curry design open-label curry study: sof + rbv for hcv with liver cancer before transplantation ≥...

CURRY

Design Open-label

CURRY Study: SOF + RBV for HCV with liver cancer before transplantation

≥ 18 yearsChronic HCV infection

Any genotypeHCV RNA ≥ 10,000 IU/mlTreatment naïve or not

Hepatocellular carcinomaOn waiting list for liver transplantation

Child-Pugh ≤ 7 and MELD < 22 SOF 400 mg : 1 pill qdRBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Objective– Primary endpoint : post-transplant response 12 weeks after transplantation

[pTVR12] (HCV RNA < 25 IU/ml) in patients with HCV RNA < 25 IU/ml at last assessment before transplantation, by intention to treat, with 2-sided 90% CI and upper bound of recurrence rate of 65%

SOF + RBV SVR12N = 61

Duration : until transplantation or 48 weeks

Standard post-transplantation immunosuppressive regimen of solumedrol/prednisone, tacrolimus, and/or mycophenolate mofetil (up to 2 g/day) for the first 12W after transplantation

Curry MP. Gastroenterology 2015;148:100-107

N = 61Median age, years 59

Female 20%

IL28B CC genotype 22%

HCV RNA log10 IU/ml, median 6.2

Genotype 1a / 1b / 2 / 3a / 4a 39% / 34% / 13% / 11% / 2%

Prior HCV treatmentYes

Null responsePartial responseBreakthroughRelapseUnknown response

75%24%24%7%

20%26%

Baseline MELD score : < 8 / 9-10 / 11-14 58% / 25% /18%

Underwent transplantation , Nwith HCV RNA < 25 IU/ml

4643

pTVR1, N (% [90% CI]) 37/43 (86% [74% - 94%])

pTVR12, N (% [90% CI]) 30/43 (70% [56% - 81%])

Confirmed HCV recurrence, N 10/13

Baseline characteristics and outcome


Curry MP. Gastroenterology 2015;148:100-107 CURRY


Curry MP. Gastroenterology 2015;148:100-107

Multivariate analysis of factors associatedwith absence of recurrence post-transplantation

Odds ratio (95% CI) p

Consecutive days HCV RNA < 25 IU/ml with target not detected prior to transplantation

1.047 (1.015 - 1.096) < 0.001

Genotype other than 1b 9.83 (0.55 – 939.15) 0.19

CURRY

HCV Recurrence and resistance analysis– 10 confirmed recurrence after liver transplantation

• Genotype 1a, N = 2; 1b, N = 7; 3a, N = 1• ILB28 non-CC, N = 10• Recurrence at W1 (N = 3), W2 (N = 2), W4 (N = 4), or W12 (N = 1)

post-transplantation• Duration of SOF+ RBV pre-transplantation < 12 weeks , N = 4

– NS5B sequencing • At baseline :

– 4 patients with L159F variant : 4/4 relapsed– 1 patient with N142T : achieved SVR12

• 29 patients with failure before transplantation or recurrence after transplantation

– no S282T mutant– 12 patients with other variants as minor subpopulations (< 10%)

in 11/12 : N142T (N = 2), L159F (N = 5), S282G (N = 1), L230F (N = 3); L159F + S282R + L230F + V321A (N = 1)



Adverse events– Median duration of exposure to study regimen : 21 weeks– Serious adverse events, N = 11 – ≥ Grade 3 adverse event, N = 11– Discontinuation due to adverse event, N = 2

(pneumonia, sepsis/acute renal failure)– Most common adverse events :

• Fatigue (38%) Dyspnea (11%)• Headache (23%) Cough (11%)• Anemia (21%) Insomnia (11%)• Nausea (16%) Constipation (10%)• Rash (15%) Pruritus (10%)

– Most common grade 3-4 laboratory abnormalities : grade 3 decrease in hemoglobin level, grade 3 hyperglycemia, grade 3-4 bilirubin elevation, lymphopenia < 500/mm3

• 12 patients with RBV dose reduction, but no transfusion, no epoetin needed



Summary– In this pilot study, SOF + RBV before liver transplantation

prevented recurrence of HCV infection in 70% of patients with chronic HCV infection and liver cancer who achieved an HCV RNA level < 25 IU/ml before transplantation and in almost half of the total patients in the study

– The rate of discontinuation owing to adverse events was low, and most adverse events were those associated with RBV therapy—fatigue, anemia, headache, and nausea—as were the laboratory abnormalities of decreased hemoglobin and increased bilirubin

– Enrichment in minor resistance-associated variants, although rare, may encode for marginal reductions in susceptibility to SOF

– Limitations• Low sample size• Exclusion of patients with decompensated liver disease



curry design open-label curry study: sof + rbv for hcv with liver cancer before transplantation ≥...

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