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

SFGH CRC: A“Hub” for Multidisciplinary T1 Research

SFGHCRC

Cardiovascular(FMD, IMT, etc)

Hsue

SCOPE CohortDeeks/Martin

Neurology(CSF Biomarkers)

Price

Gut MucosalBiospy CoreSomsouk/Hunt

Clinical TrialsHunt, Hatano, Hsue, Deeks

Clinical Lab

Immunology Core Lab

Sinclair

Virology Core Lab

Liegler

Specimen BankASB Basic

LaboratoriesMcCune/Nixon

Lymph Node BiopsyHatano

HIV+ Patients Still Have a 10y Shorter Life Expectancy than HIV- Controls

Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95

Prob

abili

ty o

f Sur

viva

l

Pre-HAART (1995–1996)

Early HAART (1997–1999)

Survival from Age 25 YearsN= 3,990

1

0.75

0.5

0.25

0

25 30 35 40 45 50 55 60 65 70

Age, years

Late HAART (2000–2005)

Population controls

(See Also: ART-CC, Lancet, 2008; Lewden, JAIDS, 2007)

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

Many Chronic Diseases of Aging May Be Driven By Lifestyle Factors and ART Toxicity

Lifestyle(smoking, etc.)

ARTToxicity

PrematureAging

Deeks and Phillips, BMJ, 2009

Persistent Immune Activation and Inflammation May Also Play Important Role

Lifestyle

ARTToxicity

PersistentInflammation

PrematureAging

Deeks and Phillips, BMJ, 2009

Sooty Mangabey

• Infect with SIV

• High Levels of Viral Replication

• No AIDS, normal lifespan

Rhesus Macaque

• Infect with SIV

• High Levels of Viral Replication

• AIDS and death

Silvestri, Immunity, 2003

An Important Clue from Nature

• Minimal Immune Activation • Massive Immune Activation

T Cell Activation Declines with ART

Hunt et al, JID, 2003 and 2008

But Remains Abnormally High During ART-mediated Viral Suppresion

Hunt et al, JID, 2003 and 2008

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

Maraviroc Intensification Trial Schematic

Randomize (N=42) ART>1yVL<75

CD4<350

Add Maraviroc BID x 24 weeksART alonex 12 weeks

Add Placebo BID x 24 weeks ART alone 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)

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

Baseline Characteristics

CharacteristicPlacebo Maraviroc

Median (IQR)N=22

Median (IQR)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)

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

Similar CD4 Count Increase in Both Arms

No evidence for difference in the rate ofCD4+ T cell recovery between arms, P=0.97

CD8+ T Cell Activation Declined Significantly in the Placebo Arm

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

Maraviroc Increases CD8 Activation Compared to Placebo

P values represent difference between groups in the change from baseline at each timepoint.

Maraviroc Prevents the Decline in CD4 Activation Compared to Placebo

P values represent difference between groups in the change from baseline at each timepoint.

CD4+

CD8+

No Change in Rectal T Cell Activation on Placebo

But Maraviroc Causes a Nearly 2-fold increase in Rectal T Cell Activation

CD4+

CD8+

MVC intensification increases sCD14 levels

Δ Wk 0-4P=0.053

Δ Wk 0-24P=0.017

Δ Wk 24-36P=0.31

MVC arm had a mean 0.33 µg/mL greater increase in sCD14from baseline to week 24 (95%CI: 0.06, 0.61, p=0.017)

Interestingly, sCD14 levels tended to increase further after discontinuation of MVC.

Why does CCR5 inhibition increase T cell and monocyte

activation in vivo?

Lederman, JAMA, 2006

Ligand approaches CCR5 Binding and Signaling Ligand-Receptor Internalization

• 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.

X XXMaraviroc

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

MVC-mediated Increases in CCR5 ligands are associated with increases in sCD14

Spearman’s rho: 0.34, P=0.017

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

Baseline Reactive Hyperemia

Vasodilation

Brachial Artery

Normal Brachial ArteryEndothelium-Dependent Vasomotion

Despite MVC-mediated Increases in T cell and Monocyte Activation, No difference in FMD

Δ Wk 0-4P=0.40

Δ Wk 0-24P=0.61

Δ Wk 24-36P=0.89

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)

ConclusionsMaraviroc 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

SFGH CRC: A“Hub” for Multidisciplinary T1 Research

SFGHCRC

Cardiovascular(FMD, IMT, etc)

Hsue

SCOPE CohortDeeks/Martin

Neurology(CSF Biomarkers)

Price

Gut MucosalBiospy CoreSomsouk/Hunt

Clinical TrialsHunt, Hatano, Hsue, Deeks

Clinical Lab

Immunology Core Lab

Sinclair

Virology Core Lab

Liegler

Specimen BankASB Basic

LaboratoriesMcCune/Nixon

Lymph Node BiopsyHatano

Acknowledgements

UCSFLee GilmanJoy MadambaMelissa KroneJeffrey MartinSteven Deeks

CWRUBenigno RodriguezJane BaumMichelle GallagherMichael BanchyMichael Lederman

Rush/CORE CenterOluwatoyin AdeyemiJulia LeeMieoak BahkHamid Bouiri Alan Landay

StanfordDebbie SlamowitzRobert ShaferCindy PadillaMartha HamiltonNancy Shulman

Clinical Trial Sites Lederman Laboratory (CWRU)Brian ClagettNicholas FunderburgKathy Medvik

Karolinska InstituetVictor DahlSarah Palmer

UCSF/SFGH GI DivisionMa Somsouk

UCSF/SFGH Cardiology DivisionPriscilla HsueAmanda Schnell

UC Davis Mucosal ImmunologyTimothy HayesBarbara Shacklett

This trial was supported by investigator-initiated grants from: Pfizer labs, Inc., and AMFAR

NURSING Elizabeth Madruga, RN Bernadette Tobin, RNLorna Aquino, RNBeverly Schmidt, RNNenette Dignadice, RNRosemarie Dario, LVNOscar Gomez Cruz, HAAntonio Everett, HAHector Vizoso, RNEileen Magnaye, RNBrenda Herrera, RNMelinda Rowan, RNCory Groom, RN

Acknowledgements:SFGH CRC

SPECIMEN PROCESSINGWendy StaubBenny Tong Fabiola Carrillo

BIONUTRITIONViva TaiJennifer CulpMarilou TarapeMarlene HomMay Yee

ADMINMark Jacobson, M.D. -Medical DirectorEunice Stephens -Operations DirectorGabriel Ortiz -Analyst