1 / 24

Antiretroviral-Treated Patients Exhibiting a Suboptimal CD4+ T Cell Response

Antiretroviral-Treated Patients Exhibiting a Suboptimal CD4+ T Cell Response. H Hatano 1 , TL Hayes 2 , N Sandler 3 , PW Hunt 1 , E Sinclair 1 , D Douek 3 , BL Shacklett 2 , SG Deeks 1 1 University of California, San Francisco, CA, USA 2 University of California, Davis, CA, USA

fisseha
Télécharger la présentation

Antiretroviral-Treated Patients Exhibiting a Suboptimal CD4+ T Cell Response

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Antiretroviral-Treated Patients Exhibiting a Suboptimal CD4+ T Cell Response H Hatano1, TL Hayes2, N Sandler3, PW Hunt1, E Sinclair1, D Douek3, BL Shacklett2, SG Deeks1 1University of California, San Francisco, CA, USA 2University of California, Davis, CA, USA 3National Institutes of Health, Bethesda, MD, USA

  2. Delay in HAART Initiation:CD4 count at HAART Initiation, 2003–05 Egger M, CROI ‘07

  3. Delay in ARV Initiation Has Significant Consequences • Early HAART improves mortality(Severe, NEJM ‘10) • An important consequence of a delay in ARV initiation may be immunologic non-response • 25% of patients who start HAART at CD4<200 are unable to achieve CD4>500even after more than 7 years of HAART (Kelley, CID ’09) • Despite viral suppression with HAART, CD4<350 associated with increased AIDS-related and non-AIDS related morbidity(El-Sadr, NEJM ’06; Baker, AIDS ‘08)

  4. Clinical Factors Associated with Immunologic Non-Response • Older age • Male gender • Lower CD4 nadir • Chronic HCV Hunt, AIDS ’03; Lederman, CROI ’10; Greub, Lancet ’00

  5. Potential Mechanisms of Immunologic Non-Response Volberding and Deeks, Lancet 2010

  6. Potential Mechanisms of Immunologic Non-Response Volberding and Deeks, Lancet 2010

  7. Need for Further Study Regarding Mechanisms of Suboptimal CD4+ Gains Volberding and Deeks, Lancet 2010

  8. Study Objectives • To compare virologic and immunologic measurements in immunologic responders and non-responders • To examine the biologic predictors of suboptimal CD4+ gains among immunologic non-responders

  9. Study Design I • Immunologic responders (n=233) • CD4  350 x1yr despite VL < 40 x1yr • Non-responders (n=104) • CD4 < 350 x1yr despite VL < 40 x1yr

  10. Immunologic Non-Responders Have Higher Levels of Plasma HIV RNA Non-Responders: 3.4 copies/mL Responders: 0 copies/mL p = 0.09

  11. Immunologic Non-Responders Have Higher Levels of CD4+ T Cell Activation p = 0.38 p < 0.0001 Non-Responders: 24% Non-Responders: 8% Responders: 21% Responders: 5%

  12. Immunologic Non-Responders Have Lower Frequencies of Naïve CD8+ T Cells Non-Responders: 14% Responders: 25% p = 0.0003

  13. Study Design II • Cross-sectional study focusing on immunologic non-responders (n=30) • CD4 < 350 for  1 year, despite VL < 40 copies/mL on HAART for  1 year • Gut-associated lymphoid tissue (GALT) samples were obtained from 21/30 subjects

  14. Study Measurements • Immune activation (blood and GALT) • % CD38+HLA-DR+ CD8+ T cells • HIV-specific T cell responses (blood and GALT) • % gag-specific IFNg+IL2+ CD8+ T cells • Microbial translocation • Plasma LPS

  15. Baseline Characteristics

  16. PBO RGV In this cohort, addition of raltegravir to a stable HAART regimen did not alter steady-state level of HIV persistence or host responses p = 0.33 Hatano, CROI ‘10

  17. Higher Levels of PD1 Expressing Activated CD8+ T Cells Are Associated with Lower CD4+ T Cell Counts rho = - 0.47, p = 0.009

  18. Higher Levels of CD8+ T Cell Activation Are Associated with Higher Levels of LPS rho = 0.45, p = 0.06

  19. Higher Levels of GALT CD8+ T Cell Activation Are Associated with Lower Nadir CD4+ T Cell Counts rho = - 0.50, p = 0.04

  20. Higher Levels of HIV-specific T Cells are Associated with Higher CD4+ T Cell Counts CD8 CD4 rho = 0.44, p = 0.06 rho = 0.46, p = 0.05

  21. Summary • In this cohort of immunologic non-responders, we observed: • Strong negative correlation between CD4+ T cell count and immune activation • Positive association between LPS and immune activation • Negative association between nadir CD4+ T cell count and GALT immune activation • Positive association between HIV-specific responses and absolute CD4+ T cell count

  22. Slide #22 Limitations: Biology associated with low CD4+ T cells on early HAART (most of whom will eventually reconstitute an effective immune system) may prove to be different than long-term immunologic non-responders Kelley CF, CID ‘09

  23. Conclusions • An important consequence of a delay in ARV initiation may be immunologic non-response • Initiating treatment later may lead to: • Larger viral reservoir, most of which resides in gut(Anton, AIDS ’03; Chun, JID ’08; Chomont, Nat Med ’09; Yukl, CROI ‘10) • Persistent blood and mucosal immune activation • Greater microbial translocation • Suboptimal CD4+ T cell gains with HAART • There remains a compelling need to develop immune-based therapeutics that improve T cell function and reduce inflammation

  24. Acknowledgements UC Davis Timothy Hayes Barbara Shacklett Karolinska Institute Viktor Dahl Sarah Palmer UCSF/CIL Elizabeth Sinclair Joseph M. McCune NIAID/VRC Netanya Sandler Daniel Douek UCSF/BSRI Tzong-Hae Lee Michael Busch Funding NIAID K23AI075985 Merck, Inc. UCSF/SFGH Peter Hunt Rebecca Hoh Joy Madamba Marcia Smith Lee Gilman Ma Somsouk Jeffrey Martin Steven Deeks UCSF/SFVAMC Harry Lampiris Joseph Wong Thank you to all of the patients who participated in this study.

More Related