1. Should we treat HIV Controllers ? IAS 2013 Pr Olivier Lambotte Department of internal medicine and clinical immunology Bicêtre Hospital, University Paris South

2. International guidelines for anti-retroviral treatment USA (NIH) ANRS European AIDS Clinical Society International AIDS Society = ART is recommended for all HIV-1 infected patients Reasons: -To block viral replication leads to immune reconstitution with CD4 T cell increase -Control of HIV leads to reduced immune activation and its consequences (immunological and clinical) -To block viral replication leads to reduced HIV transmission

3. What would be the reasons to treat a HIV controller ? HIV controllers can be considered as a model of functional cure...

4. What would be the reasons to treat a HIV controller ? Viral replication ? Decrease of the CD4 T cell count ? Both ? What’s about the role of immune activation and chronic inflammation in these patients ?

5. Viral replication Viral escape (Sajadi et al. JAIDS 2009, Rachinger CID 2008) –A rare event which should question a superinfection (Sajadi et al. JAIDS 2009, Rachinger CID 2008) –Controllers are able to control burst of viral replication (Rachinger et al) –On a 4-year period, in the French cohort (220 patients), 5 « viral escapes » with two consecutive VL > 2000 RNA copies/mL –Only 2 are treated, the 3 others became « viremic controllers »

6. Viral replication The virus –It can be a reason to treat a controller BUT viral replication is present in all (?) controllers There is a low-grade viral replication in all (?) controllers (range  ART-treated patients [1-10 RNA copies/mL] –Hatano et al. (J Virol 2009): longitudinal follow-up 45/46 patients HIC had  1 detectable usVL -CO21 ANRS Codex: first 100 enrolled patients - 76 4 < usVL < 400 - 24 usVL < 4 - At 12 months: among the 16 with a sample, only 8 have a usVL still < 4 RNA copies/mL

7. The CD4 T cells The decrease of the CD4 T cell count In the US Army cohort, the CD4 T cell counts decreased in 6 / 25 controllers (Okulicz et al JID 2009) In the French Observatory, two-third of the controllers had a negative slope of their CD4 T cell count Loss of 14 [-12 ; -16] CD4/year In the French ANRS CO21 Cohort: –At enrollment, the median CD4 T cell count was 752/mm3 [IQR : 540 -957] –10 confirmed « immunological escape » = two consecutive CD4 T cell counts < 350/mm3 –8 are treated by ART

8. What is driving the CD4 T cell decrease in Controllers ? The virus Immune activation Immunosenescence

9. CD4 T cell decrease is related to HIV Possible role of blips –  1 blip was associated with a negative slope of CD4 T cell counts in controllers of the French Observatory (Boufassa et al. PLoS One 2011)

10. The virus is involved in some HIC Detectable VL in 34/35 samples

11. What is driving the CD4 T cell decrease in Controllers ? The virus –Yes, but not in all patients –Role of blips –Very slow CD4 T cell recovery in 36 HIV controllers on ART from 4 cohorts Immune activation Immunosenescence (Sedaghat et al CID 2009)

12. CD4 T cell decrease is related to immune activation 12 Hunt P et al. JID 2008 HIV controllers have higher activation of CD4 and CD8 T cells than HIV-

13. S Potter J Virol 2007

14. Correlation between the CD4 T cell count in controllers and CD4 and CD8 T cell activation (P Hunt JID 2008 )

15. Immune activation in HIV controllers has several causes Appay et al. 2008

16. 16 Microbial translocation is higher in controllers than in healthy donnors (collaboration ANRS EP36) Brenchley J et al. Nat Med 2006 Microbial translocation is correlated with CD8 T cell activation Hunt et al JID 2008

17. A consequence of chronic inflammation: Cardiovascular risk seems to be increased in HIV controllers Hsue P, AIDS 2009 AIDS 2012 Consequences of immune activation seem to be present in HIV Controllers

18. What is driving the CD4 T cell decrease in Controllers ? The virus Immune activation –Microbial translocation –Anti-HIV immune response –Other unknown mechanisms Immunosenescence –Decreased lymphopoiesis in controllers with low CD4 T cell counts (Sauce et al. Blood 2011)

19. But real life is not simple …

20. 1992 62006 Spontaneous fluctuations of CD4 T cell counts are common in HIV controllers Even with periods below 500 /mm3, with or without a clear relation with viral blips

21. Should we treat HIV controllers ? Two major points –It is not an emergency –The patient’s opinion is essential > observance If the CD4 T cell decrease is significant and durable with/without viral replication : YES with ART If the CD4 T cell count is stable without blips: NO (situation of functional cure ?) In the other situations...

22. Should we treat HIV controllers ? Two major points –It is not an emergency –The patient’s opinion is essential > observance In the other situations: To target immune activation is a major goal and a suject of research : Combination of hydroxychloroquine, statine, low dose steroids, etc... WITH ART We need markers which could help the clinician –Markers of immune activation on CD4 / CD8 T cells –Biomarkers of inflammation –Viral DNA, us RNA...

23. INSERM U1012 Olivier Lambotte Camille Lécuroux Isabelle Girault Stéphane Hua Christine Bourgeois Alain Venet Sandie Gérard Nicolas Noel INSERM U1018 Faroudy Boufassa Laurence Meyer CHU Bicêtre Cécile Goujard Jean-François Delfraissy Katia Bourdic Institut Pasteur Asier Saez-Cirion Gianfranco Pancino USA Peter Hunt Florencia Pereyra CHU Necker Christine Rouzioux Patients and clinicians !! Cohorte ANRS CO21

24. Profil transcriptionnel des infections par le SIV pathogènes et non pathogènes Manches et al. JCI 2009

26. Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection (Murray et al. J Virol 2010)