A presentation by Peter W. Hunt, M.D., Assistant Professor in Residence at the University of California, San Francisco (UCSF), conducted at the San Francisco General Hospital (SFGH) and supported by CTSI's Clinical Research Services. Learn more about the service at http://ctsi.ucsf.edu/our-work/clinical-research-services

1. A Clinical Trial of CCR5 Inhibition
in Treated HIV Infection:
Highlighting Multidisciplinary T1 Research
from the SFGH CRS
Peter W. Hunt, M.D.
Assistant Professor in Residence
UCSF, SFGH HIV/AIDS Division

2. SFGH CRC:
A“Hub” for Multidisciplinary T1 Research
Clinical Trials
Hunt, Hatano,
Hsue, Deeks Cardiovascular
SCOPE Cohort (FMD, IMT, etc)
Deeks/Martin Hsue
Lymph Node
Gut Mucosal
Biopsy
Biospy Core Hatano
Somsouk/Hunt
SFGH Neurology
(CSF Biomarkers)
Specimen
Bank
CRC Price
ASB Basic
Laboratories
McCune/Nixon
Virology
Core Lab Immunology
Liegler Core Lab
Sinclair
Clinical Lab

3. HIV+ Patients Still Have a 10y Shorter Life
Expectancy than HIV- Controls
Survival from Age 25 Years
N= 3,990
1
Probability of Survival
0.75 Population
controls
0.5
Late HAART
(2000–2005)
0.25
Early HAART
(1997–1999)
Pre-HAART
0 (1995–1996)
25 30 35 40 45 50 55 60 65 70
Age, years
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95 (See Also: ART-CC, Lancet, 2008; Lewden, JAIDS, 2007)

4. Many morbidities associated with
aging also appear to be increased in
treated HIV disease
• Cardiovascular disease [1-3]
• Cancer (non-AIDS) [4]
• Bone fractures / osteoporosis [5,6]
• Liver disease [7]
• Kidney disease [8]
• Cognitive decline [9]
• Frailty [10]
1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2; Hsue P, et al. Circulation. 2004;109:316-319. 3. Grinspoon SK,
et al. Circulation. 2008;118:198-210. 4. Patel P, et al. Ann Int Med, 2008;148:728-736. 5. Triant V, et al. J Clin Endocrinol Metab.
2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8.
Choi A, et al. AIDS, 2009;23(16):2143-49. 9. McCutchan JA, et a. AIDS. 2007 ;21:1109-1117. 10. Desquilbet L, et al. J Gerontol A
Biol Sci Med Sci. 2007;62:1279-1286

5. Many Chronic Diseases of Aging May Be
Driven By Lifestyle Factors and ART Toxicity
ART
Toxicity
Premature
Aging
Lifestyle
(smoking, etc.)
Deeks and Phillips, BMJ, 2009

6. Persistent Immune Activation and
Inflammation May Also Play Important Role
ART
Toxicity
Premature
Aging
Lifestyle
Persistent
Inflammation
Deeks and Phillips, BMJ, 2009

7. An Important Clue from Nature
Sooty Mangabey Rhesus Macaque
•Infect with SIV •Infect with SIV
•High Levels of Viral Replication •High Levels of Viral Replication
•No AIDS, normal lifespan •AIDS and death
•Minimal Immune Activation •Massive Immune Activation
Silvestri, Immunity, 2003

8. T Cell Activation Declines with ART
Hunt et al, JID, 2003 and 2008

9. But Remains Abnormally High During
ART-mediated Viral Suppresion
Hunt et al, JID, 2003 and 2008

10. CCR5 Inhibition:
A Potential Intervention to Reduce T Cell Activation
• Maraviroc is a CCR5 inhibitor and the only currently approved
ARV drug that targets a host element.
• In addition to blocking HIV entry, maraviroc blocks binding of
natural CCR5 ligands.
– Contribute to T cell and monocyte trafficking and activation
• Potential immunologic benefit to blocking CCR5 supported by:
– CCR5 ∆32 causes delayed HIV disease progression.
– Natural hosts of non-pathogenic SIV have low CCR5 on central
memory T cells and low T cell activation.
• Hypothesis: Adding maraviroc to a suppressive regimen will
decrease T cell activation in treated HIV infection

11. Maraviroc Intensification Trial
Schematic
Randomize ART alone
(N=42) Add Maraviroc BID x 24 weeks x 12 weeks
ART>1y
VL<75 ART alone
CD4<350
Add Placebo BID x 24 weeks x 12 weeks
Study Visits at Weeks: -2 0 1 2 4 6 8 12 16 20 22 24 28 36
T Cell Activation, biomarkers, Low-level Viremia (SCA), FMD (Cardiovascular)
Clinical monitoring, CD4 count
Flexible Sigmoidoscopy, Rectosigmoid Biopsy (UCSF only)

12. CCR5 Expression is Much More Common
on T Cells in Rectal Mucosa

13. Baseline Characteristics
Placebo Maraviroc
Characteristic Median (IQR) Median (IQR)
N=22 N=23
Age, years 50 (43 to 57) 50 (46 to 56)
Male Gender, No. (%) 20 (91) 23 (100)
CD4 count, cells/mm3 202 (161 to 256) 206 (131 to 260)
Plasma HIV RNA level, copies/ml <48 <48
Duration of current ART regimen, months 31 (15 to 43) 30 (21 to 42)
Hepatitis C Virus Antibody Positive, No. (%) 2 (14) 3 (20)

14. Early Decline in Plasma HIV RNA Levels
by Single Copy Assay in Both Arms

15. Similar CD4 Count Increase in Both Arms
No evidence for difference in the rate of
CD4+ T cell recovery between arms, P=0.97

16. CD8+ T Cell Activation Declined
Significantly in the Placebo Arm

17. While CD8+ T Cell Activation Tended
to Increase in the Maraviroc Arm

18. Maraviroc Increases CD8 Activation
Compared to Placebo
P values represent difference between groups
in the change from baseline at each timepoint.

19. Maraviroc Prevents the Decline in CD4
Activation Compared to Placebo
P values represent difference between groups in
the change from baseline at each timepoint.

20. No Change in Rectal T Cell Activation on Placebo
CD4+
CD8+

21. But Maraviroc Causes a Nearly 2-fold increase in
Rectal T Cell Activation
CD4+
CD8+

22. MVC intensification increases sCD14 levels
Δ Wk 24-36
Δ Wk 0-4 Δ Wk 0-24 P=0.31
P=0.053 P=0.017
MVC arm had a mean 0.33 µg/mL greater increase in sCD14
from baseline to week 24 (95%CI: 0.06, 0.61, p=0.017)
Interestingly, sCD14 levels tended to increase further after discontinuation of MVC.

23. Why does CCR5 inhibition
increase T cell and monocyte
activation in vivo?

24. Ligand approaches CCR5 Binding and Signaling Ligand-Receptor Internalization
Lederman, JAMA, 2006
• Maraviroc blocks internalization of receptor-ligand complexes leading to:
• Increased CCR5 expression on cell surface
• Increase in soluble ligands in plasma and tissues
(Lin/Corbeau, AIDS, 2007; Nakata/Mitsuya, Antiviral Threrapy, 2010)
• CCR5 ligands (MIP-1α, MIP-1β and RANTES) also bind other chemokine
receptors (CCR1 on monocytes/neutrophils, CCR4/CCR4 on T cells)
(Wolpe, J Exp Med, 1988; Fahey, JI, 1992)
• Current Hypothesis: Activation of monocytes via CCR1 and T cells via
CCR3/CCD4 might explain increased T cell and monocyte activation.

25. >2-fold Increase in Plasma MIP-1β (CCR5 Ligand)
Levels During Maraviroc Intensification

26. MVC-mediated Increases in CCR5 ligands
are associated with increases in sCD14
Spearman’s rho:
0.34, P=0.017

27. Brachial Artery Flow-Mediated Dilation
Endothelial Stimulus:
Reactive hyperemia after
five minute cuff occlusion.
Stimulates functioning
endothelial cells to release
NO. NO diffuses into vascular
smooth muscle. Muscle
relaxes.
Control stimulus:
Nitroglycerin, an
endothelium-independent
vasodilator
Quantity measured:
Diameter of artery, using B-
mode ultrasound

28. Normal Brachial Artery
Endothelium-Dependent Vasomotion
Vasodilation
Brachial Artery
Baseline Reactive Hyperemia

29. Despite MVC-mediated Increases in T cell and
Monocyte Activation, No difference in FMD
Δ Wk 24-36
Δ Wk 0-24
Δ Wk 0-4 P=0.89
P=0.61
P=0.40
ART + Study Drug ART only
Mean +0.46% greater week 24 change from baseline in MVC arm
(95% CI: -0.36% to +1.28%, P=0.61)

30. Conclusions
Maraviroc intensification in HIV+ subjects with
incomplete ART-mediated CD4 recovery:
• Causes a nearly 2-fold increase in T cell activation in GALT,
and more modest increases in peripheral blood.
• Also increases monocyte activation.
– CCR5 ligand signaling through other chemokine receptors should be
explored as a possible causal mechanism.
• No clear effect on vascular function (by FMD)
– Could decreased chemotaxis abrogate a negative effect of monocte
and T cell activation?
• The clinical implications of these findings are unclear.
– CADIRIS, ANRS studies with clinical endpoints ongoing

31. SFGH CRC:
A“Hub” for Multidisciplinary T1 Research
Clinical Trials
Hunt, Hatano,
Hsue, Deeks Cardiovascular
SCOPE Cohort (FMD, IMT, etc)
Deeks/Martin Hsue
Lymph Node
Gut Mucosal
Biopsy
Biospy Core Hatano
Somsouk/Hunt
SFGH Neurology
(CSF Biomarkers)
Specimen
Bank
CRC Price
ASB Basic
Laboratories
McCune/Nixon
Virology
Core Lab Immunology
Liegler Core Lab
Sinclair
Clinical Lab

32. Acknowledgements
Clinical Trial Sites Lederman Laboratory (CWRU)
UCSF Rush/CORE Center Brian Clagett
Nicholas Funderburg
Lee Gilman Oluwatoyin Adeyemi Kathy Medvik
Joy Madamba Julia Lee
Melissa Krone Mieoak Bahk Karolinska Instituet
Victor Dahl
Jeffrey Martin Hamid Bouiri Sarah Palmer
Steven Deeks Alan Landay
UCSF/SFGH GI Division
Ma Somsouk
CWRU Stanford
UCSF/SFGH Cardiology Division
Benigno Rodriguez Debbie Slamowitz
Priscilla Hsue
Jane Baum Robert Shafer Amanda Schnell
Michelle Gallagher Cindy Padilla
UC Davis Mucosal Immunology
Michael Banchy Martha Hamilton Timothy Hayes
Michael Lederman Nancy Shulman Barbara Shacklett
This trial was supported by investigator-initiated
grants from: Pfizer labs, Inc., and AMFAR

33. Acknowledgements:
SFGH CRC
NURSING SPECIMEN PROCESSING
Elizabeth Madruga, RN Wendy Staub
Bernadette Tobin, RN Benny Tong
Lorna Aquino, RN Fabiola Carrillo
Beverly Schmidt, RN
BIONUTRITION
Nenette Dignadice, RN
Viva Tai
Rosemarie Dario, LVN
Jennifer Culp
Oscar Gomez Cruz, HA
Marilou Tarape
Antonio Everett, HA
Marlene Hom
Hector Vizoso, RN
May Yee
Eileen Magnaye, RN
Brenda Herrera, RN ADMIN
Melinda Rowan, RN Mark Jacobson, M.D. -Medical Director
Cory Groom, RN Eunice Stephens -Operations Director
Gabriel Ortiz -Analyst