Download - F/C AETC Faculty HIV/HCV
F/C AETC FacultyHIV/HCV
Thursday, June 26, 2014 | 1:30-2:30pm (EDT)
Facilitator/Didactic PresenterDushyantha T. Jayaweera MD, MRCOG (UK), FACP
University of Miami
Case Discussant(s)Patrick Marsh, MD
University of South Florida
HIV/HCV: Highlights from EASLHCV 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 DiseasesFaculty Member, Florida/Caribbean AIDS Education and Training Center
Liver Transplantation (OLT)
Treatment ofestablished disease
Treatment before histologic recurrence
Potential Strategies for Treatments of HCV in Peri-Transplant Population
Pre-OLT Rx
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: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively)
Day 0 Week 24Week 12
SVR12
SVR12
3D + RBV(N=208)
3D + RBV(N=172)
All patients to be followed through 48 weeks post-treatment
Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.
0
20
40
60
80
100
TURQUOISE-II Results:ITT SVR12 Rates of 92% to 96%
SVR1
2, %
Pati
ents
91.8
191/208
Non-inferiority threshold: 43%
Superiority threshold: 54%
95.9
165/172
P=0.089
Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.
12 Weeks3D + RBV
24 Weeks3D + RBV
TURQUOISE-II Results:ITT SVR12 Rates by HCV Subtype
Poordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.
0
20
40
60
80
100 88.6 98.594.2 100
GT 1a GT 1b
SVR1
2, %
Pati
ents
124/140 67/68114/121 51/51
12-week arm24-week arm
3D + RBV
TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in
HCV Subtype 1a
0
20
40
60
80
100 92.2
12-week arm24-week arm
92.9
Naïve Prior RelapseResponse
3D + RBV
SVR1
2, %
Pati
ents
59/64 14/1552/56 13/13
93.3 100 100 100 80.0 92.9
11/11 40/5010/10 39/42
Prior PartialResponse
Prior NullResponse
HCV Subtype 1aPoordad F, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O163.
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 12 Wk 24
SVR12
LDV/SOF, n=20GT 1CPT class B
LDV/SOF + RBV, n=19GT 1Prior SOF exposure
Gane E, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O6.
SVR
12
(Per
cent
age)
GT 1CPT Class B
Median total bilirubin,mg/dL (range) 1.5 (0.7-3.7)
Median serum albumin,g/dL (range) 3.1 (2.3-3.8)
Median INR (range) 1.2 (1.0-3.0)
Ascites, n (%) 4 (20)
Hepatic encephalopathy, n (%) 6 (30)
Median platelet count,103/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, 2014. Abst. O6.
65
13/20
7 relapsers
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
SOF 400 mg + RBV 1000‒1200 mgSVR12
Observation SOF 400 mg + RBV 1000‒1200 mgSVR12
Arm 1n=25
Arm 2n=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, 2014. Abst. O68.
Wk 0 Wk 24 Wk 48 Wk 96Wk 72
HC
V R
NA
< LL
OQ
(Per
cent
age)
Results: Virologic Response on Treatment
WeekAfdhal N, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O68.
5/9 9/97/16 12/16 8/8 8/8 7/715/16 15/16 14/15
Laboratory Results: Mean Change in MELD Score from Baseline through Week 24
-6
-4
-2
0
2
4
6
-6
-4
-2
0
2
4
6
CPT A Patients (n=20) CPT B Patients (n=29*)
MEL
D c
hang
e fr
om b
asel
ine
SOF + RBV Observation 24 weeks
n=2 n=5 n=1 n=3
Afdhal N, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O68.
1 patient had only a baseline MELD score before withdrawing consent and is not
depicted.
SOF Compassionate Use ProgramSOF + RBV ± Peg
n=104
Completed 24-48 weeks treatmentn=72
Forns X, et al. 49th EASL; London, England; April 9-13, 2014. 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
Post transplant compensated and decompensated cirrhosis
(liver biopsy (F4) or clinical decompensation)
n=56
Early term due to AEn=7
Liver transplantn=12
Deathn=13
Forns X, et al. 49th EASL; London, England; April 9-13, 2014. 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).
81/93 53/85
Forns X, et al. 49th EASL; London, England; April 9-13, 2014. 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
60/104 22/104 22/104
Clinical Cases: Fibrosing Cholestatic Hepatitis (2 Patients with FCH)
• Viral load undetectable by Week 4 (Patient 1) and Week 12 (Patient 2) resulting in SVR12Forns X, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O62.
0
5
10
15
20
25
0
500
1000
1500
2000
2500
3000
0 12 24 360
5
10
15
20
25
0
500
1000
1500
2000
2500
3000
0 12 24 36 48 60
Patient 1 (SOF + RBV 24 Weeks)
GG
T (IU
/L)
GG
T (IU
/L)Bilirubin (m
g/dL)
Bilirubin (m
g/dL)
HCV RNA 8.7 log10 IU/mL
4
HCV RNA 8 log10 IU/mL
SOF + RBVTreatment
SOF + RBVTreatment
OffTreatment
OffTreatment
Patient 2 (SOF + RBV 48 Weeks)
FU12
BLWeek 4BLFU12
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 0 Week 24
SVR12
To Week 72
3D + RBV(N=34)
Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O114.
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.
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, 2014. Abst. O114.
Perc
enta
ge P
atie
nts
34/34 34/34 32/33 25/26
Study M12-999: Pre-Treatment and On-Treatment Tacrolimus Ctrough Concentrations
• Ctrough 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 (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
Tacr
olim
us C
once
ntra
tion
(ng/
mL)
Kwo P, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O114.
(Treatment Weeks 1-4)
Question & Answer Session