Transcript A5273-CROI 2016 Primary Results Final Out - UZ-UCSF

ACTG 5273 Randomized Trial of
Second-line ART Supports WHO
Guidance
Alberto La Rosa1, Linda Harrison2, Babafemi Taiwo3, Carole L
Wallis4, Lu Zheng2, Peter Kim5, Nagalingeswaran Kumarasamy6,
Mina Hosseinipour7, John W. Mellors8, Ann C. Collier9.
1Asociacion
Civil Impacta Salud y Educacion, Lima, Peru; 2Harvard TH Chan
School of Public Health, Boston, Massachusetts, USA; 3 Northwestern University,
Chicago, USA; 4BARC-SA and Lancet Laboratories, Johannesburg, South Africa;
5 Division of AIDS, National Institute of Allergy and Infectious Diseases,
Bethesda, Maryland, USA; 6YRG CARE, Chennai, India; 7 University of North
Carolina, Chapel Hill, North Carolina, USA; 8 University of Pittsburgh, Pittsburgh,
Pennsylvania, USA; 9 University of Washington, Seattle, Washington, USA.
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Background and Rationale
 Current standard in RLS:
— 1st line: 2 NRTIs + 1 NNRTI,
— 2nd line: 2 NRTIs + PI/r
 Prolonged exposure to failing first-line
regimen
 Cross resistance among NRTIs

Genotyping not available or not affordable for
routine care
 Leads to potential PI monotherapy
 Rationale: NRTI-sparing regimen LPV/r + RAL
may provide a potent and safe alternative to
LPV/r + NRTIs”
2
Study Schema
Phase III, open-label, randomized, non-inferiority study
15 sites in 9 low-middle income countries
48 weeks
3 continents
Primary endpoint
Planned N=600
Failing on
NRTIs + NNRTI
as initial regimen
with
VF: confirmed >1,000
cps/mL
•
•
•
96 weeks f/u
for each participant
LPV/r + RAL
(n = 300)
1:1
LPV/r + best available NRTIs
(n = 300)
Primary objective: To determine whether the efficacy of RAL arm is noninferior to that of NRTI arm by 48 weeks
Primary endpoint: Time to VF= confirmed VL>400 cps/mL at > 24 wks
N adjusted to 480 after results of SECOND LINE, EARNEST and A5234:
 Power >90% and 10% non-inferiority margin maintained
 Follow up shortened to 52 weeks after the last enrollment
Baseline Characteristics
Female
Age median (Q1, Q3) years
Country
India
Malawi
South Africa
(N=512)
RAL (N=258)
NRTI (N=254)
52 %
50%
39 (34, 44)
38 (33, 43)
Other (Zimbabwe, Kenya, Tanzania, Peru,
31
22
20
27
HIV-1 subtype C
83 %
79 %
Years on 1st Line: median (Q1, Q3)
4.1 (2.2, 6.3)
4.0 (2.2, 6.0)
HIV RNA median (Q1, Q3) log10/mL
4.6 (4.0, 5.2)
4.5 (3.9, 5.1)
CD4 median (Q1, Q3) cells/mL
138 (49, 268)
133 (56, 274)
4%
4%
Thailand, and Brazil)
Resistance test prior to entry
%
%
%
%
31
22
20
28
%
%
%
%
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Summary of First Line Regimen and
NRTIs Chosen for the NRTI study arm
RAL (N=258)
NRTI (N=254)
TDF containing
ZDV containing
d4T containing
3TC containing
39 %
36 %
25 %
100%
35 %
35 %
30 %
100%
EFV containing
NVP containing
46 %
54 %
38 %
62 %
Regimen prior to entry
NRTI
NNRTI
Chosen NRTI (NRTI arm only)
FTC, TDF
3TC, ZDV
3TC, ABC
FTC, ZDV, TDF
3TC, ZDV, ABC
68 %
19 %
8%
3%
2%
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Follow-up data
 Follow up Median (Q1, Q3): 87 (71, 96) weeks.
 LTFU by week 48: 2.4%
 Only 6 participants (4 RAL arm , 2 NRTI arm)
discontinued study treatment by week 48.
 8% of participants substituted NRTIs
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Results: Primary Endpoint
Time to virologic failure (confirmed VL>400 c/mL at/after 24 weeks)
Difference in failure probability by week 48
RAL - NRTI: -3.4% (95% CI -8.4, 2.5)
1: RAL
2: NRTI
Upper bound of CI
<10%
(non-inferiority boundary)
RAL non-inferior
Upper bound of CI
> zero
RAL not superior
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Proportion (95% CI) of HIV-1 RNA ≤ 400
cps/ml over Time (missing=ignored)
RAL
NRTI
RAL
NRTI
No difference found with other virologic cut points: <200 or <40 cps/ml
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Mean (95% CI) change in CD4+ Count
from Baseline over Time
RAL
NRTI
RAL
NRTI
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No differences in AIDS events,
Serious Non-AIDS events and deaths
Most frequent AIDS events (N)
RAL
NRTI
Total
10
7
17
Extrapulmonary TB
0
3
3
Other
3
3
6
RAL
NRTI
Total
Myocardial infarction
1
0
1
Stroke
0
1
1
Renal disease
0
2
2
Other
5
2
7
RAL
NRTI
Total
3
3
6
Pulmonary TB
Most frequent Serious Non-AIDS
events (N)
Deaths (N)
Deaths
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Cumulative Probability of Toxicity Event
Symptoms, signs and laboratory abnormalities grade >3
1: RAL
2: NRTI
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Mean (95% CI) change in Total Cholesterol and
Triglycerides from baseline over time
RAL
Total Cholesterol
NRTI
Triglycerides
p<0.05
Also higher levels of LDL and non HDL cholesterol in RAL arm
No difference in HDL, TC/HDL ratio, and glucose
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Resistance at study entry
RAL (N=258) NRTI (N=254)
Samples tested
244 (95%)
246 (97%)
92 %
3%
1%
2%
2%
96 %
1%
1%
0%
2%
89 %
90 %
54 %
22 %
22 %
2%
50 %
26 %
20 %
4%
K65R (%)
23 %
21 %
≥3 IAS* NRTI mutations (%)
52 %
53 %
Resistance by class*
NRTI and NNRTI mutations
NNRTI only
NRTI only
NRTI + NNRTI + PI mutations
No major IAS mutations
M184V/I (%)
TAMS (%)
0
1–2
3–4
>5
* 2014 IAS-USA Update of drug resistance mutations in HIV-1. Wensing et al., 2014
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GSS at study entry for prescribed NRTIs
GSS was calculated by assigning the NRTIs a score of:
high-level resistance
• 0
• 0.25 intermediate resistance
• 0.5 low-level resistance
• 0.75 potential low-level resistance
• 1
susceptible
Based on the Stanford algorithm version 7.0
NRTI (N=254)
Specific NRTI GSS:
median (Q1:Q3)
1.00 (0.25, 1.00)
Specific NRTI GSS category
0 - <1
1 - <2
2
48 %
49 %
3%
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Effect of Prescribed NRTI GSS on
primary endpoint of time to VF
1: RAL
2: NRTI specific GSS<1
3: NRTI specific GSS≥1
NRTI GSS <1 vs >1
week 48 difference -8.4%
95% CI: -16.6%, -0.3%
p= 0.04
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Associations of other NRTI Resistance
Characteristics at Entry with the risk of
Virologic Failure (VF) – Both arms included
No difference by arm
Results consistent when adjusted for entry HIV-1 RNA, week 4 selfreport adherence, prior exposure to TDF, and country
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Resistance at virologic failure
RAL Arm
NRTI Arm
Total
Patients with VF
46 (18%)
50 (20%)
96 (19%)
Patients with VF and samples available
Patients with new mutations
39 (85%)
45 (80%)
84 (88%)
10 (26%)
13(29%)
23 (27%)
M184V/I
1 (3%)
1 (2%)
2 (2%)
K65R
0 (0%)
0 (0%)
0 (0%)
TAMS
0 (0%)
4 (9%)
4 (5%)
Q151M
0 (0%)
0 (0%)
0 (0%)
T69N
0 (0%)
1 (2%)
1 (1%)
M46I
0 (0%)
3 (7%)
3 (4%)
L76V
0 (0%)
2 (4%)
2 (2%)
V82A
0 (0%)
2 (4%)
2 (2%)
T66A
1 (3%)
0 (0%)
1 (1%)
T97A
3 (8%)
0 (0%)
3 (4%)
Y143C/R
2 (5%)
0 (0%)
2 (2%)
6 (15%)
0 (0%)
6 (7%)
New NRTI Mutations
New Major PI Mutations
New Integrase Mutations
N155H
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Conclusions
 LPV/r + RAL was non-inferior to LPV/r + NRTIs in
this well powered randomized trial in resource limited
settings with minimal access to resistance testing
—
Both regimens provided high virologic efficacy (>90% at 48w)
—
Both regimens provided similar CD4 cell increases
—
Supports WHO guidance for 2nd Line ART
 The efficacy of the NRTI arm through 48 weeks was not
compromised by study entry NRTI resistance
—
Response was better with greater evidence of NRTI resistance
—
Is resistance a marker of better adherence? Impaired virus?
 A shorter time to G>3 toxicity (signs, symptoms and
laboratory abnormalities) was observed for the NRTI arm
 Modest elevations of TC, LDL and TG were more frequent in
the RAL arm
 About 25% of participants with virologic failure developed
new resistance mutations
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Team Members
Acknowledgments
Participating Sites
Role
Study Co-Chair
Study Co-Chair
Study Vice-Chair
Study Vice-Chair
CSS Representative
Clinical Trials Specialist
Clinical Trials Specialist
Data Manager
Drug Co. Representative
Drug Co. Representative
Drug Co. Representative
Drug Co. Representative
Immunologist
Field Representative
Industry Representative
Industry Representative
Industry Representative
Investigator Investigator
Investigator Investigator
Name
Ann C. Collier
Alberto La Rosa
John Mellors
Babafemi Taiwo
Flavio Pontes
Lara Hosey
Jennifer Rothenberg
Bernadette Jarocki
Randi Leavitt
James Rooney
Site ID
11101
SiteName
Wits HIV CRS
11201
11301
11302
11501
11601
11701
Durban Adult HIV CRS
IMPACTA Barranco, CRS
IMPACTA San Miguel, CRS
Chiang Mai Univ. ACTG CRS
NARI Pune CRS
YRG CARE Medical Ctr., VHS CRS
12001
12101
12301
University of North Carolina Lilongwe CRS
Instituto de Pesquisa Clínica Evandro Chagas
Soweto ACTG CRS
Brad Saget
Wendy Snowden
Michael
Lederman
Janet Nicotera
12601
Asmeret Kidane
12901
30301
Krishna Sewal
Jean van Wyk
30313
Sandra Cardoso
31441
Mina Hosseinipour
Nagalingeswaran Kumarasamy
Cynthia Riviere
Laboratory Data Manager (LDM) Laura Hovind
Laboratory Technologist
Carmen Irizarry
Medical Officer
Peter Kim
Pharmacologist
Ed Acosta
Protocol Pharmacist
Ana Martinez
Senior Statistician
Lu (Summer) Zheng
Statistician
Linda Harrison
Virologist
John Mellors Carole
Virologist
Wallis
University of Pittsburg Lab
Elias Halvas
Lancet/BARC lab
Raquel Viana
Moi University International CRS
Kilimanjaro Christian Medical CRS
College of Med. JHU CRS - Blantyre
UZ-Parirenyatwa CRS - Harare
BJ Medical College CRS
Study participants
HIV Genotyping Labs/Staff
Univ. of Pittsburgh
Lancet/BARC Labs
Lou Halvas
Raquel Viana
Industry Collaborators
AbbVie
Gilead Sciences, Inc
GlaxoSmithKline
Merck and Company
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