strategie per ottimizzare il risultato clinico della haart prof. adriano lazzarin università...
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Strategie per ottimizzare il risultato clinico
della HAART
Prof. Adriano LazzarinUniversità Vita-Salute San Raffaele
Milano
Break-study (FTC weekly)
Soria A. et al, in press
Is VL < 50 Achievable in Treatment-Experienced Patients With MDR HIV?
1. Cahn P, et al. ICAAC. 2007. Abstract H-717. 2. Kumar P, et al. EACS 2007. Abstract P7.2/06. 3. Lalezari J, et al. ICAAC 2007. Abstract H-718a.
34%
63%*
Weeks
Pati
en
ts (
%)
*P < .001 vs PL
0 2 4 8 12 16 240
20
40
60
80
100 BENCHMRK-1 and -2[2]
RAL + OBRPL + OBR
MVC BID + OBRPL + OBR
47%*
16%
Weeks0 4 8 16 24 32 40 48
0
20
40
60
80
100MOTIVATE 1[3]
25%
49%* *P < .0001 vs PL
Pati
en
ts (
%)
Weeks
Pati
en
ts (
%)
0 2 4 8 12 16 240
20
40
60
80
100
*P < .0001 vs PL
DUET 1 and 2[1]
ETR + OBR PL + OBR
59%*
41%
MOTIVATE 1 and 2: Virologic Suppression by LPV/RTV Use, Wk 24
van der Ryst E, et al. IAS 2007. Abstract WEPEB115LB.
0
60
100
Pat
ien
ts (
%)
20
40
80
HIV-1 RNA < 400 copies/mL HIV-1 RNA < 50 copies/mL
0
60
100
Pat
ien
ts (
%)
20
40
80
60.0
87.096.3
LPV/RTV First Use
26.0
59.860.6
LPV/RTV Exp/Resistant
n = 10 2327 50 12794
50.0
69.674.1
LPV/RTV First Use
22.0
41.747.9
LPV/RTV Exp/Resistant
10 2327 50 12794
Placebo + OBR MVC QD + OBR MVC BID + OBR
DUET Week 96: response (VL <50 copies/mL TLOVR) by PSS*
*DRV considered sensitive if FC 10; ENF counted as sensitive if used de novo; etravirine not included in the PSS calculation; analysis excludes patients who discontinued except for VF
Trottier B et al. CAHR 2009. Abstract P148
Patients in the etravirine + BR group achieved consistently higher response rates than patients in the placebo + BR group, irrespective of number of active background agents; the difference was most apparent in patients with no active background agents
Pat
ient
s w
ith V
L <
50 c
opie
s/m
L a
t W
eek
96
(%
)Placebo + BR (n=477)etravirine + BR (n=497)
Number of active background ARVs (PSS)0 1 2
46%
6%
61%
29%
76%
59%
39/84 5/81 117/191 52/181 168/222 126/215
p<0.0001
p<0.0001
p<0.0001
100
90
80
70
60
50
40
30
20
10
0
Figure 1 – Trend of the virological and immunological parameters
Bars represent first and third quartiles.
0 10 20 30 40 500
50
100
150
200
250
300
350
400
0.00
0.05
0.10
0.15
0.20
0.25
CD4+ (cells/uL) CD4+/CD8+ ratio
follow-up (weeks)
Me
dia
n c
ha
ng
e C
D4
+(c
ells
/uL
)
Me
dia
n c
ha
ng
e C
D4
+/C
D8
+ra
tio
0 8 16 24 32 40 480
20
40
60
80
100
HIV-1 RNA<400 copies/mL
HIV-1 RNA<50 copies/mL
follow-up (weeks)
Pro
po
rtio
n o
f p
ati
en
ts (
%)
ICI - TRIAL
New scenario in rescue therapy: new naive patients
Main safety haematological findings in 28 HIV-1 infected failing pts receiving raltegravir, maraviroc and etravirine alone as salvage therapy.
Baseline Week 48 Change W48 p-value
Haemoglobin (g/dL)
13.6 (12.3-15.1)
15.1 (14.5-15.9)
1.1 (0.6-2.5)
<0.0001
Platelet count (109/mm3)
178 (149-207)
203 (163-243)
7.5 (-17/+61)
0.047
White blood cells (106/mm3)
5150 (4100-5900)
6700 (5300-8300)
1400 (0-2900)
0.0007
Lymphocytes (106/mm3)
1800 (1400-200)
2300 (2000-2900)
600 (100-950)
0.0002
Neutrophils (106/mm3)
2450 (2000-3700)
3800 (2600-4700)
500 (-200/+1300)
0.061
Increase of RBC, WBC and PTL N° after the NUCS step
BL W4 W12 W24 W36 W48 p-value
Creatinine (mg/dl)
0.99 0.98 0.97 0.91 0.94 0.88 0.0011
ICI - TRIAL
Nozza S et al, submitted
0 10 20 30 40 500
100
200
300
400
0
5
10
15
20
25
30
CKcreatininaacido urico
LDH
follow-up (weeks)
Med
ian
val
ue
Med
ian v
alue
ICI - TRIAL
Nozza S et al, submitted
The Next line of drugs for cART in failing MEXP
Elvitegravir ViiV 572 Rilpivirine Bevirimat Elvucitabine New NNRTI, and NRTI Therapeutic vaxins
…but mainly recycling of hold drugs active against revertant virus (NA,PI/r, entry inhibitors)
Naive: 2 - Reduce the treatment discontinuation due to SAE
Early decrease in CD38 expression on CD4+ cells on MVC
The kinetics of change in the proportion of CD38+ on CD4+T cells and in the density of of CD38+ on CD4+T cells were similar
IRIS Zone
To prevent the disease progression in HIV controlled patients
that enough a simplified maintenance Rx?
SEMPLIFICATION:a long-term treatment strategy in HIV controller
Time
VL
Induction Maintenance strategy
3 drugs required
Which antiviral strength Do we need to maintain full viral suppression • PI/r ? • 2 drugs ? • Others ?
4–5 log drop
Which markers do we use ?- HIV RNA < 50 copies- Viral DNA ?- GSS in DNA ?
Schematic representation; Katlama C, personal communication
Boosting PIs alone: for potency and genetic barrier could be an option for
monotherapy in maintenance ART
0
10
20
30
40
50
60
70
80
90
100
DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT)
MONET: Primary Efficacy Analysis:MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F HIV RNA <50 copies/mL at Week 48, TLOVR, S = F
Table EFF 4-5
HIV RNA<50 byWeek 48(%)
Per Protocol analysis (PP) Intent to Treat analysis (ITT)Primary analysis
N=123 N=123 N=129 N=127
87.8% 86.2% 85.3% 84.3%
-1.6%; lower limit 95%CI: -10.1% -1%; lower limit 95%CI: -9.9%
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
Elite controller: a selected core of LTNP
FINDINGS HIV RNA (ultrasensitive method) is found
in all controller (except one). High levels of proviral DNA and cell based
RNA is proven.
HIV negativeBefore ART Under ART
Ln
Brenchley JM, et alJ Exp Med. 2004 Sep 20;200(6):749-59.
Primary HIV Infection of Gut-Associated Lymphoid Tissue (GALT) is the First Pathogenic Event Leading to Substantial CD4+ T cell
Destruction and the main source of persistant activation
HIV-HIV- HIV+HIV+
G. Pantaleo et al., Nature 1994
Lymph Nodes GALT
Response to long-term antiretroviral treatment in 47 HIV+ with HIV-RNA < 1 copies/mL and >500 CD4/mcl
HIV-1 RNA Log copies/ml
Median (IQR)
CD4+ T-cells (cells/mcl)Median (IQR)
CD8+ T-cells (cells/mcl)Median (IQR)
Pre-therapy
4.68 (4.37-5.02)
243 (130-354) 675 (537-918)
After 4 years
<1.69 (NA)* 485 (405-696)* 738 (530-983)
After 7 years
<1.69 (NA)* 648 (564-737)* 647 (468-877)
F. Cossarini et al, ongoing study
CD8+ CD38+ T cells decay over time
Pretherapy Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 After Year 70
20
40
60
80
CD
8+
CD
38+
cells
(% C
D8+
T c
ells/
L)
CD8+ HLA-DR+ T Cells decay over time
Pretherapy Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 After Year 70
20
40
60
CD
8+
HL
A-D
R+
cells
(% C
D8+
T c
ells/
L)
CD38+ cells in HIV-Uninfected and infected subjects after 7 years on treatment
CD4+38+ HIV+ CD4+38+ HIV- CD8+38+ HIV+ CD8+38+ HIV-0
20
40
60
80
100
CD
38+
T c
ells
(%
CD
4+
or
CD
8+
cells
)
HLA-DR+ cells in HIV uninfected and infected subjects after 7 years on treatment
CD4+HLA-DR+ HIV+ CD4+HLA-DR+ HIV- CD8+HLA-DR+ HV+ CD8+HLA-DR HIV--0
20
40
60
80
HL
A-D
R+
T c
ells (
% C
D4+
or
CD
8+
ce
lls)
CD38+ HLA-DR+ Cells in HIV- uninfected and infected ubjects after 7 years on treatment
CD4+CD38+DR HIV+ CD4+CD38+DR HIV- CD8+CD38+DR HIV+ CD8+CD38+DR HIV-0
20
40
60
CD
38+
HL
A-D
R+
T c
ells (
% C
D4+
or C
D8+
cells)
Conclusions
The study doesn’t show a linear correlation between HIV-1 RNA on treatment and CD38+HLA+ T cells subsets.
HIV-RNA on antiretroviral treatment is therefore not a sufficient stimulus to mantain levels of T cell activation, which does not support the possibility of ongoing rounds of viral replication in the plasma compartment.
Most of the virus is in central memory and transitional memory CD4+ T cells
Courtesy of Brigitte Autran
Not HIV but ……..