Transcript pag.ias2013.org

Efficacy of initial combination
antiretroviral therapy for HIV-1:
a meta-analysis
Frederick J. Lee1, Janaki Amin2, Andrew Carr1
Centre for Applied Medical Research, St Vincent’s Hospital 1
Kirby Institute, University of New South Wales 2
Sydney, Australia
7th IAS Conference on HIV Pathogenesis, Treatment & Infection
July 2013, Kuala Lumpur, Malaysia
Background
Overview
 Initial antiretroviral therapy (ART)
− ‘backbone’ (2 NRTIs) + third drug
(NNRTI / rPI / INSTI)
 DHHS guidelines: when to start
− mostly driven by CD4 count / clinical stage
− HIV viral load not a criterion since 2007
 DHHS guidelines: what to start
− ‘Preferred’ &‘Alternative’ regimens
− current ‘Preferred’ regimens:
• TDF-FTC/3TC + EFV / rDRV / rAZV / RAL
Background
Overview
 Guidelines based on serial assessment of
individual trials
 Systematic review / meta-analysis
− more patients / regimens, so more power to
• evaluate subpopulations
• identify predictors of ART success
 Limitations of previous ART meta-analyses
− only some regimens
− short follow-up durations
− more recent studies:
• new drugs / studies
• longer follow-up
Objectives
Primary and secondary
 Primary = overall efficacy
− determined by undetectable viral load
− all studies over maximum follow-up period
 Secondary
 efficacy over time
− 48, 96, & 144 weeks
 efficacy by 2012 DHHS guidelines
− ‘Preferred’ vs. ‘Alternative’ ART
 efficacy by baseline viral load
− ≥100,000 vs. <100,000 copies/mL
 predictors of efficacy and of failure
Methods
Study selection
 Inclusion criteria
−
−
−
−
treatment-naïve, HIV-1+ adults
prospective design
≥48 weeks duration
intent-to-treat (ITT) efficacy analysis
 Exclusion criteria
− retrospective or cross-sectional design
− combinations not recommended for
toxicity/poor efficacy (e.g. monotherapy)
− directly observed therapy
Methods
Data sources
 Databases sourced (to Dec 31, 2012)
− MEDLINE
− clinical trial registries (Cochrane, NIH, ISRCT)
− conference abstracts & presentations (CROI,
IAS, ICAAC, Glasgow)
− product labels & medical reviews (FDA,
EMA)
− study synopses from manufacturers
 Manufacturers approached for missing data,
kindly provided by:
− BMS, Gilead, MSD, ViiV Healthcare
Methods
Data collection
 Database construction
−
−
−
−
study characteristics
eligibility criteria
participant & disease characteristics
ART characteristics
Methods
Statistics
 Descriptive
− unit of analysis = treatment group
− variables expressed as
• percentage
• mean, weighted for group size
 Predictive
− linear regression approach
• multivariable
• backwards, step-wise variable selection
 Analyses performed using STATA (v.11)
− parameters not displayed if not significant
or not of particular interest
Study characteristics
Characteristics
Randomised
Placebo
Phase
Sponsorship
Year
commenced
yes
yes
2
3
4
academic
industry
both
pre-1996
1997-1999
2000-2002
2003-2005
2006-2008
2009-2010
Groups Participants
Mean,
(n=216)
(n=40,124)
%
196
68
50
96
70
55
123
38
10
53
43
61
31
17
36,534
17,630
4,386
26,325
9,413
10,681
26,547
2,896
641
8,108
9,331
13,062
6,597
2,346
91.1
43.9
10.9
65.6
23.5
26.6
66.2
7.2
1.6
20.2
23.3
32.6
16.4
5.8
Study characteristics
Characteristics
Eligibility
restrictions
Duration
(weeks)
Efficacy
analysis
viral load
ALT / AST
haemoglobin
CD4 count
genotype
AIDS (CDC C)
prior IDU
48
96
144
ITT M=F
ITT NC=F
TLOVR
Groups Participants
Mean,
(n=216)
(n=40,124)
%
184
173
133
122
62
11
5
131
60
25
62
84
70
33,915
31,536
24,224
19,428
12,563
1,436
223
20,165
11,629
8,330
7,127
13,676
19,321
84.5
78.6
60.4
48.4
31.3
3.6
0.6
50.3
29.0
20.8
17.8
34.1
48.2
Participant characteristics
Characteristic
Age
Sex
Race
Risk factors
men
white
black
MSM
heterosexual
IDU
Previous AIDS
CD4 count
log10cp/mL
HIV RNA
≥100,000 cp/mL
Hepatitis C
Mean (SD)
37 (2)
76% (15)
65% (17)
27% (17)
52% (19)
38% (15)
10% (9)
12% (13)
248 (81)
4.9 (0.2)
43% (11)
10% (9)
ART characteristics
Dosing
Characteristics
Pills per day, mean (SD)
Doses per day, mean (SD)
Dosing with food, %
fasting only
fasting + food
food only
no restriction
Groups, Participants,
Mean,
n
n
%
216
216
40,124
40,124
6.3 (3.6)
2.0 (0.7)
59
22
65
70
9,754
5,108
11,947
13,315
24.3
12.7
29.8
33.2
ART characteristics
Key NRTI backbones & third drug classes
Groups, Participants,
NRTI backbones
AZT-3TC
TDF-FTC
d4T-3TC
ABC-3TC
d4T-ddI
TDF-3TC
Third drug classes
NNRTI
PI (boosted)
PI (unboosted)
NRTI
INSTI
Mean,
n
n
%
56
45
27
26
20
9
10,832
10,123
3,988
5,516
2,349
1,970
27.0
25.2
9.9
13.7
5.9
4.9
94
56
38
12
9
19,512
9,724
5,686
1,771
2,150
48.6
24.2
14.2
4.4
5.4
Efficacy
All studies
Follow-up,
All
studies
48
96
144
216
216
85
25
Participants, n
40,124
40,124
19,959
8,330
Follow-up, weeks (SD)
82 (38)
48
96
144
ART efficacy, % (SD)
60 (16)
66 (16)
60 (16)
52 (18)
Groups, n
weeks
Efficacy
All studies
Follow-up,
All
studies
48
96
144
216
216
85
25
Participants, n
40,124
40,124
19,959
8,330
Follow-up, weeks (SD)
82 (38)
48
96
144
ART efficacy, % (SD)
60 (16)
66 (16)
60 (16)
52 (18)
ART cessation, % (SD)
25 (11)
20 (9)
28 (11)
34 (10)
adverse events
8.1
6.9
7.5
10
patient decision
11
8.5
14
15
virological failure
3.5
2.4
4.8
4.4
other
4.7
3.3
6.4
8.3
Groups, n
weeks
Efficacy: all studies from 1994 to 2010
Efficacy
Predictors (all studies): NRTI backbone
Multivariable analysis
Efficacy,
TDF-FTC
ABC-3TC
AZT-3TC
ddI-FTC
TDF-3TC
ddI-3TC
d4T-3TC
d4T-ddI
AZT-ddI
%, (SD)
Coeff
73 (10)
63 (7)
48 (15)
78 (-)
69 (5)
65 (8)
55 (12)
44 (13)
42 (4)
Ref
-7.6
-13.3
7.9
-1.2
-7.9
-11.4
-18.4
-35.3
r2,NRTI backbone type = 35.3%
95% CI
p
p group
0.003
-18.0, -8.5 <0.001
-11.6, 27.4
0.426
-8.5, 6.2
0.758
-16.6, 0.8
0.075
-16.8, -5.9 <0.001
-24.9, -12.0 <0.001
-51.9, -18.7 <0.001 <0.001
-12.7, -2.6
Efficacy
Predictors (all studies): third drug class
Multivariable analysis
Efficacy,
%, (SD)
Coeff
NNRTI
61 (15)
Ref
INSTI
84 (5)
PI (boosted)
95% CI
p
11.9
4.6, 19.2
0.002
67 (9)
-0.9
-4.7, 3.0
0.660
NRTI
51 (12)
-10.7
-17.4, -4.1
0.002
PI (unboosted)
42 (11)
-15.0
-19.4, -10.6
<0.001
r2, third drug class = 43.0%
p group
Efficacy
Predictors (all studies): study design
Efficacy,
% (SD)
Study
phase
Analysis
2
3
4
ITT M=F
ITT NC=F
TLOVR
Eligibility restriction
Genotype yes
CD4
Treatment
Pills / day
Doses / day
no
yes
no
64 (15)
62 (16)
54 (16)
53 (17)
59 (15)
64 (15)
72 (10)
55 (15)
54 (18)
66 (11)
Multivariable analysis
r2
(%) Coeff
95% CI
p
p group
3.8
2.1
21.7
6.2
19.2
22.3
Ref
-6.4
-7.5
-10.1, -2.7 0.001
-11.5, -3.6 <0.001 <0.001
Efficacy
By pre-treatment viral load
Groups, n
All
studies
Pre-treatment viral
load
<100,000 ≥100,000
216
98
Participants, n
40,124
Follow-up, weeks (SD)
82 (38)
ART efficacy, % (SD)
60 (16)
ART cessation, % (SD)
25 (11)
13,184
9,694
81 (36)
70 (15)
62 (15)
no data
Mean difference for <100,000 vs. ≥100,000 subgroups =
8.4% (95% CI 6.0 to 10.9), p<0.001
Efficacy
Predictors (all studies): viral load ≥100,000
Efficacy, r2
% (SD)
(%) Coeff
Placebo
PI (boosted)
64 (11)
81 (5)
65 (11)
Ref
7.9 -6.3
24.0 -1.8
Ref
14.5
6.5
NRTI
43 (17)
-20.0
PI (unboosted)
43 (11)
-10.0
yes
no
67 (13)
57 (15)
Pills per day
Third drug
class
NNRTI
INSTI
Multivariable analysis
95% CI
p
p group
-12.0, -0.5
0.034
<0.001
0.034
<0.001
-2.8, -0.8
4.5, 24.4
0.005
0.042
0.2, 12.8
-29.1, <0.001
10.8
-19.9, -0.2 0.045
Efficacy
By DHHS regimen
DHHS recommendation
‘Preferred’ ‘Alternative’
other
27
36
153
Groups, n
Participants, n
5,677
8,556
25,891
Follow-up, weeks (SD)
99 (41)
86 (35)
77 (37)
ART efficacy, % (SD)
75 (8)
65 (7)
55 (17)
Mean difference for ‘Preferred’ vs. ‘Alternative’ regimens =
10% (95% CI 7.6 to 15.4), p<0.001
Efficacy
By DHHS regimen
DHHS recommendation
‘Preferred’ ‘Alternative’
other
27
36
153
Groups, n
Participants, n
5,677
8,556
25,891
Follow-up, weeks (SD)
99 (41)
86 (35)
77 (37)
ART efficacy, % (SD)
75 (8)
65 (7)
55 (17)
ART cessation, % (SD)
20 (8)
25 (8)
27 (12)
5.3
7.3
9.0
adverse events
9.0
11.0
11.0
patient decision
3.6
2.8
3.7
virological failure
3.4
4.5
5.0
other
Efficacy
By DHHS regimen
TDF-FTC/3TC
plus
Groups,
Participants,
Follow-up, Efficacy,
n
n
weeks
% (SD)
EFV
14
2,729
108
72 (8)
rAZV
9
1,776
87
75 (7)
rDRV
1
343
96
79 (-)
RAL
3
829
99
82 (8)
Similar efficacy across DHHS-’Preferred’ regimens,
although trend to superior efficacy with raltegravir
Participant decision (11%)
Cessation less likely
in industry-sponsored
studies
Adverse events (8%)
Cessation: all studies, 1994 to
2010
(overall cessation 25%)
Cessation less likely
in industry-sponsored
and phase 2 studies
Conclusions
 Overall mean efficacy of initial ART is low
− only 60% over 82 weeks
− higher with ‘Preferred’ regimens
(75% over 99 weeks)
 Treatment determinants of greater success
− TDF-FTC (vs. ABC-3TC)
− INSTI (vs. NNRTI or boosted PI) - including
when pre-treatment viral load ≥100,000 cp/mL
 Suboptimal efficacy
− most patients will interrupt initial ART
− TDF-FTC + INSTI efficacy 81% when pretreatment viral load ≥100,000 cp/mL
• need for study of 3 vs. 4 drugs?
Conclusions
 Ongoing loss in efficacy over time
− participant decision > adverse events >>
virological failure
 Significant 8.4% difference in efficacy
between higher & lower viral load groups
− similar to 10% difference between ‘Preferred’
& ‘Alternative’ DHHS regimens
− guidelines should recommend initiating ART
before viral load reaches 100,000 cp/mL
 Despite focus on co-formulation, fewer daily
pills & doses not independent predictors of
overall efficacy
Limitations
 Groups the base unit, not individuals
 Only some unpublished data available,
mostly from industry-sponsored studies
 Efficacy by viral load not randomised
 No analysis of:
− individual drugs within third drug class
e.g. NVP vs. EFV; rLPV vs. other PI
− clinical outcomes or resistance
 Multivariable method of analysis
− clinically irrelevant associations may
emerge, relevant associations missed
− dependent upon data completeness
Acknowledgements
 Data: Fraser Drummond (ViiV)
Silke Schweizer (BMS)
Carolee Welebob (MSD)
Howard Wraight (Gilead)
Rebekah Puls, Kathy Petoumenos (UNSW)
 Funding:
NHMRC of Australia (FJL)
 Potential conflicts of interest (AC)
•
•
•
•
research funding - Baxter, Gilead, MSD, Pfizer
consultancies - Gilead, MSD, ViiV
lectures - Gilead, MSD, Serono, ViiV
advisory boards - Gilead, MSD, ViiV