Sergio Serrano Villar

Biomarcadores de Inflamación en el VIH

Torremolinos,1 de Junio 2017

Simon & Cidar. Circ Res 2012

Getting Hotter As We Get Older

Kaiser Permanente HIV Cohort: Narrowing the Gap in

Life Expectancy for HIV+ vs HIV-Individuals

8 year gap with ART initiation at CD4 ≥ 500. Life expectancy ê Blacks & IVDU. ê Hispanics

Gap narrowed if no hepatitis, drug/alcohol, or smoking Marcus J, et al. 23rd CROI; Boston, MA; February 22-25, 2016. Abst. 54.

7077

19

53

1054 P<0.001

P=0.062 381 439

63 65

0

20

40

60

80 13-Year Gap

Expected years of life remaining at age 20

(dots)

Legarth/Obel, JAIDS, 2016

Survival of Older HIV+ Adults in Well-Treated

Patients in the ART Era

HIV- Controls

1996-2014

HIV+

2006-2014

2000-2005

1996-2000

~9y shorter life expectancy even

among those with no comorbidity

The Hallmarks of Aging

Otin Cell 2013

HIV and its Treatment Impact of Biological

Determinants of Aging

Adapted from Otin, Cell 2013

Inflammation Can Cause Lymphoid Tissue Fibrosis

Estes, JID, 2008; Schacker, JCI, 2002; Zeng, JCI, 2011

• Associated with low %naïve T cells and poor CD4+ T cell recovery

• May impair functional immune responses

Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)

High T Cell Activation Associated with Blunted CD4

Recovery

Monocyte Activation Associated with Cognitive

Impairment during ART

Burdo, AIDS 2013 (see also Letendre, CROI 2012, #82; Lyons, JAIDS, 2011; Ancuta PLoS One, 2012)

Inflammation Predicts Disease in Treated HIV

• Mortality (Kuller, PLoS Med, 2008; Tien, JAIDS, 2010; Justice, CID 2012)

• Cardiovascular Disease (Duprez, Atherosclerosis, 2009)

• Cancer (Breen, Cancer Epi Bio Prev, 2010; Borges, AIDS, 2013)

• Venous Thromboembolism (Musselwhite, AIDS, 2011)

• Type II Diabetes (Brown, Diabetes Care, 2010)

• COPD (Attia, Chest, 2014)

• Bacterial Pneumonia (Bjerk, PLoS One, 2014)

• Cognitive Dysfunction (Burdo, AIDS, 2013; Letendre CROI 2012)

• Depression (Martinez, JAIDS, 2014)

• Frailty (Erlandson, JID, 2013)

Slide courtesy from Peter Hunt 2016

Immune Activation As a Tree

www.ulead.org l d

Roots

HIV reservoirs

CMV

Microbial translocation

Branches

IL-6 / Inflammation

D-dimer / Coagulation

Lymphoid Fibrosis

Leaves

End-organ diseases

Slide from Peter Hunt

¿tenemos biomarcadores

útiles?

Papel de los Biomarcadores en la Clínica

The “Inflammatory Soup” In treated HIV infection immunological predictors of disease progression are

linked but poorly correlated

Serrano-Villar. Datos no publicados

15

SMART Study: Interrupting ART Increases

the Risk of Heart Disease

El-Sadr. NEJM 2006

Kuller et al. PLoS Med 2008

Biomarker

All-Cause Mortality

(N=85)

Fatal or Non-fatal CVD

(N=136)

OR P-value OR P-value

hs-CRP 3.1 0.02 1.6 0.20

IL-6 12.4 <0.0001 2.8 0.003

Amyloid A 3.1 0.05 1.6 0.12

Amyloid P 1.1 0.78 2.8 0.002

D-dimer 41.2 <0.0001 2.0 0.06

The increase of inflammatory biomarkers is moderate but

the impact on long-term mortality is strong

Neuhaus et al. JID 2010 Grund et al. Plos One 2016

Hunt, JID 2014

(see also : Tenorio, JID 2014)

Inflammatory Markers Predict Mortality

Independent of Nadir and Current CD4 count

Gut Epithelial

Barrier Dysfunction

Inflammation /

Coagulation

IDO-1 Induction

Monocyte Activation

Nivel de Evidencia y Recomendación

de algunos actos médicos

Vitamina D

PSA

AAR

CD4

Pruebas diagnósticas

Pautas de TAR

Vitamina D

Estatinas en

ancianos

etc…

Actos terapéuticos

Lancet Infect Dis 2015

CID 2013 Hayle, JAMA Intern Med 2013

Ahn. JAIDS 2015

¿Es Necesario Monitorizar los CD4 en un paciente en TAR?

hsCRP – Clinical Guidelines

• RCV bajos <1 mg/L

• RCV intermedio 1-3 mg/L

• RCV elevado >3 mg/L

• Causa inflamatoria >10mg/L

Pearson. Circulation 2003. Ridker Circulation 2003

hsCRP – Clinical Guidelines

• RCV bajos <1 mg/L

• RCV intermedio 1-3 mg/L

• RCV elevado >3 mg/L

• Causa inflamatoria >10mg/L

Pearson. Circulation 200. Ridker Circulation 2003

• RCV bajos <1 mg/L

• RCV intermedio 1-3 mg/L

• RCV elevado >3 mg/L

• Causa inflamatoria >10mg/L

Pearson. Circulation 200. Ridker Circulation 2003

Anti-inflammatory effects of statins

• Statins in subjects with low LDL and high

inflammation reduce CVD/mortality

(44%)

• Greatest absolute RR observed among

those with highest levels of inflammation

• Greatest risk reduction among those who

reduce hsCRP as well as LDL-C

• Increased risk of DM (25%).

Ridker PM. NEJM 2005; Ridker PM. NEJM 2008;

Ridker PM. Lancet 2009; Ridker. Am J Cardiol 2010

• êeGFR decline and é cystatin-C at 24w1

• êLP-PLA22 and oxidative LDL at 24 weeks3

• êLp-PLA2, IP-10, tissue factor+ patrolling monocytes, T cell activation, but did not alter hsCRP, IL-6 or D-dimers at 48w4

• é BMD at week 485

• êNT-proBNP at 96 w6

• é BMD and insulin resistance at 96w7 , êoxLDL and

• êIMT at week 968

• é lean body mass at 96w9

1, Longenecker, CID 2014; 2, Ross Eckard, JID 2014; 3, Hileman, AIDS 2016; 4, Funderburg JAIDS 2015; 5, Erladson; AIDS 2015; 6, Dirajlal-

Fargo, AIDS 2015; 7, McComsey CROI 2015 abstract#134; 8, McComsey CROI 2015 abstract#137; 9, Erlandson, AIDS Res Hum Retro 2015

Saturn-HIV trial

Saturn vs. Jupiter

• LDL lowering higher in Jupiter (28% vs. 50%)

• No impact on inflammatory markers in HIV (and 37% reduction vs. placebo

in Jupiter).

• No impact in inflammatory biomarkers in other studies.

Will statins target the inflammatory pathways of interest in HIV?

SATURN JUPITER

N 147 17.802

Age 46 years 66 years

LDL (mg/dL) 96 108

hsCRP (mg/L) 1.6 4.2

Rosuvastatin dose 10mg 20mg

Duration 6 months 1.9 years

Funderburg, AIDS 2015; Lo, Lancet HIV 2015; Nou, AIDS 2015

CD4/CD8 <1

CD4/CD8 >1

On antiretroviral therapy

Ce

lls/

uL

Time (years) after acute HIV infection

CD4/CD8 Dynamics during HIV infection

CD4

CD8

CD4/CD8 >1 CD4/CD8 <1

Untreated infection

Sainz. AIDS 2013

Serrano-Villar. J of Infect 2013

The CD4/CD8 Ratio as a Marker of CD8+ T-cell

Activation/Senescence in treated HIV-Infected Children and

Young Adults

0 20 40 600

1

2

3

G

r = -0.414, p = 0.012

CD8+ HLADR

+CD38

+ T-cells (%)

CD

4/C

D8

rati

o

0 10 20 30 400

1

2

3

H

r = -0.389, p = 0.017

CD8+ CD57

+CD28

-T-cells (%)

CD

4/C

D8

rati

o

0 20 40 600.0

0.5

1.0

1.5

2.0

2.5

r = -0.752, p <0.001

CD8+ HLADR

+PD-1

+ T-cells (%)

CD

4/C

D8

rati

o

0.4 0.6 0.8 1.00.0

0.5

1.0

1.5

2.0

r = -0.192, p = 0.037

A

Carotid intima-media thickness (mm)

CD

4/C

D8

rati

o

<1 1³

0.4

0.6

0.8

1.0

p < 0.001

A

CD4/CD8 ratio

Car

oti

d in

tim

a-m

edia

thic

knes

s (m

m)

80 90 100 110 1200.0

0.5

1.0

1.5

2.0

2.5r = 0.215, p = 0.013

C

eGFR (mL/min/1.73 m2)

CD

4/C

D8

rati

o

The CD4/CD8 Ratio is Associated with Markers of Age-Associated Disease in

Virally Suppressed HIV-Infected Subjects with Adequate CD4 Recovery

Serrano-Villar. HIV Medicine 2015

Serrano-Villar. Plos One 2014

The CD4/CD8 Ratio Associated with Severe Non-AIDS

events and mortality in treated HIV-infected patients

P <0.0001

Best CD4/CD8 ratio cut-off: 0.4

AUC: CD4/CD8 ratio Vs. Non-AIDS events

The CD4/CD8 Ratio Predicts Adverse Outcomes

Beyond the CD4 and CD8 Counts Beta P

Madrid Cohort (N=66): Serious Non-AIDS Events (all subjects ≥500 CD4/mm3)

CD4 T cells -0.66 0.859

CD8 T cells 2.29 0.048

CD4/CD8 ratio -5.08 0.045

SOCA Cohort (N=192): Non-AIDS mortality

CD4 T cells All subjects -1.52 0.009

Subjects with CD4≥500 -4.09 0.525

CD4 T cells All subjects 0.28 0.392

Subjects with CD4≥500 2.37 0.246

CD4/CD8 ratio All subjects -1.38 0.012

Subjects with CD4≥500 -5.04 0.194

Estimations adjusted by age, sex, nadir CD4 and duration of ART

•Nested case-control study within the

Madrid cohort: treated individuals with

≥500 CD4.

•Each 10% decrease of CD4/CD8 ratio was

associated with a 48% increased risk of

serious non-AIDS events

•Nested case-control study within the

SOCA cohort: subjects who started ART at

AIDS diagnosis

•Each 10% decrease of CD4/CD8 ratio was

associated with a 15% of non-AIDS

mortality.

The CD4/CD8 ratio has prognostic significance in all treated adults:

• in those with low CD4+ T cell counts much of the risk is driven by the CD4 count (immunodeficiency).

• in those with high CD4+ T cell counts is driven by CD8+ T cell count (inflammation).

Serrano-Villar S. PLoS Pathogens 2014

Frontiers Microbiol 2015

Serrano-Villar. Future Virology 2015

Mortalidad no-SIDA

Fragilidad

IAM

Cáncer

Progresión IMT, sarcopenia, ERC

Infecciones bacterianas

Respuesta a vacunas (VEB, fiebre amarilla)

20152015Recuperación inmunológica durante el TAR

Inmunoactivación/Inmunosenescencia/Reservorio viral

AIDS Rev 2017

El Cociente CD4/CD8 Predice los Problemas Actuales

Riesgo aumentado si

CD4/CD8 <0.4-0.5

Sainz AIDS 2013, Serrano-Villar J Infec 2013, Emu Plos One 2014, Freeman CID 2015, Rosado-Sánchez CID 2016

Serrano-Villar HIV Med 2014, Bernal JIAS 2014, Bernal Morel AIDS Res Hum Retr 2016

Serrano-Villar, Plos One 2014, Borges CID 2016, Hema Plos One 2016

Helleberg, JID 2015, Castilho AIDS 2016

Collin Plos One 2016

Serrano-Villar Plos Pathogens 2014, Mussini Lancet HIV 2015

Avelino-Silva Plos Neglect Trop Dis 2016

Terzian J Wom Health 2009, Brañas Age Aging 2017

Sauter Medicine 2016, Rafi JAC 2016

Serrano-Villar & Deeks. Lancet HIV 2015

The CD4/CD8 ratio: an Emerging Biomarker

for HIV

Serrano-Villar & Deeks. Lancet HIV 2015

The CD4/CD8 ratio: an Emerging Biomarker

for HIV

Está justificado monitorizar este marcador en la práctica clínica

Candidate indications of microbiota-oriented personalized medicine in HIV

Diagnosis

Identify at-risk subjects

-immune recovery

-anal cancer, CVD disease

-pulmonary TB

Therapeutic

Identify potential responsiveness from

preventive (PREEP) and therapeutic options

Influence dietary and other environmental

changes to decrease long-term risk

Adapted from Brennan & Garett. Ann Rev Microbiol 2016

Therapeutic

Enhance therapeutic efficacy

Target the microbes within the lesion (HSIL)

for immunomodulation

Treat with reengineered bacteria as adjuvant

therapy

Microbiota-Oriented Personalized Medicine

Intestinal Microbiota

Metabolism of L-Carnitine

Promotes Atherosclerosis

Wang Nature 2011; Koeth Nat Med 2013 Tang NEJM 2013

Plaque burden in HIV-infected

patients is associated with

trimethylamine

Srinivasa JAIDS 2016

Searching for the cause of genital inflammation

and vulnerability to HIV in African Women

Anahtar. Immunity 2015

Cervicovaginal Microbiota: Simpler is Better!

Abundance of Penile Anaerobes, IL-8, and the Risk of HIV

Acquisition, Uganda

Liu. mBio 2013 Liu. CROI 2017. Abstract 87

Segal. Cell Host Microbe 2017

Cribbs. Microbiome 2016

The Lung Microbiome Could Affect the Risk of

Pulmonary Diseases in HIV

Louis. Nat Rev Microbiol 2014

Campylobacter

(LSIL) Cytolethal distendin toxin.

DNA damage1

Peptostreptococcus

(LSIL) Linked with colon cancer2

Gardnerella

(HSIL) Decreases in cervical cancer3

Bifidobacterium

(HSIL) Enhances anti-tumor activity and

anti-PD-L1 activity5

Pseudomonas

(HSIL) Induces kynurenine pathway and

inflammation4

Serrano-Villar AIDS 2017 1 Martínez. Int J Med Microbiol 2006. 2 Candela. World J Gastroenterol 2014. 3 Audirac-Chaulifor. Plos One 2014 4 Favre. Sci Transl Med 2010. Sivan. Science 2014.

C

In

Fecal and Epithelium-Adherent Bacteria Predictive of

HSIL in HIV-Infected MSM

Conclusiones

1. La inflamación es un factor que afecta a la salud de nuestros

pacientes.

2. En la gran mayoría de los pacientes, hoy tiene más sentido

monitorizar la PCR (>3mg/L) y el CD4/CD8 (<0.4) que los CD4.

3. En los próximos años es probable que sumemos marcadores

microbiológicos predictores de complicaciones al arsenal de

biomarcadores por validar.

Agradecimientos: Dra. Noemí González Pérez de Villar