Transcript Slide 1

The effect of short-course ART in PHI
Final results from an international
randomised controlled trial
SPARTAC
Sarah Fidler
for SPARTAC Trial Investigators
Imperial College, London, UK
www.imperial.ac.uk/medicine/spartac
Background
• HIV-induced immunological destruction begins early and
despite later ART, is never completely reversed
• Observational studies: encouraging data suggest potential
immunological benefit of early ART
• David Ho ‘HIT HIV HARD HIT EARLY’ [1995]
• Hypothesis: ART initiated as near to HIV transmission
as possible may protect against HIV-induced immune
damage
Currently no evidence from randomised trial
to inform best clinical management of PHI
Primary Objective
• To determine the effect of two short
course ART schedules of different
durations compared with no immediate
ART in Primary HIV infection on time to
CD4 <350 or initiation of long-term ART
Trial Design
• Definition of PHI
– laboratory evidence of infection within 6 months of a previous
negative test, <3 bands WB, RITA incident, antibody negative PCR+
• Randomisation to one of three arms:
– 48-week short course ART (ART-48)
– 12-week short course ART (ART-12)
– No therapy (Standard of Care SOC)
• Primary end point
– time to CD4 <350 cells/mm3 or long-term ART initiation
• Sample size
– 360 providing 90% power to detect relative reduction in risk of time
to CD4 <350 cells/mm3 of 50% and 25% in ART-48 and ART-12
compared to SOC respectively over an average follow-up of 4 years
Secondary objectives
• Development of an AIDS defining illness or death
• HIV-specific CD4+ and CD8+ T-cell responses at week 60
• Slope of CD4 decline after intervention
• Development of new drug resistance by week 120
• Differences in blood pressure from randomisation at
weeks 12 and 48
• Time to virological failure of first long-term ART
regimen
Enrolment & Exclusions
SCREENED
429
58 EXCLUDED
15 not PHI
19 protocol exclusions
24 other reasons
RANDOMISED
371
SOC
124
ART-12
123
ART-48
124
SOC
124
ART-12
120
ART-48
123
5 EXCLUDED
2 not equivocal
1 HIV-neg>8 months
1 remained HIV-neg
1 randomisation error
International Sites
•
•
•
•
•
•
•
•
Australia
Brazil
Ireland
Italy
South Africa
Spain
Uganda
United Kingdom
Total
Sites
Participants
10
1
1
2
9
1
1
11
35
36 (10%)
17 (5%)
2 (1%)
23 (6%)
118 (32%)
2 (1%)
19 (5%)
149 (40%)
366
Baseline demographics
SOC
ART-12
ART-48
Sex
male
74
(60%)
71
(59%)
74
(60%)
female
49
(40%)
49
(41%)
49
(40%)
Age median (IQR)
31
(25,39)
32
(24,39)
33
(26,41)
Predominant risk factor
MSM
72
(59%)
64
(53%)
69
(56%)
WSM
50
(41%)
55
(46%)
53
(43%)
not known
1
(1%)
1
(1%)
1
(1%)
CD4 median (IQR)
543 (404,715) 519 (433,638) 605 (463,750)
Viral Load mean log10 (IQR log10)
4.70 (3.68,5.24) 4.39 (3.59,5.18) 4.43 (3.81,5.13)
Estimated duration of infection at
11
(8,15)
12
(9,15)
12
(9,15)
randomisation (weeks) mean (IQR)
Subtype B
70
(57%)
67
(56%)
71
(58%)
Subtype C
40
(33%)
40
(34%)
40
(33%)
Subtype Other
13
(11%)
12
(10%)
11
(9%)
Baseline Resistance
Any
8
(7%)
5
(4%)
8
(7%)
NRTI
5
2
6
NNRTI
5
3
3
PI
1
0
1
Median (IQR) follow up 4.2 years (3.5-7.2 years) with 13% lost to follow-up
91% Combivir + Kaletra
Total
219
147
32
(60%)
(40%)
(25,40)
205
(56%)
158
(43%)
3
(1%)
559 (435,700)
4.53 (3.67,5.18)
12
(9,15)
208
120
36
(57%)
(33%)
(10%)
21
13
11
2
(6%)
Time to primary endpoint
1.00
Probability of not reaching
primary endpoint
ART48 HR 0.63
(0.45,0.90), p=0.01
0.75
SOC
0.50
ART12 HR 0.93
(0.67,1.29), p=0.67
0.25
0.00
SOC
ART-12
ART-48
0
.5
1
1.5
123
120
123
109
110
121
93
95
117
82
84
109
2
2.5
Time (years)
75
79
100
66
71
88
3
3.5
4
4.5
59
63
80
46
49
63
30
32
41
18
21
19
Time to primary endpoint
Time to primary endpoint
Median, weeks (95% CI)
Difference vs. SOC
Difference vs. ART12
SOC
ART12
ART48
157 (114,213) 184 (140,214) 222 (189,270)
27
(-25,79) 65
(17,114)
38
(-3,79)
Hazard ratio
95% CI
p
ART12 vs. SOC
0.93
0.67 - 1.29
0.67
ART48 vs. SOC
0.63
0.45 - 0.90
0.01
ART48 vs. ART12
0.68
0.48 - 0.96
0.03
Duration of infection and time to
Primary Endpoint
1.00
Probability of not reaching
primary endpoint
ART-48 ≤12 wks
0.75
ART-48 >12 wks
0.50
SOC >12 wks
SOC ≤12 wks
0.25
ART48 vs SOC < 12 w HR = 0.48
[0.30, 0.78] p=0.003
0.00
0
.5
1
1.5
2
2.5
3
3.5
4
4.5
29
30
38
42
24
22
32
31
14
16
20
21
8
10
11
8
Time (years)
SOC >12 wks
SOC ≤12 wks
ART-48 >12 wks
ART-48 ≤12 wks
53
70
64
59
47
62
63
58
42
51
60
57
41
41
55
54
36
39
50
50
32
34
42
46
HIV RNA changes following ART interruption*
* Adjusted for baseline
Change in log10 HIV RNA
from baseline
.2
SOC
0
ART-12
.2
ART-48
.4
.6
.8
12
24
36
48
60
Weeks from ART interruption (ART-48 and ART-12) or randomisation (SOC)
Number measurements censored due to long-term ART initiation
SOC
1
6
7
ART-12
3
4
10
ART-48
0
2
5
9
17
9
14
18
9
Changes in CD4 values for ART-48
and SOC groups over entire study
Mean (pointwise 95% CI)
200
100
Average CD4 count over 4.5 years for ART-48
was 138 [90,185] cells/mm3 higher than SOC
ART-48
0
-100
SOC
-200
Weeks from randomisation
Secondary end points
• No significant difference between the groups for AIDS, death
or serious adverse events
• No difference in CD4 decline after ART interruption in
treatment groups compared to decline from randomisation in
SOC (p=0.92).
• In contrast to SMART there was no rebound in IL-6 and a
drop in d-dimer compared with baseline levels 4 weeks after
stopping ART.
• Virological failure on long-term ART was similar across groups
• Drug resistance by week 120: 6 had Stanford scores 4-5; 5 NNRTIassociated mutations and one PI-associated
• CD8+ & CD4+ HIV-specific responses: Analyses ongoing
Conclusions
• Spartac is the largest ever RCT in PHI enrolling men and women in both
developed and developing world settings
•
ART-48 associated with a significant delay in time to CD4 <350 or long-term ART
initiation, although the actual delay may not have been any longer than the time
spent on treatment
– Overall this effect was greater when ART-48 was started closer to the time of
HIV infection. (p=0.09)
• Compared to standard of Care
– ART-48 associated with significant reduction in viral set point of HIV RNA of
0.44 (0.25,0.64) log10 copies/ml sustained to 60 weeks after stopping therapy
– ART-48 conferred a higher average CD4 count of 138 cells over 4.5 years
• Interruption of ART in PHI had no evidence of harm; development of drug
resistance, or CD4 recovery after starting long-term ART
• No evidence of a benefit of ART-12
THANKS
All The study participants
Trial Steering Committee (TSC): Independent TSC
Members: A Breckenridge (Chair), P Clayden, C
Conlon, F Conradie, J Kaldor*, F Maggiolo; F Ssali
Country Principal Investigators: D A Cooper, P
Kaleebu, G Ramjee, M Schechter, G Tambussi, J.Miro
J Weber
Trial Physician: Sarah Fidler
Trial Statistician: Abdel Babiker
Data and Safety Monitoring Committee (DSMC): T
Peto (Chair) A McLaren (in memoriam), V Beral, G
Chene, J Hakim
Co-ordinating Trial Centre: MRC Clinical Trials Unit,
London (A Babiker, K Porter, M Thomason, F Ewings,
M Gabriel, D Johnson, K Thompson, A Cursley*, K
Donegan*, E Fossey*, P Kelleher*, K Lee*, B
Murphy*, D Nock*)
Central Immunology Laboratories and Repositories:
The Peter Medawar Building for Pathogen Research,
University of Oxford, UK (R Phillips, J Frater, L Ohm
Laursen*, N Robinson, P Goulder, H Brown)
Central Virology Laboratories and Repositories:
Jefferiss Trust Laboratories, Imperial College,
London, UK (M McClure, D Bonsall*, O Erlwein*, A
Helander*, S Kaye, M Robinson, Lisa Cook*, Gemma
Adcock*)
Clinical Endpoint Review Committee: N Paton, S
Fidler
Imperial College Trial Secretariat: S Keeling, A
Becker
Imperial College DSMC Secretariat: C Boocock
* Left the study team before the trial ended
Investigators and Staff at Participating Sites
Australia: St Vincent’s Hospital, Sydney (A Kelleher), Northside Clinic, Melbourne (R Moore), East Sydney
Doctors, Sydney, (R McFarlane), Prahran Market Clinic, Melbourne (N Roth), Taylor Square Private Clinic,
Sydney (R Finlayson), The Centre Clinic, Melbourne (B Kiem Tee), Sexual Health Centre, Melbourne (T Read),
AIDS Medical Unit, Brisbane (M Kelly), Burwood Rd Practice, Sydney (N.Doong) Holdsworth House Medical
Practice, Sydney ( M. Bloch) Aids Research Initiative, Sydney ( C. Workman). Coordinating centre in Australia:
Kirby Institute University of New South Wales, Sydney (P Grey, D A Cooper, A Kelleher, M Law).
Brazil: Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade federal do Rio de Janeiro, Rio
de Janeiro (M Schechter, P Gama, M Mercon*, M Barbosa de Souza, C Beppu Yoshida, J R Grangeiro da Silva, A
Sampaio Amaral, D Fernandes de Aguiar, M de Fátima Melo, R Quaresma Garrido
Italy: Ospedale San Raffaele, Milan (G Tambussi, S Nozza, M Pogliaghi, S ChiappettaL Della Torre, Elisa
Gasparotto,), Ospedale Lazzaro Spallanzani, Roma (G D’Offizi, C Vlassi, A Corpolongo)
South Africa: Cape Town: Desmond Tutu HIV Centre, Institute of Infectious Diseases, Cape Town (R Wood, J
Pitt, C Orrell, F Cilliers, R Croxford, K Middelkoop, L G Bekker, C Heiberg, J Aploon, N Killa, E Fielder, T Buhler)
Johannesburg: The Wits Reproductive Health and HIV Institute, University of Witswatersrand, Hillbrow Health
Precinct, Johannesburg. (H Rees, F Venter, T Palanee) Contract Laboratory Services, Johannesburg Hospital,
Johannesburg (W Stevens, C Ingram, M Majam, M Papathanasopoulos) Kwazulu-Natal: HIV Prevention Unit,
Medical Research Council, Durban (G Ramjee, S Gappoo, J Moodley, A Premrajh, L Zako)
Uganda: MRC/Uganda Virus Research Institute, Entebbe (H Grosskurth, A Kamali, P Kaleebu, U Bahemuka, J
Mugisha*, H F Njaj*)
Spain: Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona (JM Miro, M López-Dieguez*, C Manzardo,
JA Arnaiz, T Pumarola, M Plana, M Tuset, MC Ligero, MT García, T Gallart, JM Gatell)
UK and Ireland: Royal Sussex County Hospital, Brighton (M Fisher, K Hobbs, N Perry, D Pao, D Maitland, L
Heald), St James’s Hospital, Dublin (F Mulcahy, G Courtney, S O’Dea, D Reidy), Regional Infectious Diseases
Unit, Western General Hospital and Genitourinary Dept, Royal Infirmary of Edinburgh, Edinburgh (C Leen, G
Scott, L Ellis, S Morris, P Simmonds), Chelsea and Westminster Hospital, London (B Gazzard, D Hawkins, C
Higgs), Homerton Hospital, London (J Anderson, S Mguni), Mortimer Market Centre, London (I Williams, N De
Esteban, P Pellegrino, A Arenas-Pinto, D Cornforth*, J Turner*) North Middlesex Hospital (J Ainsworth, A
Waters), Royal Free Hospital (M Johnson, S Kinloch, A Carroll, P Byrne, Z Cuthbertson), Barts & the London
NHS Trust, London (C Orkin, J Hand, C De Souza), St Mary’s Hospital, London (J Weber, S Fidler, E Hamlyn, E
Thomson*, J Fox*, K Legg, S Mullaney*, A Winston, S Wilson, P Ambrose), Birmingham Heartlands Hospital (S
Taylor, G Gilleran)
Next steps
• Explore the mechanisms
• HIV-specific immune responses
• Was there functional preservation?
• Viral reservoir and evolution
• ART-12 was insufficient to suppress viral reservoirs but ART-48 did alter the
natural pattern- was it long enough?
• Preliminary data suggests there was an effect on reservoir size and limitation of
viral evolution
• Is the next study continuous therapy?
• Having shown that ART-48 is safe and may confer individual benefit
does this provide further support for UTT to limit transmission?
Baseline resistance
Number with a resistance test
Number with resistance at Stanford level 4-5
Any
NRTI
NNRTI
PI
Number with new resistance by week 120
Any
NRTI
NNRTI
PI
SOC
ART-12
ART-48
Total
123 (100%) 119 (99%) 122 (99%) 364 (99%)
8 (7%)
5
5
1
5 (4%)
2
3
0
8 (7%)
6
3
1
21(6%)
13
11
2
2
0
2
0
1
0
1
0
2
0
2
0
1
0
0
1
International trial sites
UK = 152
Spain = 2
Ireland = 2
Italy = 19
Uganda = 20
Brazil = 17
South Africa = 118
Australia = 37
IL-6 and d-dimer levels at baseline and
change 4 weeks after stopping ART
IL-6 0.00 (-0.07,0.06)
log10 value of biomarker
1
d-dimer -0.46
(-0.68,-0.29)
.5
0
-.5
-1
-1.5
Mean change (95% CI) in log10
IL-6 0.15 (-0.08,0.36)
.05
d-dimer -0.07 (-0.13,-0.01)
0
-.05
-.1
-.15
Baseline
(randomisation)
4 weeks after stopping ART
(adjusted for baseline)
Enrolment by country
Country
Australia
Brazil
Ireland
Italy
South Africa
Spain
Uganda
UK
Pilot
Main
Overall
N Sites
10
1
1
2
9
1
1
SOC
(Site%)
13 (35%)
6 (35%)
1 (50%)
8 (35%)
40 (34%)
0 (0%)
6 (30%)
ART-12
(Site%)
11 (30%)
6 (35%)
0 (0%)
8 (35%)
40 (34%)
0 (0%)
7 (35%)
ART-48
(Site%)
13(35%)
5 (29%)
1 (50%)
7 (30%)
39 (33%)
2 (100%)
7 (35%)
Total
37(10%)
17 (5%)
2 (1%)
23 (6%)
118 (32%)
2 (1%)
20 (5%)
1 10 (34%) 10 (34%)
9 (31%)
29 (8%)
10 41 (33%) 41 (33%) 41 (33%) 123 (33%)
35 124 (33%) 123 (33%) 124 (33%) 371 (100%)