Design

Objective– Difference in SVR ≥ 40% between the 2 groups, 99% power

SOF + RBV

Placebo

Randomisation3 : 1*

Double blind

HCV infectionGenotype 2 or 3

Intolerant to prior IFN-treatment, ineligible, or unwilling

IFN-based regimenHCV RNA ≥ 10,000 IU/mlCompensated cirrhosis

allowed * Randomisation was stratified on cirrhosis (presence or absence)

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3

W12

SVR12

SVR12

W24

– SOF : 400 mg qd– RBV (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

N = 71

N = 207

POSITRON Jacobson IM. NEJM 2013; 368:1867-77

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3

Placebo N = 71

SOF + RBV N = 207

Mean age, years 52 52Female 52% 43%Race : white/black 93% / 6% 91% / 4%Body mass index, mean 28 29HCV genotype 2 / 3 48% / 52% 53% / 47%IL28B CC genotype 41 % 47%HCV RNA log10 IU/ml, mean (SD) 6.3 ± 0.76 6.3 ± 0.77Cirrhosis 18% 15%Reason for not using IFN treatment

Contra-indication 46% 43%Unacceptable side effects 11% 8%Patient’s decision 42% 49%

Discontinued treatment, N 3 (AE) 6 (4 AE)Returned for post-treatment W4 visit 71 204Returned for post-treatment W12 visit - 171

Baseline characteristics and patient disposition

POSITRON Jacobson IM. NEJM 2013; 368:1867-77

HCV RNA < 25 IU/ml SOF + RBVPlacebo SVR12 by genotype and cirrhosis

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3

POSITRON

25

50

100

75

99% 100

0

During treatmentW4

8378

92

21

94

No cirrhosisN 204 202 71 207 207 92 17 84

W12

Post-treatment (SVR)W4 W12 Cirrhosis

Genotype 2 Genotype 3

68

14No cirrhosis Cirrhosis

0

Jacobson IM. NEJM 2013; 368:1867-77

OR (95% CI) pFemale vs male 2.67 (1.2 - 5.94) 0.016Genotype 2 vs 3 8.66 (3.62 - 20.73) < 0.0001Duration on prior IFN-based therapy≤ 12 weeks vs no> 12 weeks vs no

0.57 (0.18 - 1.8)0.13 (0.038 - 0.45)

ns0.0013

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3 Virologic breakthrough during treatment : none Relapse in patients with HCV RNA < 25 IU/ml at end of completed

treatment– 40/201 (20%) in patients who completed treatment– 2/4 (50%) in patients who did not complete treatment

Multivariate analysis of factors associated with SVR12

Resistance testing (sequencing) – Done in 39/42 relapses

• No SOF-associated mutation (S282T)• 5 NS5B substitutions in > 2 subjects (no change in susceptibility to SOF)

POSITRON Jacobson IM. NEJM 2013; 368:1867-77

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3

PlaceboN = 71

SOF + RBV N = 207

AE leading to treatment discontinuation 3 4Serious adverse event 2 (3%) 11 (5%)AE occurring in > 10% in either group

Fatigue 24% 44%Nausea 18% 22%Headache 20% 21%Insomnia 4% 19%Pruritus 8% 11%Anemia 0 13%Irritability 1% 9%Cough 3% 5%Diarrhea 6% 9%Rash 8% 9%Arthralgia 1% 8%

Adverse events, n (%)

POSITRON Jacobson IM. NEJM 2013; 368:1867-77

POSITRON Study: SOF + RBV for HCV genotypes 2 and 3

Summary– In this phase III study, 12 weeks of treatment with SOF and RBV

resulted in a SVR12 in 78% of patients for whom interferon treatment was not an option

• In genotype 2 infection, high response rates (SVR12 > 92%) were observed in all patient subgroups

• In genotype 3 infection, response rates were lower than in genotype 2 infection, especially in the subgroup of patients with cirrhosis

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

– The rate of premature discontinuation of treatment with SOF and RBV due to adverse events was low (2%)

– In conclusion, 12 weeks of treatment with SOF and RBV can be an effective option for patients with HCV genotype 2 infection

Jacobson IM. NEJM 2013; 368:1867-77POSITRON