TURQUOISE-I:
SAFETY AND EFFICACY OF
ABT-450/R/OMBITASVIR,
DASABUVIR, AND RIBAVIRIN
IN PATIENTS CO-INFECTED
WITH HEPATITIS C AND HIV-1
Mark S. Sulkowski, Joseph J. Eron, David Wyles, Roger Trinh, Jay Lalezari,
Jihad Slim, Joseph Gathe, Peter J. Ruane, Chia Wang, Richard Elion,
Fritz Bredeek, Robert Brennan, Gary Blick, Amit Khatri, Krystal Gibbons,
Yiran B. Hu, Linda Fredrick, Tami Pilot-Matias, Barbara Da Silva-Tillmann,
Barbara McGovern, Andrew L. Campbell, Thomas Podsadecki
20th International AIDS Conference
• Melbourne, Australia •
21 July 2014
Disclosures
MS Sulkowski: Consultant/Advisory Board: AbbVie, BMS, Gilead, Idenix Pharmaceuticals, Janssen, Merck, Tobira Therapeutics;
Data Safety Monitoring Board: Gilead (funds paid to Johns Hopkins University); Study Steering Committee: Pfizer; Grant/Research
support: AbbVie, Boehringer Ingelheim, BMS, Gilead, Merck, Janssen, Vertex Pharmaceuticals (funds paid to Johns Hopkins
University).
JJ Eron: Grant/Research support: AbbVie, Merck, BMS, GSK/ViiV; Consultant; AbbVie, Gilead, BMS, GSK/ViiV, Merck, Janssen.
D Wyles: Grant/Research support: AbbVie, BMS, Gilead, Merck, Vertex Pharmaceuticals; Consultant/Advisor: AbbVie, BMS, Gilead,
Janssen.
J Lalezari: Research support: AbbVie.
J Slim: Speaker Bureau: AbbVie, BMS, Gilead, Merck, Janssen, Genentech.
J Gathe: Grant/Research support: AbbVie, Tobira, Boehringer Ingelheim, BMS, GSK, Parexel, Gilead, Huesped.
PJ Ruane: Grant/Research support: AbbVie, BMS, Gilead, Merck, Idenix, ViiV, Janssen; Consultant/Advisor: AbbVie, Merck, Gilead:
Speaker: Gilead, ViiV, Merck.
C Wang: Nothing to disclose.
R Elion: Grant/Research support: AbbVie, Merck, BMS, GSK/ViiV, Gilead; Consultant: Gilead, BMS, GSK, ViiV; Speakers bureau:
BMS, Merck, ViiV, Gilead, Janssen.
F Bredeek: Grant/Research support: AbbVie, BMS, Gilead, Merck, Sumagen, ViiV; Consultant/Advisor: AbbVie, Merck, ViiV.
R Brennan: Grant/Research support: AbbVie, Pfizer, Cubist Pharmaceuticals Inc, Achillion, Sanofi Pasteur, ViiV, GSK.
G Blick: Grant/Research support: AbbVie, Gilead Sciences, Pfizer, Sangamo Biosciences, ViiV; Consultant/Advisor: BMS, Merck,
Serono, ViiV; Speaker: AbbVie, Auxilium, BMS, Merck, Serono, ViiV.
R Trinh, A Khatri, K Gibbons, YB Hu, L Fredrick, T Pilot-Matias, B Da Silva-Tillmann, B McGovern, AL Campbell, and T Podsadecki:
Employees of AbbVie and may hold stock or options.
The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval
of the presentation. All authors had access to all relevant data.
This presentation contains information on the investigational products ABT-450/r, ombitasvir (ABT-267), and dasabuvir (ABT-333) and investigational use of ribavirin.
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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Background
Coinfection with HCV occurs in 20 – 40% of persons living with HIV
HCV/HIV coinfection is associated with more rapid liver disease
progression2
Liver-related disease is a leading cause of morbidity and mortality in
HCV/HIV coinfected patients in the era of ART1
The addition of direct-acting antivirals to pegIFN/ribavirin (RBV) has
improved sustained virologic response (SVR) rates, but these regimens
are associated with the well-known treatment-limiting toxicities of IFNbased therapy3-5
IFN-free regimens have shown promise with higher SVR rates and an
improved safety profile
1Kitahata
MM, et al. N Engl J Med. 2009;360:1815-26. 2Martin-Carbonero L, et al. Clin Infect Dis. 2004;38:128-33.
MS, et al. Lancet Infect Dis. 2013;13:597-605. 4Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96.
5Rodriguez-Torres M, et al. IDWeek 2013.
3Sulkowski
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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3 Direct-Acting Antiviral Regimen (3D)
The multi-targeted 3D regimen includes:
• ABT-450, a potent NS3/4A protease inhibitor (identified by AbbVie
and Enanta) co-dosed with low-dose ritonavir* (ABT-450/r) to
increase the peak, trough, and overall drug exposures of ABT-450,
enabling once daily dosing6
• Ombitasvir (ABT-267), a potent NS5A inhibitor
• Dasabuvir (ABT-333), a non-nucleoside NS5B RNA polymerase
inhibitor
ABT-450, ritonavir, and ombitasvir are co-formulated as a single tablet
Extensive phase 1 drug-drug interaction studies in healthy volunteers
with tenofovir, emtricitabine, atazanavir, and raltegravir indicated no
clinically meaningful alterations in HCV or HIV drug exposures
*Ritonavir does not have antiviral activity against HCV.
6Menon
R, et al. HepDART 2009.
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3 Direct-Acting Antiviral Regimen (3D)
The 3D regimen, with and without RBV, has been studied in >2700
patients to date
High SVR12 rates were achieved with 3D + RBV in genotype (GT) 1infected patients within a phase 3 program
• ≥96% SVR12 in treatment-naïve and -experienced patients after 12
weeks of treatment7-10
• 92 – 96% SVR12 in treatment-naïve and -experienced patients with
cirrhosis treated for 12 or 24 weeks11
TURQUOISE-I is a 2-part, multicenter, phase 2/3 study assessing the
safety and efficacy of 3D + RBV in HCV GT1/HIV-1 coinfected patients,
including those with cirrhosis
7Feld
8Ferenci
9Zeuzem
10Andreone
JJ, et al. N Engl J Med. 2014;370:1594-603.
S, et al. N Engl J Med. 2014;370:1604-1614.
11Poordad F, et al. N Engl J Med. 014;370:1973-82.
P, Bernstein D, et al. N Engl J Med. 2014;370:1983-92.
P, et al. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.04.045.
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Part 1 Study Design (N = 63)
Open-label Treatment
3D + RBV
(N = 31)
All patients will be followed for 48
weeks after HCV treatment end
SVR12
SVR4
3D + RBV
(N = 32)
Day 1
Week 12
Week 24
Week 36
3D: coformulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD;
dasabuvir, 250 mg BID
RBV: 1000 or 1200 mg daily according to body weight in 2 divided
doses (<75 kg and ≥75 kg, respectively)
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Study Analyses
Efficacy analyses
• Rapid virologic response (RVR; week 4 of treatment)
• End-of-treatment response (EOTR; week 12 or 24 of treatment)
• Sustained virologic response (SVR4 and SVR12; post-treatment
week 4 and 12, respectively)
• On-treatment HCV virologic failure
• Post-treatment HCV viral relapse
Safety analyses
• Maintenance of plasma HIV-1 RNA suppression
• Treatment-emergent adverse events
• On-treatment lab abnormalities
Virologic response is defined as HCV RNA <LLOQ (25 IU/mL)
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Key Eligibility Criteria
•
•
•
•
18 to 70 years of age
BMI ≥18 and <38 kg/m2
HCV GT1 infection (plasma HCV RNA >10,000 IU/mL)
HCV treatment-naïve or pegIFN/RBV-experienced
– For pegIFN/RBV-experienced, prior: Relapse*, Partial response†,
or Null response‡
• Child-Pugh A Cirrhosis
• HIV-1 infected
– Plasma HIV-1 RNA <40 copies/mL
– CD4+ count ≥200 cells/mm3 or CD4+% ≥14%
– Stable atazanavir or raltegravir-inclusive ART regimen
*Relapse: HCV RNA undetectable at or after the end of treatment, but with a detectable level within 52 weeks thereafter
† Partial response: >2 log IU/mL HCV RNA reduction at treatment week 12 but detectable at end of treatment
10
‡ Null response: <2 log IU/mL or <1 log IU/mL HCV RNA reduction at treatment week 12 or 4, respectively
10
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TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I:
Baseline Demographics and Disease Characteristics
Male, n (%)
Black, n (%)
Age, mean ± SD
Cirrhosis, n (%)
IL28B non-CC genotype, n (%)
HCV genotype 1a, n (%)
HCV RNA (log10 IU/mL), mean ± SD
Prior pegIFN/RBV experience, n (%)
Naïve
Relapse
Partial response
Null response
CD4+ T-cell count/mm3, mean ± SD
Atazanavir HIV-1 ART regimen
Raltegravir HIV-1 ART regimen
12-Week Arm
(N = 31)
24-Week Arm
(N = 32)
29 (94)
7 (23)
50.9 ± 6.0
6 (19)
26 (84)
27 (87)
6.54 ± 0.57
29 (91)
8 (25)
50.9 ± 8.3
6 (19)
25 (78)
29 (91)
6.60 ± 0.78
20 (65)
1 (3)
5 (16)
5 (16)
633 ± 236
16 (52)
15 (49)
22 (69)
3 (9)
2 (6)
5 (16)
625 ± 296
12 (38)
20 (63)
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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3D + RBV Regimen
12-Week Arm
TURQUOISE-I Results:
ITT Virologic Response Rates
100
100
100
96.8
96.9
31
31
32
32
30
31
31
32
24-Week Arm
93.5
96.9
93.5
% Patients
80
60
40
20
0
RVR
EOTR
(Week 4)
(Week 12 or 24)
SVR4
SVR12
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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3D + RBV Regimen
12-Week Arm
TURQUOISE-I Results:
ITT Virologic Response Rates
100
24-Week Arm
100
100
96.8
96.9
93.5
96.9
93.5
31
31
32
32
30
31
31
32
29
31
31
32
29
31
% Patients
80
60
40
20
0
RVR
EOTR
(Week 4)
(Week 12 or 24)
SVR4
SVR12
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Reasons for Non-Response
Virologic failure occurred in 2 patients; both were prior null responders
with HCV genotype 1a infection and had compensated cirrhosis
• Each had resistance-associated variants in at least 2 targets at the
time of virologic failure not present at baseline
HCV IL 28B Regimen
Type of
Variants at Time of Failure
Patient GT
GT
Duration Virologic Failure NS3
NS5A
NS5B
1
1a
T/T
12 wks
Relapse at PT
D168V M28T S556G
Week 2
2
1a
T/T
24 wks Breakthrough at None
Q30R S556G
Week 16
1 patient (12-week Arm) withdrew consent but had an undetectable
HCV RNA at last study visit (week 10)
No patient discontinued due to adverse events
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Treatment-Emergent Adverse Events ≥ 10%
Event, n (%)
Any AE
Serious AE
Fatigue
Insomnia
Nausea
Headache
Upper respiratory tract infection
Pruritus
Cough
Ocular icterus
Diarrhea
12-Week Arm
(N = 31)
28 (90.3)
0
18 (58.1)
5 (16.1)
5 (16.1)
6 (19.4)
4 (12.9)
6 (19.4)
2 (6.5)
5 (16.1)
1 (3.2)
24-Week Arm
(N = 32)
28 (87.5)
0
12 (37.5)
7 (21.9)
6 (18.8)
4 (12.5)
5 (15.6)
2 (6.3)
5 (15.6)
1 (3.1)
4 (12.5)
The majority of adverse events were mild or moderate in severity
5 severe adverse events were reported: insomnia, hypophosphatemia, disseminated
herpes zoster, tooth abscess, and vertigo
No treatment-emergent serious adverse events were reported
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: On-Treatment Laboratory Abnormalities
Parameter, n (%)
Hemoglobin <10 g/dL
Hemoglobin <8 g/dL
Total bilirubin >3X ULN
ALT >5X ULN
AST >5X ULN
12-Week Arm
(N = 31)
4 (12.9)
0
11 (35.5)
0
0
24-Week Arm
(N = 32)
3 (9.4)
0
6 (18.8)
0
1 (3.1)
6 patients reduced RBV dose due to hemoglobin declines; all achieved SVR
Indirect hyperbilirubinemia was the most common laboratory abnormality
•
15/17 (88.2%) patients experiencing grade 3 total bilirubin elevations
were receiving atazanavir-inclusive ART
5 patients (2 in the 12-week Arm, and 3 in the 24-week Arm) had a confirmed
HIV-1 RNA ≥40 copies/mL (but <200 copies/mL) during the treatment period
• All 5 patients achieved plasma HIV-1 RNA re-suppression while
maintaining the same HIV-1 ART regimen without 3D + RBV interruption
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Summary
This study evaluated the IFN-free 3D + RBV regimen in HCV treatmentnaïve and –experienced patients coinfected with HIV-1, including those
with cirrhosis:
• SVR12 rate of 93.5% was achieved with 12 weeks of 3D + RBV
• SVR4 rate of 96.9% was achieved with 24 weeks of 3D + RBV
• 3D + RBV coadministered with atazanavir or raltegravir ART was
well-tolerated with no treatment-emergent serious adverse events
and no patient discontinuations due to adverse events
These results are consistent with those in HCV GT1-monoinfected
populations receiving the 3D + RBV regimen
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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TURQUOISE-I: Next Steps
A cohort of patients on a stable darunavir-inclusive ART regimen who
will receive treatment with the 3D + RBV regimen for 12 weeks (Part
1b) will be evaluated
TURQUOISE-I, Part 2 will be conducted globally and will initiate later
this year
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Acknowledgements
The authors would like to express their gratitude to the patients and
their families, investigators, and coordinators who made these studies
possible.
The authors thank AbbVie employees Christine Collins, Sandra Lovell,
Rakesh Tripathi, Martin King, Karmin Robinson-Morgan, Gretja Schnell,
Jill Beyer, and Thomas Reisch for contributions to the study. Medical
writing support was provided by Douglas E. Dylla, an employee of
AbbVie.
TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-Infected with Hepatitis C and HIV-1 | AIDS 2014 | 21 July 2014
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