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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

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

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  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.

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