Background

1. 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: nonen@im.wustl.edu Immune Discordance on Highly Active Antiretroviral Therapy Can Still be Regarded as a Therapeutic SuccessNur F. Önen MD, MRCP1 , Rachel Presti MD PhD1, E. Turner Overton MD1 , Cecilia Blair1 and Kristin Mondy MD1.Washington University School of Medicine, St. Louis, Missouri, USA1. Abstract # 952 ABSTRACT RESULTS 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, T-cell 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. Figure 1. Absolute CD4 + T cell counts after HAART initiation. Table 3. Comparison of activation and memory T-cells between discordant vs. concordant immune responders. Table 2. Clinical outcomes during long-term follow up. BACKGROUND aPercentage of total events. CD38+HLADR+ = marker of activation, CD45RO+ = marker of memory cell. • In patients with viral suppression for a mean of 6.3 years, discordant responders had significantly higher levels of memory CD4+ T cells (CD45RO+) with a reduced naïve:memory CD4+ ratio (p<0.05 for all). • Levels of activated CD4+ T cells (CD38+HLADR+) were higher among those with immune discordance, although this did not reach statistical significance. • Levels of memory and activated CD8+ T cells were similar between groups. • Suboptimal immune reconstitution on fully suppressive highly active antiretroviral therapy (HAART) is frequently observed in clinical trials and cohort studies. • Recent studies suggest that markers of immune maturation and activation may predict CD4+ T cell recovery in patients on suppressive HAART. • The long-term outcomes of immune discordance on HAART in terms of overall morbidity and mortality remains poorly studied. METHODS CONCLUSION 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. • 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. • T cell-activation may blunt long-term CD4+ T cell gains and interventions to reduce T-cell activation may facilitate further CD4+ T cell recovery in patients with sub-optimal immune reconstitution. • Low pre-HAART viral load was associated with immune discordance and may have implications for the use of viral load in future treatment guidelines. aMean ±standard error of mean, bmedian (interquartile range), ARV = antiretroviral, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor. • Independent factors associated with immune discordance on multivariable analyses: • Male gender. • Lower pre-HAART HIV-RNA viral load. • 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 Research Grant which enabled this study to be done. aMean ± standard error of mean, bMedian and interquartile range. NHL = non-Hodgkin’s lymphoma, OI = opportunistic infection.