Download CD4 explosion after effective HAART in HIV people: the hidden

CD4 explosion after effective HAART
in HIV people:
the hidden meaning
Miriam Lichtner
Ricercatore Malattie Infettive
Dipartimento Sanità Pubblica e Malattie Infettive
Sapienza Università di Roma, polo pontino
Background
The number of circulating CD4+ T lymphocytes in patients
with human immunodeficiency virus is the most robust
predictive factor for:
assessing HIV disease stage
predicting progression to clinical AIDS and AIDS-related death
 determining antiretroviral treatment eligibility
monitoring response to therapy
 The kinetic and the magnitude of CD4+ T recovery is
extremely variable among ART treated subjects.
2015 Italian guidelines HIV
Important Tools:
• Absolute number CD4+
• % CD4+
• CD4/CD8 ratio
Two particular populations can be described:
1) The ‘CD4-exploders’ (CD4e), defined as people gaining a large amount
of cells under a defined time:
 a high amount of virgin T cells and a reduced T cells with a phenotype typical of
lymphocytes with an increased tendency to undergo cell activation/death (Mussini et
al. 2000)
 higher plasma levels of IL-7, a cytokine with a crucial importance for the generation
and survival of T cells.
 BUT high amount of IL-7 has shown to be related to breast cancer, colon cancer,
hematological malignancies, autoimmune diseases (such as multiple sclerosis,
rheumatoid arthritis) (Kim et al., 2008).
2) The “CD4 peak achievers” (CD4a), who reach a very high level of
CD4+ T cells:
- Never studied as a separated population
It could be important to further characterize these
populations and investigate whether such extreme CD4
recoveries might modify persons’ risk of severe non-AIDS
event (sNAE) or death.
Aim of the study
Incidence and clinical-demographic features of “CD4
exploder” (CD4e) and “CD4 peak achiever” (CD4a) over
suppressive cART in ICONA cohort
To evaluate the association between these conditions and
the risk of sNAE/death and all cause mortality
Methods
Inclusion criteria:
All Icona HIV+ patients enrolled before December 2015, who started cART from
naïve and achieved/maintained VL<50cp/ml
Arbitrary definition:
 CD4 exploders (CD4e) = gain/maintenance >600 cells/mm3 above precART after 2 years of ART
 CD4 peak achievers (CD4a) = achievement of absolute CD4>1000 followed
by at least another consecutive >1000 value after 2 years ART
1.
We aim to estimate the incidence of these 2 endpoints by 2, 5 and 10 years of suppressive cART
and to identify factors independeently associated with the chance of being a CD4 explorer or
absolute peak achiever using standard survival analysis (Kaplan-Meier curves, Cox regression).
Unadjusted and adjusted HR will be calculated.
2.
CD4 explorer and CD4 absolute peak achiever will be used as covariates in a survival analysis with
time zero 2 years after viral suppression and endpoint time to severe non-AIDS events in those who
were still free from non-AIDS cancer at that point. Kaplan-Meier curves and Cox regression
analyses will be employed. Unadjusted and adjusted HR will be calculated after controlling for a
number of factors that are associated with both CD4 explosion and risk of severe-non AIDS.
Methods

Endpoints: to be a CD4e; to be a CD4a
Incidence by 2 years of suppressive cART;
Kaplan-Meier curves/Cox regression model to identify factors independently
associated;

Endpoint: sNAE (malignancies, CCVD, renal, liver, pneumonia,
sepsis)/death and all cause mortality
Survival analysis with T0 2 years from the date of VL suppression
comparing the risk of sNAE/death in the two populations.
Incidence of CD4 exploders and
CD4 peak achievers by years
CD4 e n=879/7259 (12%)
By 2 years
CD4 a n=747/7259 (10.2%)
By 2 years
Total population Characteristics
N= 7259
Gender, n(%)
Female
1705 (23.5%)
AIDS diagnosis, n(%)
Yes
468 (6.4%)
Median (IQR)
37 (32, 43)
Age, years
HCV
positivity
867 (11.9%)
Risk factors
Eterosexual
2925 (40.3)
IDU
1149 (15.9%)
1,35
1,06
0,77
0,2
1,04
0.00
Time since HIV diagnosis
<0.001
CD4 nadir
0,015
cART with PI
0, 065
AIDS
1,11
CMVIgG+ vs. CMVIgG-
0,038
HCVAb+ vs. HCV Ab-
1,07
Hetero vs. MSM
0,8
Hetero vs. IVDU
p<0,001
Female vs. male
Age, +10 year
AHR 95%IC
Adjusted Hazard ratio
of being a CD4 exploder (Cox regression)
5
0,074
1,48
1,22
1
0,2
<0.001
1
<0,001
Time since HIV diagnosis
0,8
CD4 nadir
0, 066
cART with PI
1,03
AIDS
0,75
0,87
CMVIgG+ vs. CMVIgG-
0,006
HCVAb+ vs. HCV Ab-
1,12
Hetero vs. MSM
0,8
Hetero vs. IVDU
p<0,001
Female vs. male
Age, +10 year
AHR 95%IC
Adjusted Hazard ratio
of being a CD4 peak achiever
(Cox regression)
5
0,021
1,35
1,34
1,33
1,25
1,02
Adjusted Hazard ratio of being a
CD4 peak achiever AND a CD4 exploder
=HIV people who gained more than
600 and achieved 1000 or more CD4
• Higher CD4 nadir
•
Female gender
• cART with PI
• Younger age
• HCV (AHR:0.65, p=0.018)
PROSPECTIVE ANALISYS
Prospective analysis
Study populations:
CD4 e n = 338/3935
CD4 a n = 303/3935
CD4 e + CD4a n= 187
Events during 5 years:
176 SNAE
42 death
Type of SNAE and death includes
both composite endpoints
Survival analysis
End point: SNA event and all cause death
log rank p=0.030
CD4 exploders
log rank p=0.09
CD4 peak achievers
1,63
1,36
1,16
0,98
0,2
0,059 0,945
0,98
Time from cART initiation to
baseline
0,53
CD4 peak achiever
0,16
CD4 exploder
0,015
cART with PI
0, 029
AIDS
1
CMVIgG+ vs. CMVIgG-
p<0,001
HCVAb+ vs. HCV Ab-
CD4 nadir
1,62
Female vs. male
Age, +10 year
AHR 95%IC
Hazard Ratio of composite SNA or all cause
mortality (95% CI) p-value
5
0,024
0,97
1,09
Conclusions 1
• A high CD4 recovery after 2 years effective cART , have been observed
in 12% and 10%, but the cumulative incidence continue to increase
over 10 years of FU without a “plateau effect”
• Female gender and young age augment the risk to obtain a CD4
expansion and, or a CD4 peak (>1000) underling the importance to
consider gender and age in approaching HIV subjects
• Interestingly AIDS at presentation doesn’t seem to be an obstacle for
achieving CD4 peak, but could increase the possibility to have a high
delta suggesting a “survival selection bias” or a specific enhance of
immunity during OI
• Considering coinfections, only HCV seems to decrease the chance to
obtain the two endpoints, even if with a marginal p value and HCV-RNA
has not been considered
• PI based therapy seems to be associated to about 40% higher
possibility to obtain the two endpoints confirming data that has been
observed in clinical practice but not always in case control study
Conclusions 2
• Regarding the clinical impact, CD4 expanders seem to have a significant lower
risk for SNAE/all cause death, while achieving CD4 peak seems to play a minor
role.
• Adjusting for other known confounders, CD4 expansion was associated with
50% decreased risk of SNAE/all cause death, while older age, HCV positivity
and a longer time of cART initiation to virological suppression increase the risk.
• These results suggest that not only a “standard” immune recovery should be
induced by cART, but high expansion of CD4 is needed to reduce morbidity
and mortality in HIV population.
• To increase the proportion of CD4 exploders that is about 10%-30% special
strategy should be used. Initial use of PI seems to be important, together with a
rapid suppression of HIV replication and other immune intervention (IL-2, IL-7)
Further analysis
• A better characterization of the cause of death should be done in
order to understand the role of CD4 expansion and peak achievement
on the different pathology such us cerebro-cardiovascular disease
and cancer
• A more precise distinction of the two populations to better
understand the role of peak achievers
• To assess the degree of residual T and monocyte immune
activation in CD4 e and CD4a (biological studies)
• To evaluate the plasma level of IL7, IL7RA polymorphisms and
apoptotic factors in the two populations (biological studies)
• To study the role of the new INI-based therapy in determining CD4e
and CD4a
• To evaluate the impact of HCV eradication for the different endpoint.
Authors
Giulia Marchetti1, Alessandro Cozzi Lepri3, Serena Vita4, Annalisa
Saracino5, Andrea Gori6, Cristina Mussini7, Giordano
Madeddu8, Antonella d'Arminio Monforte1 for the ICONA Foundation
Study
1Clinic
of Infectious Dis, University of Milan, San Paolo Hospital, Milano, 2University of Rome
Sapienza, Polo Pontino, Latina, 3UCL Medical School, Royal Free Campus, London, 4University
of Rome Sapienza, Roma, 5University of Bari, Bari,6University of Milano-Bicocca, Milano,
7University of Modena and Reggio Emilia, Modena, 8University of Sassari, Sassari
ICONA FOUNDATION STUDY COHORT
BOARD OF DIRECTORS
A d’Arminio Monforte (Vice-President), M Andreoni, G Angarano, A Antinori, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino,
G Ippolito, A Lazzarin, CF Perno, F von Schloesser, P Viale
SCIENTIFIC SECRETARY
A d’Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C Mussini, M
Puoti
STEERING COMMITTEE
M Andreoni, A Ammassari, A Antinori, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, L Calza, MR
Capobianchi, A Castagna, F Ceccherini-Silberstein, A Cingolani, P Cinque, A Cozzi-Lepri, A d’Arminio Monforte, A De Luca, A Di
Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, S
Marcotullio, L Monno, C Mussini, S Nozza, M Puoti, E Quiros Roldan, R Rossotti, S Rusconi, MM Santoro, A Saracino, M
Zaccarelli.
STATISTICAL AND MONITORING TEAM
A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, A Tavelli
BIOLOGICAL BANK INMI
F. Carletti, S. Carrara, A Castrogiovanni, A. Di Caro, F. Petrone, G. Prota, S Quartu, S. Truffa.
PARTICIPATING PHYSICIANS AND CENTERS
Italy A Giacometti, A Costantini, C Valeriani (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi
(Bergamo); P Viale, E Vanino, G Verucchi (Bologna); F Castelli, E Quiros Roldan, C Minardi (Brescia); T Quirino, C Abeli (Busto
Arsizio); PE Manconi, P Piano (Cagliari); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca (Chieti); L Sighinolfi, D Segala
(Ferrara); F Mazzotta, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); C Mastroianni,
V Belvisi (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, AP Castelli (Macerata); M Galli, A Lazzarin, G Rizzardini, M Puoti,
A d’Arminio Monforte, AL Ridolfo, R Piolini, A Castagna, S Salpietro, L Carenzi, MC Moioli, C Tincati, G Marchetti (Milano); C
Mussini, C Puzzolante (Modena); A Gori, G Lapadula (Monza); N Abrescia, A Chirianni, G Borgia, F Di Martino, L Maddaloni, I
Gentile, R Orlando (Napoli); F Baldelli, D Francisci (Perugia); G Parruti, T Ursini (Pescara); G Magnani, MA Ursitti (Reggio
Emilia); R Cauda, M Andreoni, A Antinori, V Vullo, A Cristaudo, A Cingolani, G Baldin, S Cicalini, L Gallo, E Nicastri, R Acinapura,
M Capozzi, R Libertone, S Savinelli, A Latini (Roma); M Cecchetto, F Viviani (Rovigo); MS Mura, G Madeddu (Sassari); A De
Luca, B Rossetti (Siena); P Caramello, G Di Perri, GC Orofino, S Bonora, M Sciandra (Torino); M Bassetti, A Londero (Udine); G
Pellizzer, V Manfrin (Vicenza).