5 0.04

HCV RNA > 800,000 IU/ml 5.7 1.4 – 24.4 0.02



Bivariate model of baseline characteristics associated with relapse

Viral kinetic model– No differences in viral decay based on RBV dose or

baseline characteristics– Fully fitted PK-viral kinetics model (10 patients on

weight-based RBV and 10 patients on low-dose RBV) : significantly slower loss rate of free virus (clearance) in relapsers than participants who achieved SVR (clearance : 3.57 vs 5.60 per day; p = 0.009)



Histologic response 29 paired liver biopsies

– Improvement in inflammation in 27 (93%)

5

10

15HAI Inflammation score

0Pre

treatmentEnd of

treatmentPre

treatmentEnd of

treatment

p = 0.003 p < 0.0001

p = 0.07

SOF + weight-based RBV SOF + low-dose RBV


Part 1 Part 2SOF + weight-

basedN = 10

SOF + weight-based RBVN = 25

SOF + low-dose RBVN = 25

Discontinuation for adverse event 0 0 0

Serious adverse event 0 0 1

RBV dose reduction 2 (20%) 5 (20%) 3 (12%)

Headache 20% 28% 28%

Anemia 40% 32% 16%

Fatigue 40% 16% 24%

Nausea 10% 16% 20%

Dyspnea 10% 8% 8%

Vomiting 0 4% 12%

Dizziness 0 8% 14%

Pruritic rash 0 8% 0

Myalgia 0 0 8%

Hyperbilirubinemia grade 3 0 4% 0


Adverse events and laboratory abnormalities, n (%)


Summary– In a population of patients with chronic HCV infection with

genotype 1 with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of SOF + weight-based or low-dose RBV resulted in SVR24 rates of 68% and 48%, respectively

– The viral kinetics-pharmacodynamics model demonstrated a significantly slower loss rate of infectious virus in participants who subsequently relapsed.

• the mechanism of incomplete clearance of HCV and relapse in these participants remains elusive

– Limitations • relatively small sample size • higher, though small, increase in the number of discontinuations with

low-dose RBV


w24 ≥ 18 years chronic hcv infection genotype 1 treatment naïve early fibrosis to compensated...

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