Openlabel Chronic HCV infection Genotype 1 Failure to achieve SVR 12 on a shortcourse of 1 st line LDVSOFcontaining regimen No cirrhosis N 34 SVR 12 Coformulated ledipasvirsofosbuvir LDV 90 mgSOF 400 mg 1 pill qd ID: 602818
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Slide1
LDV/SOF
Open-label
Chronic HCV infection
Genotype 1
Failure to achieve SVR12 on a short-course of 1st lineLDV/SOF-containing regimen No cirrhosis
N = 34
SVR
12
Co-formulated ledipasvir-sofosbuvir (LDV 90 mg/SOF 400 mg) : 1 pill qd
SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF
Design
ObjectivePrimary endpoint : SVR12 (HCV RNA < 12 IU/ml) by intention to treat
SYNERGY-D
W12
Wilson EM.
Clin
Infect Dis 2016; 62:230-8Slide2
SYNERGY-D
Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF
N = 34
Mean
age, years
59
Female
18%
Race : white / black
82% / 18%
Genotype 1a / 1b, N
26 / 8
Fibrosis stage F0-F2 / F3, N
33 / 1
HCV RNA log
10
IU/ml, median
6.1Prior relapse toLDV/SOF + GS-9669 x 6 weeksLDV/SOF + GS-9451 x 4 weeksLDV/SOF + GS-9451 + GS-9669 x 4 weeks11419Weeks to retreatment, mean25.1RAVs > 25-fold resistance : NS5A / NS5B85.3% / 2.9%
Baseline characteristics
SYNERGY-D
Wilson EM.
Clin
Infect Dis 2016; 62:230-8Slide3
SVR
12 (HCV RNA < 43 IU/ml)ITT
Per protocol : 31/32 (96.9%)2 patients withdrew consent1 relapse at W8 post-treatment
LDV/SOF
N = 34Serious adverse event
1 (chest pain in a cocaine user, unrelated)
Death,
grade 3 or 4 adverse event
0
Adverse
event leading to discontinuation
0Diarrhea
2 (5.9%)
Fatigue
2 (5.9%)
Constipation
2 (5.9%)
Grade 3 laboratory abnormality3 (8.8%)Adverse events, N (%)SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF010075502591.2
34
%
SYNERGY-D
Wilson EM.
Clin
Infect Dis 2016; 62:230-8Slide4
SYNERGY-D
Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOFDeep sequencing at baseline (before 1st LDV/SOF treatment), at relapse, and prior to retreatmentPrior to retreatmentNS5A RAVs : 29/34 : SVR12
in 26/29 (89.7%) [ITT] ; 96.3% per protocolRAVs with > 100 fold resistance to LDVL31M/V/I, N = 17 (L31M, N = 16)Q30R/H/T, N = 13 (Q30R, N = 8)Y93H/C/N, N = 7 (Y93H, N = 6)NS5B RAV : 1/34 : 1/1 achieved SVR12L159F
Relapse (n=1)Genotype 1b, 1st treatment with LDV/SOF + GS-9451 x 6 weeks. RAV at baseline = L31M, at 1st relapse and prior to retreatment : L31M + Y93H, no NS5B mutant. At failure (relapse of retreatment) : emergence of S282T + V321I (NS5B), no additional NS5A RAVs
SYNERGY-DWilson EM. Clin Infect Dis 2016; 62:230-8Slide5
SYNERGY-D
Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOFSummaryPatients with HCV genotype 1 infection who had accumulated RAVs during previous short-course combination therapy containing LDV/SOF achieved an SVR12
rate of 91% when retreated with 12 weeks of LDV/SOFOf the 27 patients with mutations associated with > 25-fold baseline NS5A resistance in vitro who completed 12 weeks of therapy, 26 (96.3%) achieved SVR12The patient who relapsed had HCV with > 1000-fold NS5A RAVs L31M and Y93H prior to retreatment and NS5B RAVs S282T and V321I emerged following retreatment, both of which have been shown to reduce in vitro susceptibility to SOF
Retreatment was safe and extremely well tolerated. No patient discontinued the drugs due to adverse events. Side effects were generally mild
SYNERGY-DWilson EM. Clin Infect Dis 2016; 62:230-8