Transcript A PROSPECTIVE, MULTICENTER, RANDOMIZED TRIAL …

Immune Discordance on Highly Active Antiretroviral Therapy Can Still be Regarded as a Therapeutic Success
1
1
1
1
1
Nur F. Önen MD, MRCP , Rachel Presti MD PhD , E. Turner Overton MD , Cecilia Blair and Kristin Mondy MD .
1
Washington University School of Medicine, St. Louis, Missouri, USA .
ABSTRACT
RESULTS
Background
Risk factors for immune discordance on highly active antiretroviral therapy (HAART), and long-term
clinical and immunologic outcomes remain poorly characterized.
Methods
Retrospective analysis of 298 HIV+ patients with baseline CD4+ T cell count <350 cells/mm3, who
initiated HAART between January 1996 and July 2006 and had viral suppression (HIV RNA <400
copies/mL pre-1999, <50 copies/mL thereafter) for ≥ 52 weeks. Discordant and concordant immune
responders were defined by CD4+ T cell gains of <150 or ≥ 150 cells/mm3 from HAART initiation
through 52 weeks of viral suppression. Risk factors for poor CD4+ T cell gains were analyzed by
multiple regression and long-term clinical outcome assessed. Additionally, markers of immune
maturation and activation were prospectively determined for immune discordant and concordant
responders (total n=45) with sustained viral suppression from the entire cohort.
Results
106 (36%) patients had immune discordance. In multivariable analyses, male gender, greater
number of HAART side-effects, use ever of unboosted indinavir and lower pre-HAART HIV-RNA
viral load were independent predictors of immune discordance (p<0.05). Outcomes were similar
between groups with regard to mean time on suppressive HAART (4.5 years), new opportunistic
infections (1%) and mortality (5%). Higher levels of memory (p=0.04) and activated (p=0.08) CD4+
T cells were found among those with immune discordance, up to a mean of 6.3 years after viral
suppression.
Conclusions
HIV+ patients with long-term immune discordance can still achieve very low morbidity and mortality,
suggesting immune benefits of HAART may go beyond gains in CD4+ T cells alone. In addition, Tcell activation may blunt long-term CD4+ T cell gains. Interventions to reduce T cell activation may
facilitate further CD4+ T cell recovery in this patient group.
Table 1. Characteristics of immune discordant vs. concordant responders.
Characteristics
RESULTS
Discordant
Concordant
(n=106)
(n=192)
OR (95% CI)
P value
Data at the time of FACS
analysis (mean ± S.E.M.)
600
Discordant
500
Male gender
89 (84%)
134 (70%)
2.27(1.24-4.15)
0.01
Age, (years)a
41.2 ± 0.9
38.2 ± 0.7
-
0.01
Caucasian
58 (55%)
75 (39%)
1.88(1.80-3.05)
0.01
African American
38 (36%)
108 (56%)
-
Concordant
-
Mode of transmission
Men who have sex with men
56 (53%)
79 (41%)
1.78(1.08-2.93)
0.02
Heterosexual
30 (28%)
96 (50%)
-
-
Years since HIV diagnosisa
9.8 ± 0.5
8.3 ± 0.3
-
0.01
Previous OI
60 (57%)
104 (54%)
1.11(0.69-1.78)
0.72
Prior ARV experience
34 (32%)
62 (32%)
1.01(0.61-1.68)
1.00
CD4+ T cell nadir
b
Table 3. Comparison of activation and memory T-cells between discordant vs.
concordant immune responders.
Figure 1. Absolute CD4 + T cell counts after HAART initiation.
CD4+ (cells/mm)
Abstract # 952
400
300
200
100
0
Baseline
VS
6
12
18
24
Months after HAART initiation
85 (21-180)
54(12-189)
-
0.43
4.90 ± 0.06
5.11 ± 0.07
-
0.05
Highest HIV RNA viral loada
Table 2. Clinical outcomes during long-term follow up.
BACKGROUND
•
•
Recent studies suggest that markers of immune maturation and activation may predict CD4+
T cell recovery in patients on suppressive HAART.
•
Chronic Hepatitis C
17 (11%)
16 (8%)
1.97(0.96-4.04)
0.09
Chronic Hepatitis B
9 (6%)
21 (11%)
0.72(0.32-1.62)
0.55
The long-term outcomes of immune discordance on HAART in terms of overall morbidity and
mortality remains poorly studied.
METHODS
Retrospective cohort study of patients initiated on HAART between January 1996 and July 2006.
Inclusion criteria
HIV-1 infection, age ≥ 18 years, baseline CD4+ T cells <350 cells/mm3 and viral suppression for ≥
52 weeks.
Definitions
Discordant and concordant responders defined by CD4+ T cell gains of <150 or ≥ 150 cells/mm3
from HAART initiation through 52 weeks of viral suppression and followed to death, virologic failure
(lack of re-suppression of viremia) or study termination.
Data collection
Socio-demographics, clinical, medication and laboratory data.
Sample collection and analysis
Blood samples from immune discordant and concordant responders (total n=45) with sustained
viral suppression, were obtained to determine the percentage of CD4+ and CD8+ T lymphocytes
that were memory (CD45RO+) or activated (CD38+,HLADR+), using three-color flow-cytometric
analysis on cryopreserved peripheral mononuclear cells.
Statistics
Data analyzed using SPSS version 14.0. Continuous variables compared using the Student’s t-test
or Mann-Whitney U test. Chi square or Fisher’s exact tests used for categorical variables.
All p values were two-tailed and significant at <0.05 and potential predictive factors for immune
discordance were evaluated using multivariate logistic regression analyses.
CD4+ T cell count b
HIV RNA level
Clinical Outcomes
126 (37-231)
88 (19-222)
-
0.15
HAARTa
4.68 ± 0.86
4.81 ± 0.06
-
0.19
Highest CD4+ T cell count
a
Discordant (106)
Concordant (192)
OR (95% CI)
P value
4.56 ± 0.2
4.51 ± 0.2
-
0.88
NNRTI/ ≥ 2 NRTI
45 (42%)
92 (48%)
0.86(0.52-1.42)
0.61
All PI/ ≥ 2 NRTI
58 (55%)
87 (45%)
-
-
Unboosted indinavir
27 (26%)
24 (13%)
0.52(0.24-1.13)
0.01
No. (%) with HAART-related
36 (34%)
35 (18%)
1.80(1.09-2.96)
392 (256-566)
682 (479-879)
-
<0.001
12 (6-23)
16 (8-28)
-
0.04
48.7 ± 2.5
17 (85%)
3 (15%)
15 (75%)
5 (25%)
48.7 ± 1.9
19 (76%)
6 (24%)
10 (40%)
15 (60%)
0.86
0.71
CD4+ T cell count (cells/mm3)
% <200 cells/mm3
% 201-349 cells/mm3
% ≥ 350 cells/mm3
306 ± 30
20
50
30
683 ± 49
0
0
100
<0.001
Years of viral suppression
5.6 ± 0.5
7.0 ± 0.4
0.03
CD4+ T cellsa
CD45RO+
Naïve:memory
CD38+HLADR+
55.0 ± 3.6
1.1 ± 0.3
2.9 ± 0.4
45.1 ± 3.1
1.7 ± 0.3
2.0 ± 0.2
0.04
0.04
0.08
CD8+ T cellsa
CD45RO+
Naïve:memory
CD38+HLADR+
20.5 ± 2.7
5.2 ± 0.6
1.0 ± 0.2
17.6 ± 1.8
6.4 ± 0.8
1.1 ± 0.1
0.47
0.47
0.38
0.03
• In patients with viral suppression for a mean of 6.3 years, discordant
responders had significantly higher levels of memory CD4+ T cells (CD45RO+)
• Levels of activated CD4+ T cells (CD38+HLADR+) were higher among those
• Levels of memory and activated CD8+ T cells were similar between groups.
Death
5 (5%)
9 (5%)
1.00(0.33-3.09)
Remains in clinical care
75 (71%)
150 (78%)
-
Lost to follow up
26 (25%)
33 (17%)
-
1
1
-
-
Type of opportunistic illness
NHL
Kaposi’s sarcoma
-
-
Years after viral suppression
2 and 5
8
-
-
New opportunistic illness
Weeks to viral suppression b
Age
Gender: Male
Female
Race: Caucasian/Hispanic
African American
with immune discordance, although this did not reach statistical significance.
1.00
CONCLUSION
<0.001
side-effects
P value
with a reduced naïve:memory CD4+ ratio (p<0.05 for all).
attainedb
HAART regimen type
Concordant
(n=25)
Percentage of total events. CD38+HLADR+ = marker of activation, CD45RO+ = marker of memory cell.
Years of viral suppression on
At suppressive HAART initiation
Discordant
(n=20)
a
Suboptimal immune reconstitution on fully suppressive highly active antiretroviral therapy
(HAART) is frequently observed in clinical trials and cohort studies.
Contact:
Nur F. Önen.
Washington Univ. School of Med.
Campus Box 8051, 660 S. Euclid Ave.
St. Louis, MO 63110
Phone: 314-747-1725
Fax: 314-361-5231
Email: [email protected]
• In this cohort with long-term viral suppression, immune discordance was
high but morbidity and mortality remained very low.
• Our findings suggest immune benefits of HAART may go beyond CD4+ T
cell gains.
One year CD4+ T cell gain b
99 (50-133)
269 (211-374)
-
<0.001
Mean ±standard error of mean, bmedian (interquartile range), ARV = antiretroviral, NNRTI = non-nucleoside reverse transcriptase inhibitor,
NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor.
• T cell-activation may blunt long-term CD4+ T cell gains and interventions
OI prophylaxis
at 1 yr viral suppression
61 (58%)
73 (38%)
2.21(1.36-3.58)
<0.001
to reduce T-cell activation may facilitate further CD4+ T cell recovery in
at highest CD4+ T cell count
37 (35%)
30 (16%)
2.90(1.66-5.01)
<0.001
patients with sub-optimal immune reconstitution.
a
• Low pre-HAART viral load was associated with immune discordance and
Independent factors associated with immune discordance on multivariable analyses:
Recurrent genital warts
5 (5%)
1 (1%)
9.46(1.09-82.0)
0.02
• Male gender.
Recurrent shingles
10 (9%)
7 (4%)
2.75(1.02-7.46)
0.06
• Lower pre-HAART HIV-RNA viral load.
Recurrent genital herpes
0
6 (3%)
1.57(1.44-1.71)
0.09
may have implications for the use of viral load in future treatment
guidelines.
• Any use of unboosted indinavir.
• Greater number of HAART-related side effects per person.
We would like to acknowledge Bristol-Myers Squibb for the Virology Fellows
Mean ± standard error of mean, bMedian and interquartile range. NHL = non-Hodgkin’s lymphoma, OI = opportunistic infection.
a
Research Grant which enabled this study to be done.