Transcript Document

QUEST study: Follow-up of primary
HIV infection subjects on long-term
ART randomized to therapeutic
immunization versus placebo at one
year post-stopping treatment
S Kinloch-de Loes, F C Lampe, L Perrin, D Cooper,
B Hoen, L Goh, J Andersson, A Sonnerberg,
D Smith C Tsoukas, B Autran, R El Habib,
G Theofan, A N Phillips for the QUEST study group
Background
It is unclear whether therapeutic immunization can increase
virological control in the long-term after discontinuation of
ART initiated in acute HIV infection.
The rationale for such an intervention includes the absence
of chronic immunosuppression, limited reservoirs of
integrated proviral DNA and the potential for preservation of
HIV-specific T cell responses. Therapeutic immunization
may further boost these immune responses which tend to
decrease with long-term ART.
Background
The QUEST trial assessed the impact of therapeutic
immunization of two vaccines in addition to ART versus ART
alone on HIV plasma viremia (VL) 24 weeks after treatment
interruption, in subjects who had initiated ART (Combivir®abacavir-amprenavir bd) at the time of primary HIV infection
(PHI).
Quest Study Design
The QUEST study design is shown in Figure 1.
PHI subjects (n=79) on chronic ART for >72 weeks were
randomized to one of three arms:
Arm A: ART + vaccine placebo
Arm B: ART + ALVAC-HIV vCP1452
Arm C: ART + ALVAC-HIV vCP1452 + Remune™
After 24 weeks subjects discontinued ART. Subjects were
followed with regular laboratory and clinical monitoring for an
additional 24 weeks when the primary end-point was
measured (percentage of subjects with plasma VL < 1000 HIV
copies/mL).
Figure 1. Quest Study Design
Randomisation
HAART
+ Placebo vaccines
>72 weeks HAART:
durable viremia
<50c/mL
HAART
+ Alvac HIV vCP 1452 + Placebo
Remune™
HAART
+ Alvac vCP 1452
+ Remune™
PHI
Quadruple HAART
(n = 79)
Rm = Remune™
VCP = ALVAC-HIV vCP1452
W0
W4
Rm
Rm
W8
W12
VCP
Rm
VCP
W16
W20
VCP
Rm
VCP
Week24
STOP
ART
Quest findings at 24 weeks post-stopping
Results at week 24 post-stopping ART showed:
• No difference in the percentage of subjects with viral load
<1000 HIV copies(c)/mL between the pooled ART+ vaccine
arms (B/C) and the ART+ placebo vaccine arm (A) [primary
efficacy endpoint].
• Immunogenicity in vaccine arms by IFN-gamma CD4 and
CD8 ELISPOT analysis at the end of the immunization
phase.
• Absence of correlation between immunogenicity at the end
of the immunisation phase and viremia levels at week 24
post-stopping ART.
Objective
The Quest cohort has been followed up since assessment of
the primary endpoint at 24 weeks post-stopping ART (DSMB
recommendation).
The follow-up will assess the impact of our therapeutic
strategy on VL, CD4, ART use and clinical events in the
longer term. The current analysis extends the follow-up of the
79 randomised patients to 48 weeks post-stopping ART.
Methods
Individualized forms sent to enrolling centers in Europe,
Canada and Australia recorded patient status, laboratory
parameters (viral load and CD4 count), antiretroviral treatment
details and clinical AIDS-defining events.
Data analysis was performed centrally (Royal Free and
University College Medical School, London).
Methods
Proportions of subjects with VL  1000 HIV-1 copies/mL at
week 48 post-stopping ART were assessed and compared
between arms A and B/C using Fishers exact test and an
intention to treat approach (subjects with missing VL, those
who did not stop ART and those who restarted ART were
classified as failure).
Absolute values of VL and CD4 count at week 48 poststopping ART were compared between arms A and B/C using
the Mann-Whitney test. Subjects with missing values and
those who restarted treatment were included using ‘last
observation carried forward’, providing this was at least 28
days after stopping ART.
Results
Follow-up information was received for 60 of 79 patients.
No deaths or AIDS events were reported.
Table 1 shows numbers of patients who did not stop ART,
restarted ART and had missing information at weeks 24 and
48 post-stopping ART.
Overall, 15 subjects restarted ART prior to week 48. Last VL
(c/mL) prior to ART-restart was: 50 (n=1); 10,000-100,000
(n=2); >100,000 (n=12).
No significant differences were found between arms A and
B/C for numbers restarting ART, primary VL end-point (Table
2), or median VL and CD4 count at week 48 post-stopping
ART (Table 3).
Table 1. Patient status
Week 24 post-stop ART
Week 48 post-stop ART
Total
Arm A
Arm B/C
Total
Arm A
Arm B/C
Number of patients
randomised
79
27
52
79
27
52
Number did not
stop ART
1
0
1
1
0
1
Number restarted
ART
8
3
5
15
4
11
Number missing
endpoint VL
4
1
3
17
10
7
Total number
automatic failure
13
4
9
33
14
19
Number with
endpoint VL
66
23
43
46
13
33
Table 2. VL distribution and primary endpoint
Week 24 post-stop ART
Week 48 post-stop ART
VL c/mL; n (%)
Total
Arm A
Arm B/C
Total
Arm A
Arm B/C
< 50
4 (5.1)
3 (11.1)
1 (1.9)
2 (2.5)
1 (3.7)
1 (1.9)
51 - 1000
10 (12.7)
3 (11.1)
7 (13.5)
4 (5.1)
1 (3.7)
3 (5.8)
1001 – 10,000
22 (27.9)
7 (25.9)
15 (28.9)
14 (17.7)
1 (3.7)
13 (25.0)
10,000 – 100,000
22 (27.9)
8 (29.6)
14 (26.9)
20 (25.3)
8 (29.6)
12 (23.1)
> 100,000
8 (10.1)
2 (7.4)
6 (11.5)
6 (7.6)
2 (7.4)
4 (7.7)
Did not stop
/Restarted/Missing
13 (16.5)
4 (14.8)
9 (17.3)
33 (41.8)
14 (51.9)
19 (36.5)
Primary endpoint
(VL < 1000c/mL
without restarting
ART, M=F)
14/79
(17.7%)
6/27
(22.2 %)
8/52
(15.4%)
6/79
(7.6 %)
2/27
(7.4 %)
4/52
(7.7 %)
A vs B/C
P = 0.54
P = 0.99
Table 3. Median VL and CD4 count
Week 24 post-stop ART
Week 48 post-stop ART
Total
Total
Arm A
Arm B/C
Arm A
Arm B/C
VL (c/ml)
N
Median
IQR
Range
76
4.0
3.2, 4.8
1.7, 6.5
A vs B/C
P=0.60
27
3.9
3.0, 4.9
1.7, 6.5
49
4.2
3.4, 4.8
1.7, 5.9
76
4.4
3.3, 5.0
1.7, 6.5
27
4.3
3.3, 5.0
1.7, 6.5
49
4.4
3.9, 5.0
1.7, 5.9
26
616
488,739
342,1180
49
613
451,736
312,1352
P=0.51
CD4 (/mm³)
N
Median
IQR
Range
75
644
505, 773
330,1284
A vs B/C
P=0.74
26
656
520, 739
342,1051
49
625
495, 773
330, 1284
75
613
467, 739
312,1352
P=0.84
Using ‘last observation carried forward’ if at least 28 days after stopping ART
Conclusion
The safety of our intervention was demonstrated by the
preservation of CD4 counts and the absence of deaths or
AIDS events in subjects who initiated ART at PHI with or
without the addition of therapeutic immunization and later
interrupted ART. The re-initiation of ART during this additional
follow-up occurred mainly because of high VL.
The proportions of subjects fulfilling the primary efficacy endpoint (<1000 c/mL) decreased at week 48 compared to week
24 post-stopping ART, with no major impact of immunization
on VL or CD4 count over the present follow-up period.
References
1. Rosenberg ES et al. Science.1997;278:1447-50.
2. Oxenius A et al. Proc Natl Acad Sci USA. 2000;97:3382-7.
3. Altfeld M et al. J Exp Med. 2001;193:169-80.
4. Kinloch-de Loes S et al. J Infect Dis 2005; 192: 607-17.
Acknowledgements
Quest Study Group: Recruiting centres: Australia: M. Bloch (Holdsworth House General Practice, Darlinghurst, New South Wales), D Baker (407
Doctors Clinic, Surry Hills, Sydney NSW 2010), R Finlayson (Taylor Square Private Clinic, Surry Hills, Sydney NSW 2010), P Grey, D Smith, D
Cooper (National Centre in HIV Epidemiology and Clinical Research, Sydney). Belgium: Ph Hermanns, K Kabeya, N Clumeck (Department of
Infectious Diseases, St Pierre Hospital, Brussels). Canada: M Harris, J Montaner (John Ruedy Immune Deficiency Clinic, St Paul’s Hospital,
University of British Columbia, Vancouver), C Tsoukas (Immune Deficiency Treatment Centre, Montreal General Hospital, Montreal). France: B
Hoen (Department of Infectious Diseases, Besancon University Hospital, Besancon), P M Girard (Department of Infectious and Tropical Diseases,
Rothschild Hospital, Paris), J Modai (Department of Infectious Disease St Louis Hospital, Paris), Ph Canton, T May (Department of Infectious
Diseases, CHU Nancy, Vandoeuvres-les-Nancy), D Sereni (Department of Internal Medicine, St Louis Hospital, Paris), C Katlama (Department of
Infectious Diseases, Pitié-Salpetrière Hospital, Paris). Germany: S Staszewski (Klinikum der JW Goethe Universitat. Zentrum der Inneren Medizin,
Frankfurt), H J Stellbrink (Medizinische Poliklinik, Universitatsklinikum Eppendorf, Hamburg). Italy: G Tambussi, A Lazzarin (Clinic of Infectious
Diseases, San Raffaele Scientific Institute, Milan). Sweden: H Gaines, S Lindback, A Blaxhult (Department of Infectious Diseases, Karolinska
University Hospital, Stockholm). Switzerland: M C Bernard, B Hirschel, L Perrin (Division of Infectious Diseases, University Hospital, Geneva), K
Wolf, M Battegay (Division of Infectious Diseases, Basle University Hospital, Basle), P Vernazza (DIM, Kantonsspital, St Gallen), R Weber
(Department fur Innere Medizin, Zurich). UK: S Kinloch, T Drinkwater, Z Cuthbertson, P Byrne, M Youle, M Tyrer, S Bhagani, M A Johnson (Ian
Charleson Centre, Royal Free Hospital, London), C Higgs, D Hawkins, B Gazzard (Kobler Centre, Chelsea & Westminster Hospital, London), A.
Friedman (University Hospital of Wales, Cardiff), M Fisher (Claude Nicol Centre Research Department, Royal Sussex Country Hospital, Brighton).
GlaxoSmithKline QUEST Team (Greenford, UK): V Mallet, S Turkish, S Fortes, H Maseruka, H Steel, D Thorborn, H McDade, L E Goh.
GlaxoSmithKline monitors: Australia (M Haberl, J Young); Belgium (D Luyts, I van Steenberg); Canada (S Pratt, T Russell); France (L Beauvais, J
M Vauthier); Germany (M Sikora); Italy (C Gussetti, C M Anghileri, V Piva, D Fendt); Sweden (G Larsson); Switzerland (C Python, I Schauwecker, E
Gremlich); UK (K Studdard, P Humphreys, U Loughrey).
The Immune Response Corporation: (Carlsbad, California, USA) - R Moss, G Theofan.
Aventis Pasteur (Lyon, France) - D Blanc, C di Vita, V Mazarin, B Mouterde, R El-Habib.
DSMB - M Schechter (Canada), I Weller (United Kingdom), R Luethy (Switzerland), J M Molina (France).
Quest Core Group: S Kinloch, D Cooper, L Perrin, B Hoen, A Sonnerborg, C Tsoukas, J Andersson, F C Lampe, A N Phillips, B Autran.
Statistical analysis: F C Lampe, N Carter, A N Phillips.
Data management: J Puradiredja
Roche Molecular Systems (Alameida, CA, USA): B Dale, A Capt.
Laboratory support: L Wegmann, S Yerly, L Perrin (Laboratory of Virology, Geneva University Hospital, Geneva, Switzerland). A Samri, B Autran
(Cellular and Tissue Immunology Laboratory, Inserm U543, Pitié-Salpetrière Hospital, Paris, France). J Zaunders, P Cunningham, A Kelleher
(Centre for Immunology, St Vincent’s Hospital, NCHECR, University of New South Wales, Sydney, Australia). S Martins, G Janossy (HIV
Immunology Laboratory, Department of Immunology and Molecular Pathology, Royal Free and University College Medical School, London, UK). A L
Spetz, J Andersson (Karolinska University Hospital, Sweden). G Tambussi, A Lazzarin, A Galli (Clinic of Infectious Diseases, San Raffaele Scientific
Institute, Milan, Italy).