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Design

Objective– Non inferiority of SOF + RBV : SVR12 (2-sided significance level of 5%, lower

margin of the 95% CI for the difference = -15%, 95% power)

SOF + RBV (weight based)

PEG-IFNa-2a + RBV (fixed-dose)

Randomisation1 : 1*

Open-label, active-control

* Randomisation was stratified on cirrhosis (presence or absence), genotype (2 or 3) and HCV RNA (< or ≥ 6 log10 IU/ml)

FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

W12

SVR12

W24

SVR12

W36

N = 243

N = 256

≥ 18 yearsChronic HCV infection

Genotype 2, 3Treatment-naïve

HCV RNA ≥ 10,000 IU/ml

Compensated cirrhosisallowed

– SOF : 400 mg qd– PEG-IFNa-2a : 180 mg SC once weekly– RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg– RBV fixed-dose : 400 mg bid

Lawitz E. NEJM 2013;368:1878-87

SOF + RBV 12 WN = 256

PEG-IFN + RBV 24WN = 243

Mean age, years 48 48

Female 33% 36%

Race : white/black 87% / 5% 87% / 2%

Body mass index, mean 28 28

HCV genotype 1 / 2 / 3 1%* / 27% / 71% 28% / 72%

IL28B CC genotype 42% 44%

HCV RNA log10 IU/ml, mean (SD) 6.0 ± 0.8 6.0 ± 0.8

HCV RNA ≥ 800,000 IU/ml 57% 65%

Cirrhosis 20% 21%

Discontinued treatment, NFor AE / for virologic failure / lost to follow-up

113 / 1 / 2

5426 / 17 / 5

Returned for post-treatment W4 visit 246 233

Returned for post-treatment W12 visit 239 225

Baseline characteristics and patient disposition

* Excluded from efficacy analysis

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FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

Lawitz E. NEJM 2013;368:1878-87

HCV RNA < 25 IU/ml

SOF + RBVPEG-IFN + RBV

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FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

Lawitz E. NEJM 2013;368:1878-87

250 236 253 243 253 243 253 243 70 67 183 176 204 193 49 500

25

50

75

10099

67

9889

74 7467 67

97

78

5663

72 74

4738

W4 W12 W4 W12 Genotype 2 Genotype 3 No cirrhosis Cirrhosis

During treatment Post treatment (SVR)

SVR12 by genotype and cirrhosis

Virologic breakthrough during treatment – 1 in SOF + RBV group vs 18 (7%) in PEG-IFN + RBV group

Relapse in patients with HCV RNA < 25 IU/ml at end of completed treatment– 74/249 (30%) in SOF + RBV group vs 46/217 (21%) in PEG-IFN + RBV

group

Resistance testing (sequencing) in SOF + RBV group – 74 relapses :

– No SOF-associated mutation (S282T)– No change in susceptibility to SOF in patients with NS5B substitutions

Multivariate analysis of factors associatedwith SVR12 in SOF + RBV group

OR (95% CI) p

Genotype 2 (vs 3) 42.49 (9.54 – 189.2) < 0.0001

Cirrhosis (no vs yes) 2.94 (1.38 – 6.26) 0.005

Baseline HCV RNA < vs ≥ 6 log10 IU/ml 2.33 (1.24 – 4.37) 0.009

RBV exposure, mg/kg/day 1.26 (1.09 – 1.46) 0.002

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FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

Lawitz E. NEJM 2013;368:1878-87

Adverse events, n (%)SOF + RBV 12W

N = 256PEG-IFNa-2a + RBV 24W

N = 243

AE leading to treatment discontinuation 3 (1%) 26 (11%)

Serious adverse event 7 (3%) 3 (1%)

AE occurring in > 15% in either groupFatigueHeadacheNauseaInsomniaDecreased appetiteInfluenza-like illnessChillsRashDiarrheaPruritus MyalgiaIrritability

36%25%18%12%7%3%3%9%9%7%8%

10%

55%44%29%29%18%18%18%18%17%17%16%16%

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FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

Lawitz E. NEJM 2013;368:1878-87

Summary– In this open-label, randomised trial of previously untreated patients

with genotype 2 or 3 infection, the rate SVR12 was the same among patients who were assigned 12 weeks of SOF + RBV or 24 weeks of PEG-IFN + RBV (67% in each group)

• In genotype 2, SVR12 was higher with SOF + RBV (97% vs 78%)

• In genotype 2, SVR12 was similarly low in both groups (56% vs 63%)

– SOF + RBV was associated with fewer adverse events than PEG-IFN

+ RBV• Influenza-like constitutional symptoms and neuropsychiatric events were less

common among patients receiving SOF + RBV than among those receiving PEG-IFN + RBV.

• Although the rates of anemia was similar in both groups, neutropenia and thrombocytopenia were not observed in the SOF + RBV group

– No virologic resistance was detected in patients who did not have a sustained virologic response

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FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3

Lawitz E. NEJM 2013;368:1878-87