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A PROSPECTIVE MULTICENTER RANDOMIZED TRIAL COMPARING THE

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A PROSPECTIVE MULTICENTER RANDOMIZED TRIAL COMPARING THE Powered By Docstoc
					                                                              Immune Discordance on Highly Active Antiretroviral Therapy Can Still be Regarded as a Therapeutic Success                                                                                                                                                                                                                                                                                                    Contact:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Nur F. Önen.
                                                                                                                                                                                                                                                                                                                                                                                                                                                   Washington Univ. School of Med.
                                                                                                                                          1                                                                     1                                                                      1                                   1                                                           1                                                        Campus Box 8051, 660 S. Euclid Ave.
                                                                                 Nur F. Önen MD, MRCP , Rachel Presti MD PhD , E. Turner Overton MD , Cecilia Blair and Kristin Mondy MD .                                                                                                                                                                                                                                                                     St. Louis, MO 63110
                                                                                                                                                                                                                                                                                                                                                                                                                                                              Phone: 314-747-1725
                                                                                                                                                                       1                                                                                                                                                                                                                                                                                         Fax: 314-361-5231
                                                                                                     Washington University School of Medicine, St. Louis, Missouri, USA .                                                                                                                                                                                                                                                                              Email: nonen@im.wustl.edu
Abstract # 952

                                          ABSTRACT                                                                                                                 RESULTS                                                                                                                                                                                   RESULTS
                                                                                                                                                                                                                                                                                                                                                                                   Table 3. Comparison of activation and memory T-cells between discordant vs.
Background                                                                                                                   Table 1. Characteristics of immune discordant vs. concordant responders.                                                                                Figure 1. Absolute CD4 + T cell counts after HAART initiation.
                                                                                                                                                                                                                                                                                                                                                                                   concordant immune responders.
Risk factors for immune discordance on highly active antiretroviral therapy (HAART), and long-term
clinical and immunologic outcomes remain poorly characterized.                                         Characteristics                                    Discordant                 Concordant                 OR (95% CI)             P value                                                                                                                                    Data at the time of FACS                  Discordant              Concordant           P value
                                                                                                                                                                                                                                                                           600                                                                                                     analysis (mean ± S.E.M.)                    (n=20)                  (n=25)
Methods                                                                                                                                                     (n=106)                     (n=192)
Retrospective analysis of 298 HIV+ patients with baseline CD4+ T cell count <350 cells/mm3, who                                                                                                                                                                                                                                                                                    Age                                        48.7 ± 2.5              48.7 ± 1.9            0.86
                                                                                                                                                                                                                                                                                            Discordant
initiated HAART between January 1996 and July 2006 and had viral suppression (HIV RNA <400                                                                                                                                                                                 500                                                                                                     Gender: Male                               17 (85%)                19 (76%)              0.71
copies/mL pre-1999, <50 copies/mL thereafter) for ≥ 52 weeks. Discordant and concordant immune         Male gender                                         89 (84%)                   134 (70%)                2.27(1.24-4.15)            0.01                                              Concordant                                                                                     Female                              3 (15%)                 6 (24%)
responders were defined by CD4+ T cell gains of <150 or ≥ 150 cells/mm3 from HAART initiation




                                                                                                                                                                                                                                                         CD4+ (cells/mm)
through 52 weeks of viral suppression. Risk factors for poor CD4+ T cell gains were analyzed by        Age, (years)a                                       41.2 ± 0.9                 38.2 ± 0.7                       -                  0.01                                                                                                                                     Race: Caucasian/Hispanic                   15 (75%)                10 (40%)              0.03
                                                                                                                                                                                                                                                                           400
multiple regression and long-term clinical outcome assessed. Additionally, markers of immune                                                                                                                                                                                                                                                                                               African American                    5 (25%)                15 (60%)
                                                                                                       Caucasian                                           58 (55%)                    75 (39%)                1.88(1.80-3.05)            0.01
maturation and activation were prospectively determined for immune discordant and concordant                                                                                                                                                                                                                                                                                       CD4+ T cell count (cells/mm3)               306 ± 30                683 ± 49           <0.001
responders (total n=45) with sustained viral suppression from the entire cohort.                       African American                                    38 (36%)                   108 (56%)                        -                    -                              300                                                                                                     % <200 cells/mm3                               20                      0
Results                                                                                                                                                                                                                                                                                                                                                                            % 201-349 cells/mm3                            50                      0
106 (36%) patients had immune discordance. In multivariable analyses, male gender, greater             Mode of transmission                                                                                                                                                                                                                                                        % ≥ 350 cells/mm3                              30                     100
number of HAART side-effects, use ever of unboosted indinavir and lower pre-HAART HIV-RNA
                                                                                                                                                                                                                                                                           200
                                                                                                       Men who have sex with men                           56 (53%)                    79 (41%)                1.78(1.08-2.93)            0.02
viral load were independent predictors of immune discordance (p<0.05). Outcomes were similar                                                                                                                                                                                                                                                                                       Years of viral suppression                  5.6 ± 0.5               7.0 ± 0.4            0.03
between groups with regard to mean time on suppressive HAART (4.5 years), new opportunistic            Heterosexual                                        30 (28%)                    96 (50%)                        -                    -
                                                                                                                                                                                                                                                                           100                                                                                                     CD4+ T cellsa
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          Years since HIV diagnosisa                          9.8 ± 0.5                   8.3 ± 0.3                       -                  0.01                                                                                                                                     CD45RO+                                    55.0 ± 3.6              45.1 ± 3.1            0.04
suppression.                                                                                                                                                                                                                                                                 0                                                                                                     Naïve:memory                                1.1 ± 0.3               1.7 ± 0.3            0.04
                                                                                                       Previous OI                                         60 (57%)                   104 (54%)                1.11(0.69-1.78)            0.72
Conclusions                                                                                                                                                                                                                                                                                                                                                                        CD38+HLADR+                                 2.9 ± 0.4               2.0 ± 0.2            0.08
HIV+ patients with long-term immune discordance can still achieve very low morbidity and mortality,    Prior ARV experience                                34 (32%)                    62 (32%)                1.01(0.61-1.68)            1.00                                   Baseline           VS                 6            12            18                24
suggesting immune benefits of HAART may go beyond gains in CD4+ T cells alone. In addition, T-                                                                                                                                                                                                                                                                                     CD8+ T cellsa
cell activation may blunt long-term CD4+ T cell gains. Interventions to reduce T cell activation may                         b
                                                                                                                                                                                                                                                                                                             Months after HAART initiation                                         CD45RO+                                    20.5 ± 2.7              17.6 ± 1.8            0.47
                                                                                                       CD4+ T cell nadir                                  85 (21-180)                 54(12-189)                       -                  0.43
facilitate further CD4+ T cell recovery in this patient group.                                                                                                                                                                                                                                                                                                                     Naïve:memory                                5.2 ± 0.6               6.4 ± 0.8            0.47
                                                                                                       Highest HIV RNA viral loada                        4.90 ± 0.06                 5.11 ± 0.07                      -                  0.05                                                                                                                                     CD38+HLADR+                                 1.0 ± 0.2               1.1 ± 0.1            0.38
                                                                                                                                                                                                                                                                                           Table 2. Clinical outcomes during long-term follow up.
                                       BACKGROUND                                                      Chronic Hepatitis C                                 17 (11%)                     16 (8%)                1.97(0.96-4.04)            0.09                                                                                                                                     a
                                                                                                                                                                                                                                                                                                                                                                                   Percentage of total events. CD38+HLADR+ = marker of activation, CD45RO+ = marker of memory cell.

                                                                                                       Chronic Hepatitis B                                   9 (6%)                    21 (11%)                0.72(0.32-1.62)            0.55       Clinical Outcomes                               Discordant (106)      Concordant (192)     OR (95% CI)          P value
 •    Suboptimal immune reconstitution on fully suppressive highly active antiretroviral therapy                                                                                                                                                                                                                                                                                       • In patients with viral suppression for a mean of 6.3 years, discordant
                                                                                                       At suppressive HAART initiation                                                                                                               Years of viral suppression on                        4.56 ± 0.2           4.51 ± 0.2              -               0.88                responders had significantly higher levels of memory CD4+ T cells (CD45RO+)
      (HAART) is frequently observed in clinical trials and cohort studies.
                                                                                                       CD4+ T cell count b                               126 (37-231)                88 (19-222)                       -                  0.15       HAARTa                                                                                                                                with a reduced naïve:memory CD4+ ratio (p<0.05 for all).
 •    Recent studies suggest that markers of immune maturation and activation may predict CD4+
                                                                                                                         a
                                                                                                       HIV RNA level                                      4.68 ± 0.86                 4.81 ± 0.06                      -                  0.19       Highest CD4+ T cell count                           392 (256-566)       682 (479-879)             -             <0.001            • Levels of activated CD4+ T cells (CD38+HLADR+) were higher among those
      T cell recovery in patients on suppressive HAART.
                                                                                                       HAART regimen type                                                                                                                            attainedb                                                                                                                             with immune discordance, although this did not reach statistical significance.
 •    The long-term outcomes of immune discordance on HAART in terms of overall morbidity and
                                                                                                       NNRTI/ ≥ 2 NRTI                                     45 (42%)                    92 (48%)                0.86(0.52-1.42)            0.61                                                                                                                                         • Levels of memory and activated CD8+ T cells were similar between groups.
      mortality remains poorly studied.
                                                                                                       All PI/ ≥ 2 NRTI                                    58 (55%)                    87 (45%)                        -                    -        Death                                                  5 (5%)              9 (5%)         1.00(0.33-3.09)         1.00
                                                                                                                                                                                                                                                     Remains in clinical care                              75 (71%)            150 (78%)               -
                                          METHODS                                                      Unboosted indinavir                                 27 (26%)                    24 (13%)                0.52(0.24-1.13)            0.01
                                                                                                                                                                                                                                                     Lost to follow up                                     26 (25%)            33 (17%)                -                                                              CONCLUSION
Retrospective cohort study of patients initiated on HAART between January 1996 and July 2006.          No. (%) with HAART-related                          36 (34%)                    35 (18%)                1.80(1.09-2.96)         <0.001
Inclusion criteria                                                                                                                                                                                                                                   New opportunistic illness                                1                    1                   -                 -             • In this cohort with long-term viral suppression, immune discordance was
                                                                                                       side-effects
HIV-1 infection, age ≥ 18 years, baseline CD4+ T cells <350 cells/mm3 and viral suppression for ≥
                                                                                                                                                                                                                                                     Type of opportunistic illness                           NHL           Kaposi’s sarcoma            -                 -                 high but morbidity and mortality remained very low.
52 weeks.
                                                                                                       Weeks to viral suppression b                        12 (6-23)                   16 (8-28)                       -                  0.04                                                                                                                                         • Our findings suggest immune benefits of HAART may go beyond CD4+ T
Definitions                                                                                                                                                                                                                                          Years after viral suppression                         2 and 5                 8                   -                 -
Discordant and concordant responders defined by CD4+ T cell gains of <150 or ≥ 150 cells/mm3                                                                                                                                                                                                                                                                                               cell gains.
from HAART initiation through 52 weeks of viral suppression and followed to death, virologic failure   One year CD4+ T cell gain b                        99 (50-133)               269 (211-374)                      -                 <0.001
                                                                                                                                                                                                                                                     OI prophylaxis                                                                                                                    • T cell-activation may blunt long-term CD4+ T cell gains and interventions
(lack of re-suppression of viremia) or study termination.
Data collection                                                                                                                                                                                                                                      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
Socio-demographics, clinical, medication and laboratory data.
                                                                                                       a
                                                                                                        Mean ±standard error of mean, bmedian (interquartile range), ARV = antiretroviral, NNRTI = non-nucleoside reverse transcriptase inhibitor,
                                                                                                       NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor.                                                                   at highest CD4+ T cell count                          37 (35%)            30 (16%)        2.90(1.66-5.01)       <0.001                patients with sub-optimal immune reconstitution.
Sample collection and analysis
                                                                                                                                                                                                                                                                                                                                                                                       • Low pre-HAART viral load was associated with immune discordance and
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                  Independent factors associated with immune discordance on multivariable analyses:                                                                                                                                                                                             may have implications for the use of viral load in future treatment
                                                                                                                                                                                                                                                     Recurrent genital warts                                5 (5%)              1 (1%)         9.46(1.09-82.0)         0.02
that were memory (CD45RO+) or activated (CD38+,HLADR+), using three-color flow-cytometric                                                                                                                                                                                                                                                                                                  guidelines.
                                                                                                           • Male gender.                                                                                                                            Recurrent shingles                                    10 (9%)              7 (4%)         2.75(1.02-7.46)         0.06
analysis on cryopreserved peripheral mononuclear cells.
Statistics                                                                                                 • Lower pre-HAART HIV-RNA viral load.                                                                                                     Recurrent genital herpes                                 0                 6 (3%)         1.57(1.44-1.71)         0.09
Data analyzed using SPSS version 14.0. Continuous variables compared using the Student’s t-test            • Any use of unboosted indinavir.
or Mann-Whitney U test. Chi square or Fisher’s exact tests used for categorical variables.
                                                                                                           • Greater number of HAART-related side effects per person.                                                                                                                                                                                                              We would like to acknowledge Bristol-Myers Squibb for the Virology Fellows
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.                                                                                                                                                                          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.

				
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