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


12 Weeks3D + RBV

24 Weeks3D + RBV

TURQUOISE-II Results:ITT SVR12 Rates by HCV Subtype


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


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)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


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


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)


(Treatment Weeks 1-4)

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