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