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F/C AETC Faculty HIV/HCV Thursday, June 26, 2014 | 1:30-2:30pm (EDT) Facilitator/Didactic Presenter Dushyantha T. Jayaweera MD, MRCOG (UK), FACP University.

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Presentation on theme: "F/C AETC Faculty HIV/HCV Thursday, June 26, 2014 | 1:30-2:30pm (EDT) Facilitator/Didactic Presenter Dushyantha T. Jayaweera MD, MRCOG (UK), FACP University."— Presentation transcript:

1 F/C AETC Faculty HIV/HCV Thursday, June 26, 2014 | 1:30-2:30pm (EDT) Facilitator/Didactic Presenter Dushyantha T. Jayaweera MD, MRCOG (UK), FACP University of Miami Case Discussant(s) Patrick Marsh, MD University of South Florida

2 HIV/HCV: Highlights from EASL HCV Therapies in Cirrhosis/End-Stage Liver Disease (Up to 1.0 hour of CE/CME) Dushyantha T. Jayaweera MD, MRCOG (UK), FACP Associate Vice Provost for Human Subject Research & Professor of Medicine, University of Miami, Miller School of Medicine, Division of Infectious Diseases Faculty Member, Florida/Caribbean AIDS Education and Training Center

3 Liver Transplantation (OLT) Treatment of established disease Treatment before histologic recurrence Potential Strategies for Treatments of HCV in Peri-Transplant Population Pre-OLT Rx

4 TURQUOISE-II Study Design: Phase 3 Trial Conducted Exclusively in GT1- Infected Cirrhotic Patients (N=380)  3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID  RBV: mg daily according to body weight ( 75kg, respectively) Day 0Week 24Week 12 SVR 12 3D + RBV (N=208) (N=208) (N=172) (N=172) All patients to be followed through 48 weeks post-treatment Poordad F, et al. 49th EASL; London, England; April 9-13, Abst. O163.

5 TURQUOISE-II Results: ITT SVR12 Rates of 92% to 96% SVR12, % Patients /208 Non-inferiority threshold: 43% Superiority threshold: 54% /172 P=0.089 Poordad F, et al. 49th EASL; London, England; April 9-13, Abst. O Weeks 3D + RBV 24 Weeks 3D + RBV

6 TURQUOISE-II Results: ITT SVR12 Rates by HCV Subtype Poordad F, et al. 49th EASL; London, England; April 9-13, Abst. O GT 1aGT 1b SVR12, % Patients 124/14067/68114/12151/51 12-week arm 24-week arm 3D + RBV

7 TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a week arm 24-week arm 92.9 NaïvePrior Relapse Response 3D + RBV SVR12, % Patients 59/64 14/15 52/56 13/ /11 40/50 10/10 39/42 Prior Partial Response Prior Null Response HCV Subtype 1a Poordad F, et al. 49th EASL; London, England; April 9-13, Abst. O163.

8 ELECTRON-2: Study Design HCV GT 1, relapsed after previous treatment with SOF-containing regimens in ELECTRON-1 HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B) Wk 0 Wk 12Wk 24 SVR12 LDV/SOF, n=20 GT 1 CPT class B LDV/SOF + RBV, n=19 GT 1 Prior SOF exposure Gane E, et al. 49th EASL; London, England; April 9-13, Abst. O6.

9 SVR12 ( Percentage ) GT 1 CPT Class B Median total bilirubin, mg/dL (range) 1.5 ( ) Median serum albumin, g/dL (range) 3.1 ( ) Median INR (range) 1.2 ( ) Ascites, n (%)4 (20) Hepatic encephalopathy, n (%) 6 (30) Median platelet count, 10 3 /µL (range) 84 (44-162) ELECTRON-2 Results: Patients With CPT B Cirrhosis Error bar represents the 95% confidence interval. Gane E, et al. 49th EASL; London, England; April 9-13, Abst. O /20 7 relapsers

10 SOF+RBV with portal hypertension + decompensation: Study Design and Aim Aim: To explore the safety and efficacy of SOF+RBV in HCV-infected patients with portal hypertension ± decompensated liver disease Primary objective: SVR 12 Secondary objectives –Effects of 48 weeks of treatment on hepatic portal pressure and function –Safety and clinical improvement as measured by clinical outcomes, CPT, MELD, and biochemical test results SOF 400 mg + RBV 1000‒1200 mg SVR 12 Observation SOF 400 mg + RBV 1000‒1200 mg SVR 12 Arm 1 n=25 Arm 2 n=25 HVPG at Day 0 and Week 48 HVPG at Day 0, and Weeks 24 and 72 Afdhal N, et al. 49th EASL; London, England; April 9-13, Abst. O68. Wk 0Wk 24Wk 48Wk 96Wk 72

11 HCV RNA < LLOQ (Percentage) Results: Virologic Response on Treatment Week Afdhal N, et al. 49th EASL; London, England; April 9-13, Abst. O68. 5/99/97/1612/168/8 7/715/16 14/15

12 Laboratory Results: Mean Change in MELD Score from Baseline through Week 24 CPT A Patients (n=20) CPT B Patients (n=29*) MELD change from baseline SOF + RBVObservation 24 weeks n=2 n=5 n=1 n=3 Afdhal N, et al. 49th EASL; London, England; April 9-13, Abst. O68. 1 patient had only a baseline MELD score before withdrawing consent and is not depicted.

13 SOF Compassionate Use Program SOF + RBV ± Peg n=104 SOF Compassionate Use Program SOF + RBV ± Peg n=104 Completed weeks treatment n=72 Completed weeks treatment n=72 Forns X, et al. 49th EASL; London, England; April 9-13, Abst. O62. SOF Compassionate Use Program Results: Patient Disposition Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical biochemical and histological findings) n=48 Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical biochemical and histological findings) n=48 Post transplant compensated and decompensated cirrhosis (liver biopsy (F4) or clinical decompensation) n=56 Post transplant compensated and decompensated cirrhosis (liver biopsy (F4) or clinical decompensation) n=56 Early term due to AE n=7 Early term due to AE n=7 Liver transplant n=12 Liver transplant n=12 Death n=13 Death n=13

14 Forns X, et al. 49th EASL; London, England; April 9-13, Abst. O62. Results: Overall Virologic Response Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12) and/or no data was available (n=3 at EOT; n=7 at SVR12). 81/9353/85

15 Forns X, et al. 49th EASL; London, England; April 9-13, Abst. O62. Results: Clinical Outcomes *Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values. All patients who received ≥1 dose of SOF are included 60/10422/104

16 Clinical Cases: Fibrosing Cholestatic Hepatitis (2 Patients with FCH) Viral load undetectable by Week 4 (Patient 1) and Week 12 (Patient 2) resulting in SVR 12 Forns X, et al. 49th EASL; London, England; April 9-13, Abst. O62. Patient 1 (SOF + RBV 24 Weeks) GGT (IU/L) Bilirubin (mg/dL) HCV RNA 8.7 log 10 IU/mL 4 HCV RNA 8 log 10 IU/mL SOF + RBV Treatment Off Treatment Patient 2 (SOF + RBV 48 Weeks) FU12 BL Week 4 BL FU12

17 Study M12-999: Design 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol Day 0Week 24 SVR 12 To Week 72 3D + RBV (N=34) (N=34) Kwo P, et al. 49th EASL; London, England; April 9-13, Abst. O114.

18 Study M12-999: Calcineurin Inhibitor (CNI) Dosing with 3D Regimen A phase 1 drug-drug interaction study demonstrated that dosing tacrolimus (TAC) or cyclosporine (CYA) with the 3D regimen compared to either alone resulted in a: –7-fold increase in TAC half-life –3-fold increase in CYA half-life Based on these findings, recommended dosing during 3D treatment was: –TAC 0.5 mg once weekly or 0.2 mg every 3 days –CYA 1/5 of the daily pre-3D treatment dose given once daily Kwo P, et al. 49th EASL; London, England; April 9-13, Abst. O114.

19 Study M12-999: Preliminary Efficacy Results No patient had breakthrough One patient had a relapse (post-treatment day 3) –At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Kwo P, et al. 49th EASL; London, England; April 9-13, Abst. O114. Percentage Patients 34/34 34/3432/3325/26

20 Study M12-999: Pre-Treatment and On-Treatment Tacrolimus C trough Concentrations C trough levels were comparable pre-treatment and on-treatment TAC dose was 0.5 to 1.0 mg at 1-2 week intervals for most patients 4 patients experienced a TAC level >15 ng/mL ( ng/mL) –All 4 patients had TAC dosing errors –2 patients had associated creatinine increases (1.8 and 1.4 mg/dL), which normalized when dosing was corrected Tacrolimus Concentration (ng/mL) Kwo P, et al. 49th EASL; London, England; April 9-13, Abst. O114. (Treatment Weeks 1-4)

21 Question & Answer Session


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