f/c aetc faculty hiv/hcv thursday, june 26, 2014 | 1:30-2:30pm (edt) facilitator/didactic presenter...

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


12 Weeks3D + RBV

24 Weeks3D + RBV

TURQUOISE-II Results:ITT SVR12 Rates by HCV Subtype


0

20

40

60

80

10088.6 98.594.2 100

GT 1a GT 1b

SVR1

2, %

Pati

ents

124/140 67/68114/121 51/51

12-week arm

24-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 arm

24-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.

SV

R12

(Per

cen

tag

e)

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 mg

SVR12

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

< L

LO

Q (

Per

cen

tag

e)

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*)

ME

LD

ch

an

ge

fro

m 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 treatment

n=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 AE

n=7

Liver transplant

n=12

Death

n=13


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


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

)Biliru

bin

(mg

/dL

)

Biliru

bin

(mg

/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 4BL

FU12

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


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


Per

cen

tag

e 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

oli

mu

s C

on

cen

trat

ion

(n

g/m

L)


(Treatment Weeks 1-4)

Question & Answer Session

f/c aetc faculty hiv/hcv thursday, june 26, 2014 | 1:30-2:30pm (edt) facilitator/didactic presenter...

Documents

d rbv slide

d rbv n

d rbv svr12

b svr12

easl london

hcvinfected patients

relapsers slide

easl hcv therapies