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F/C AETC Faculty HIV/HCV

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.

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F/C AETC Faculty HIV/HCV

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  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 EASLHCV Therapies in Cirrhosis/End-Stage Liver Disease • DushyanthaT. 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 (Up to 1.0 hour of CE/CME)

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

  4. TURQUOISE-II Study Design: Phase 3 Trial Conducted Exclusively in GT1-Infected Cirrhotic Patients (N=380) SVR12 3D + RBV (N=208) SVR12 3D + RBV (N=172) All patients to be followed through 48 weeks post-treatment Day 0 Week 12 Week 24 • 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively) Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.

  5. TURQUOISE-II Results:ITT SVR12 Rates of 92% to 96% 91.8 P=0.089 95.9 SVR12, % Patients Superiority threshold: 54% Non-inferiority threshold: 43% 191/208 165/172 12 Weeks 3D + RBV 24 Weeks 3D + RBV Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.

  6. TURQUOISE-II Results:ITT SVR12 Rates by HCV Subtype 88.6 94.2 100 98.5 3D + RBV 12-week arm 24-week arm SVR12, % Patients 124/140 114/121 67/68 51/51 GT 1a GT 1b Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.

  7. TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a 92.2 92.9 93.3 100 100 100 80.0 92.9 3D + RBV 12-week arm 24-week arm SVR12, % Patients 10/10 59/64 52/56 11/11 39/42 40/50 14/15 13/13 Naïve Prior Relapse Response Prior Partial Response Prior Null Response HCV Subtype 1a Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. 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 12 Wk 24 Wk 0 SVR12 LDV/SOF+ RBV, n=19 GT 1Prior SOF exposure GT 1CPT class B LDV/SOF, n=20 Gane E, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O6.

  9. ELECTRON-2 Results:Patients With CPT B Cirrhosis 7 relapsers 65 SVR12(Percentage) 13/20 Error bar represents the 95% confidence interval. Gane E, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O6.

  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: SVR12 • 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 Wk 0 Wk 24 Wk 48 Wk 72 Wk 96 HVPG at Day 0 and Week 48 SVR12 Arm 1 n=25 SOF 400 mg + RBV 1000‒1200 mg HVPG at Day 0, and Weeks 24 and 72 SVR12 Arm 2 n=25 Observation SOF 400 mg + RBV 1000‒1200 mg Afdhal N, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O68.

  11. Results: Virologic Response on Treatment HCV RNA < LLOQ (Percentage) 5/9 7/16 9/9 12/16 8/8 15/16 8/8 15/16 7/7 14/15 Week Afdhal N, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O68.

  12. Laboratory Results: Mean Change in MELD Score from Baseline through Week 24 CPT A Patients (n=20) CPT B Patients (n=29*) SOF + RBV Observation 24 weeks MELD change from baseline n=5 n=2 n=3 n=1 1 patient had only a baseline MELD score before withdrawing consent and is not depicted. Afdhal N, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O68.

  13. 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 Post transplant compensated and decompensated cirrhosis(liver biopsy (F4) or clinical decompensation) n=56 Early term due to AE n=7 SOF Compassionate Use ProgramSOF + RBV ± Peg n=104 Liver transplant n=12 Death n=13 Completed 24-48 weeks treatment n=72 Forns X, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O62.

  14. Results: Overall Virologic Response 81/93 53/85 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). Forns X, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O62.

  15. Results: Clinical Outcomes 60/104 22/104 22/104 All patients who received ≥1 dose of SOF are included *Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values. Forns X, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O62.

  16. Clinical Cases: FibrosingCholestaticHepatitis (2 Patients with FCH) Patient 1 (SOF + RBV 24 Weeks) Patient 2 (SOF + RBV 48 Weeks) HCV RNA 8 log10 IU/mL HCV RNA 8.7 log10 IU/mL GGT (IU/L) GGT (IU/L) Bilirubin (mg/dL) Bilirubin (mg/dL) Week FU12 BL 4 BL 4 FU12 SOF + RBVTreatment OffTreatment SOF + RBVTreatment OffTreatment Viral load undetectable by Week 4 (Patient 1) and Week 12 (Patient 2) resulting in SVR12 Forns X, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O62.

  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 SVR12 3D + RBV (N=34) Day 0 Week 24 To Week 72 Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. 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, 2014. 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 Percentage Patients 34/34 34/34 32/33 25/26 Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O114.

  20. Study M12-999: Pre-Treatment and On-Treatment TacrolimusCtrough Concentrations • Ctroughlevels 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 (15.7-34.0 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) (Treatment Weeks 1-4) Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O114.

  21. Question & Answer Session

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