Effect of IL-‐7 on Cell-‐associated DNA in Blood and

Effect of IL-­‐7 on Cell-­‐associated DNA in Blood and Rectal Tissue: The ERAMUNE 01 Study Sponsored by
Chris&ne Katlama1, Sidonie Lambert-­‐Niclot2, François Lecardonnel3, Laura Papagno3, Lambert Assoumou4, Giuseppe Tambussi5, Bonaventura Clotet6, Mike Youle7, Dominique Costagliola4, BrigiOe Autran8 and the EraMune-­‐01 Study Group 1Department of Infec/ous and Tropical Diseases, Pi/é-­‐Salpêtrière Hospital, Paris; 2Laboratory of Virology, UPMC/INSERM UMR-­‐S943, Paris; ; 3ORVACS; 4Center of Methodology, UPMC/INSERM UMR-­‐S943, Paris; 5Vaccine and Immunotherapy Research Center, San Raffaele Hospital, Milan; 6HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona; 7Ian Charleson Day Center, Royal Free Hospital Hampstead, London; 8Laboratory of Cellular and Tissular Immunology, UPMC/INSERM UMR-­‐S945 (((((((((The"EraMune301"Study"Design"(
Pa-ents and Methods Screening"
q  Objective
W -4
To evaluate the propor-on of pa-ents with a reduc-on of at least 0.5 log10/106 PBMCs of the HIV reservoir aCer 56 weeks of cART intensifica-on with raltegravir et maraviroc with or without a single cycle of 3 weekly injec-ons of IL7. The following paFents were eligible: §  18 < age <70 years §  At least 3 years of suppressive ART §  CD4+ count ≥ 350 cells/mm3 §  10 ≤ Proviral DNA ≤ 1000 copies/106 PBMCs §  No ac-ve hepa--s B or C §  No prior exposi-on to immune modulators q  Study design
The EraMune-­‐01 trial was an interna-onal, mul-center, randomized, non-­‐compara-ve controlled study of therapeu-c intensifica-on plus immunomodula-on in HIV pa-ents with long-­‐
term viral suppression Results RAL/MVC/IL7
n=15
43 (36 – 48)
49 (42 – 56)
47 (41 – 53)
Sex"(%"Male)"
13/14 (93 %)
14/15 (93 %)
27/29 (93 %)
Time"on"cART"(years)"
7 (5 – 13)
13 (11 – 15)
12 (8 – 14)
CD4"nadir"(cells/mm3)"
267 (216 – 579)
248 (125 – 309)
252 (171 -351)
CD8"count"(cells/mm3)"
Ra)o"CD4/CD8"
Dura)on"of"VL"<"50"cp/
mL"(years)"
549 (416 – 769)
561 (462 – 701)
cART intensification (RAL/MVC*)
680 (540 – 881)
703 (603 – 900)
0.83 (0.54 – 1.12)
0.81 (0.56 – 0.99)
2.2 (2.1 – 2.4)
2.4 (2.3 – 2.9)
2.3 (2.1 – 2.6)
564 (320 – 869)
*RAL/MVC(doses(
!  RAL:"400"mg"BID"
!  MVC:"150/300/600"mg"BID"
depending"on"concomitant"cART"
IL-7: 3 weekly injections
(W8, 9, 10)
Dose: 20 µg/kg/week
Median change from baseline
in CD4/CD8
ratio ratio
Median changes
in CD4/CD8
RAL/MVC
RAL/MVC(interrup&on(
interruption
P-value
BL vs W56
No IL-7
0.056
IL-7
0.975
P-value
BL vs W80
No IL-7
0.035
IL-7
0.015
558 (452 – 726)
719 (642 – 954)
0.79 (0.56 – 0.93)
287 (106 – 822)
STOP
intensification
Primary Endpoint
cART intensification + IL7 (RAL/MVC/IL7)
P-value
BL vs W80
360 (228 – 828)
HIV-DNA
log10
copies
RAL/MVC(interrup&on(
No paFent reached the primary endpoint with a decrease in HIV-­‐DNA in the PBMCs ≥ 0.5 log10 at Week 56 RAL/MVC
RAL/MVC/
IL-7
Per 106
CD4 cells
BL vs W80
0.064
IL-7/Ral MVC
0.331
"""""""""""Median change
in rectal mucosa HIV DNA
Median changes in HIV-DNA in rectal mucosa
ΔW56 – BL = 0.14 (-0.14 – 0.46)
p = 0.314
""""""""""Median"changes"in"blood"CD4"subsets"
Results"expressed"in"percentages"
Median changes in blood CD4 subsets (%)
Median changes in blood CD4 subsets (%)
6
ΔW56 – BL = 0.04 (-0.09 – 0.23)
p = 0.374
0.363
Δ
W80-BL
n=28
p-value
(BL vs W56)
2.45
-0.02
(2.03-2.91)
(-0.10-0.09)
2.75
0.02
(2.50-2.94)
(-0.04-0.24)
2.78
0.02
(2.50-3.29)
(-0.08-0.19)
-0.18
0.875
(-0.35-0.04)
0.03
0.088
(-0.07-0.27)
-0.21
0.463
(-0.31-0.03)
p-value
(BL vs W80)
0.064
0.331
0.096
2.84
0.04
(2.66-3.19)
(-0.12-0.26)
-0.21
0.116
(-0.31-0.04)
0.177
•  Cell"sor)ng"of"res)ng"(DR3,"CD253,"693)"CD4"T"cell"subsets:"""""
RAL/MVC/
3.12
0.19
0.22
0.001
0.022
(2.93-3.29)
(0.07-0.36)
(0.02-0.35)
IL-7"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""Naive""
"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""Central3Memory"
"
"
"
"
"
"""""""Transi)onal3Memory"
"
"
"changes
"
"
"""""""Effector3Memory"
Median
in total HIV-DNA in each
•  Quan)fica)on"of"total"HIV3DNA"in"each"subset"ex3vivo"
CD4 subset ex vivo
p=0.001
RAL/MVC
4
RAL/MVC/IL7
2
0
p=0.023
-2
p=0.016
-4
-6
p=0.009
-8
27"
RAL/MVC
RAL/MVC
Per mL
whole
blood
0.003
IL-7
The"HIV"reservoirs"in"sorted"CD4"T"cell"subsets""
RAL/MVC/
3.12
0.00
0.07
0.198
0.397
(2.83-3.30)
(-0.04-0.23)
(-0.05-0.29)
IL-7
do"not"significantly"change""from"baseline""with"or"without"IL37"
CD4 Naive
CD4 Central
Memory
CD4
Transitional
Memory
CD4 Effector
Memory
Median(Nb(HIV@DNA(copies(/(
million(sorted(subset(cells(
RAL/MVC
Δ
W56-BL
n=27
Basline
n=27
Per 106
PBMCs
No IL-7
Median"Changes"in"Blood"HIV"DNA"
Long"Term"changes"in"Total"HIV"DNA""
in"PBMCs"(W80)"
Median changes in total HIV-DNA in PBMCs
HIV3DNA"copies/106"
PBMCs"
W80
Total
n=29)
Age"(years)"
CD4"count"(cells/mm3)"
W56
CD4 Effector HLADR+/CD4+
CD45RA+
RAL+MVC+IL@7((N=6)"
60"
50"
naive"
40"
CM"
30"
TM"
20"
TEM"
10"
0"
D0"
W56"
Nmedian(b(HIV(DNA(copies(/(million(
sorted(subset(cells(
RAL/MVC
n=14
W24
W8
"
Randomiza)on
n"
cART
((((((((Durable"(W80)"amplifica)on""
of"CD4"counts:"Results"at"W80"
Median
changes in CD4 counts "
Patients
Baseline characteristics
((((((((Pa)ents"Characteris)cs"
Post3interven)on"
interrup)on"follow3up"
Therapeu)c"Interven)on"
D0
60(
RAL+MVC((N=6)"
50(
naive(
40(
CM(
30(
TM(
20(
TEM(
10(
0(
D0(
W56(
Conclusion §  No patient neither in the Intensification with RAL/MVC nor in the
RAL/MVC /IL7 was abble to reach the primary end point of a
decrease of 0.5 log10 in cell associated DNA /106 PBMC from
baseline
§  IL-7,
as one cycle of 3 weekly injections of 20 microgr combined to ARV
intensification leads
:
§  A massive peripheral blood CD4 (and CD8) T cell
expansion :
§  IL-7 induced despite ARV intensification a success rate less
than 20% :
§  The transient increase in the HIV reservoir
§ does not reflect an increase of the reservoir within sorted
TCM,
§ but reflects the TCM expansion, the main contributor to HIV
reservoirs,
§  persisting at W56 and W80
§  which may mask the HIV reactivation effect of IL-7:
§  involving primarily the blood central-memory T cells (TCM), but not the
rectal ones,
§  although HIV mRNA transcripts were detectable in 90% enrolled
patients and before and 2-12 months after IL-7 infusions
§  contrasting with a relative decline in:
§  Naïve CD4 T cells, and senescent Effector CD4 T cells
§  Activated CD4 T cells
§  As a consequence transient increase in the HIV reservoir
(HIV-DNA copy numbers)
within the 6-8 months post-infusion
§  back to baseline values at W56 and W80 when calculated per million
PBMC,
§  but not when calculated /mm3 of blood, due to the persisting CD4 T
cell increase
§  precludes usage of IL-7 as a strategy to purge the HIV
reservoirs §  Dual RAL/MVC intensification: effects on the total
peripheral blood HIV-DNA reservoirs
§  No changes over 56 weeks
§  Trend towards a decrease at W80
§  This effect suggests a continuous low level HIV
production persisting during fully suppressive ARV
§  As assessed by detection of HIV mRNA transcripts in
CD4 T cells from 90% patients
§  Need for evaluation of long term suppressive
therapies with optimal intracellular drug penetration
The EraMune-­‐01 Study Group Center 01 (Paris): C. Katlama, R. Tubiana, M. A. Valan-n, L. Schneider, H. S-tou, B. Mory, G. Peytavin, A. Curjol, Y. Dudoit – Center 02 (Badalona): B. Clotet, B. Mothe-­‐Pujadas, P. Coll, J. Mar-nez-­‐Picado, P. Cobarsi – Center 04 (Milan): G. Tambussi, M. Pogliaghi, S. Chiappeba, L. Della Torre – Center 05 (London): M. Youle, S. Kinloch de Loës, A. Carroll, P. Byrne – Virology: V. Calvez, S. Lambert-­‐Niclot, A. G. Marcelin – Immunology: B. Autran, L. Papagno, A. Emarre – Methodology & StaFsFcs: D. Costagliola, L. Assoumou, A. Delobelle, I. Peyrole – Pharmacovigilance: A. Lillo-­‐Le Louët, V. Rouget-­‐Quermalet, V. Fulda – Monitoring (Keyrus Biopharma): K. Leplatre, M. Beuzelin, V. Campana, L. Régné, S. Sanchez – Project Management (ORVACS): F. Lecardonnel, L. Papagno. We thank CYTHERIS (T. Croughs, M. Morre), ViiV Healthcare France (C. Lemarchand, L. Finkielsztejn) and MSD France (L. Naït-­‐Ighil, F. Durand) for their support. Funded by
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