1. The role of HIV infection and Co-infections in Serious Non-AIDS Events Peter W. Hunt, M.D Associate Professor of Medicine, UCSF

2. Disclosures Consultant –Merck –BMS –Gilead –Tobira Honoraria –Gilead

3. Is HIV itself a Direct Cause of Persistent Immune Activation during "Suppressive" ART?

4. HIV RNA Persists in Plasma at Low Levels during «Suppressive» ART Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008.

5. N=40. Anton PA et al. AIDS. 2003;17(1):53-63. HIV RNA Is Also Readily Detectable in Rectal Tissue During “Suppressive” HAART 100 90 80 70 60 50 40 30 20 10 0 Patients Detectable (%) Viral loadHIV Co-culture HIV DNA Blood HIV DNA Rectal HIV RNA Rectal Plasma VL <40 copies/mL

6. Extent of Low-level Viremia Not a Strong Predictor of T cell Activaton Steel/Kelleher, Antiviral Ther, 2007 Low-level viremia may be associated with ↑ sTNF-RII B2 microglobulin (*Ostrowski, Scand J Imm, 2008) *small N…

7. Cell-associated Measures of HIV Persistence More Strongly Correlated with Immune Activation Hatano, JID, 2013 Plasma HIV RNACell-associated HIV RNA Cause or Consequence?

8. Passive HIV release from infected cells? or Productive HIV Replication? Intensifying ART with an additional agent might block the latter, but not the former.

9. No Apparent Benefit of ART Intensification in Earlier Trials 1 Dinoso JB, et al. Proc Natl Acad Sci USA. 2009;106:9403-9408. 2 Gandhi R, et al. J Infect Dis. 2010; 201(2): 293-296. 3 Jones J, et at. CROI 2009. Abstract 423b. 4 Gandhi R, et al. PLoS Med. 2010; 7(8). 5 Hatano H, et al. J Infect Dis. 2011; 203(7):960-8. Author Intensification Regimen n/NResult Dinoso, JB, et al 1 ATV/r 300/100 mg qd EFV 600 mg qd LPV/r 600/150 mg bid n=5 n=2 No decrease in extent of low-level viremia Gandhi R, et al 2 ENFn=9/19 No decrease in size of latent viral reservoir Jones J, et al 3 RAL 400 mg bidN=5 No decrease in extent of low-level viremia Gandhi R, et al 4 RAL 400 mg bidn=25/53 No decrease in extent of low-level viremia Hatano H, et al 5 RAL 400 mg bidN=15/30 No difference in low-level viremia or T cell activation

10. Integrase Inhibitor Intensification Unmasks Low-level HIV Replication 1 Buzon M, et al. Nature Medicine. 2010; 16(4): 460-465; 2 Llibre J. Antiviral Therapy, 2011; RGV May Transiently ↑2-LTR Circles 2-LTR circles during RGV Intensification Week of RGV intensification

11. Integrase Inhibitor Intensification Unmasks Low-level HIV Replication 1 Buzon M, et al. Nature Medicine. 2010; 16(4): 460-46 3 Hatano H, et al. JID, 2013 Week of RGV intensification Wk24 ∆ D-dimer Wk24 ∆ CD8 Activation Light blue: +2-LTR circle increase Dark blue: No 2-LTR circle increase

12. % Difference in Concentration c/w PBMC All patients on ATV and most on DRV had no measurable drug in Lymph Node (LN) tissue! All drugs had much lower concentrations in LN than PBMC Greater LN concentrations correlated with faster viral decay in LN Consistent with, but does not prove, that there is some continued replication in LN despite ART

13. Is passive release of HIV from infected cells a significant cause of immune activation? See Imamichi, WEAA0206LB, this afternoon! Need interventions to block this (Verdin, MOSY05, AIDS 2014)

14. Do other viruses contribute to persistent immune activation during suppressive ART?

15. Treating HCV (with IFN/Rib) decreases Immune Activation in Treated HIV Infection Gonzalez/Sandberg, J Virol, 2009 CD8 ActivationCD4 Activation Unclear if soluble markers of inflammation and monocyte activation also decline. See also: Chew, CROI, 2014 Masia, JAC, 2011 deCastro, AIDS, 2010 Jain J Vir Hep, 2014

16. Sylwester/Picker, JEM, 2005 CMV elicits massive immune responses even in asymptomatic HIV- individuals

17. Higher CMV-specific CD8+ IFN-g Production Associated with More Atherosclerosis Hsue et al, AIDS, 2006

18. Higher CMV-specific CD8+ IFN-g Production Associated with More Atherosclerosis Hsue et al, AIDS, 2006 (see also Lo, AIDS, 2010; Parrinello, JID, 2012) In ICONA cohort, CMV Ab+ patients had an adjusted 77% (P=0.001) increased risk of Serious Non-AIDS events than CMV- patients (Lichtner et al, JIAS 2012)

19. Blocking Asymptomatic CMV Replication with Valganciclovir ↓ Immune Activation in HIV+ Patients with CD4<350 despite ART -4.4% HIV- Median Hunt et al, JID, 2011 Note: Valacyclovir, which has activity against HSV1/2 but not CMV, failed to decrease immune activation (Yi et al, CID, 2013).

20. Conclusions Persistent Immune Activation during ART is an important problem HIV persistence may well contribute to this. Cryptic productive HIV replication likely persists in some individuals and in tissues –Contributes modeslty to immune activation Other viruses likely contribute to persistent immune activation duing suppressive ART –HCV, CMV

21. Acknowledgements Core Immunology Lab-UCSF Elizabeth Sinclair Lorrie Epling Mike McCune BSRI Mike Busch Tzong-Hae Lee SFGH Cardiology Priscilla Hsue U. Vermont Russ Tracy SCOPE - UCSF Steve Deeks Jeff Martin Hiroyu Hatano Vivek Jain Rick Hecht Ma Somsouk Sulggi Lee Melicent Peck Leslie Cockerham Mark Jaobson Rebecca Hoh SCOPE /OPTIONS Teams