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Sergio Serrano Villar
Biomarcadores de Inflamación en el VIH
Torremolinos,1 de Junio 2017
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Simon & Cidar. Circ Res 2012
Getting Hotter As We Get Older
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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)
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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
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The Hallmarks of Aging
Otin Cell 2013
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HIV and its Treatment Impact of Biological
Determinants of Aging
Adapted from Otin, Cell 2013
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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
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Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)
High T Cell Activation Associated with Blunted CD4
Recovery
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Monocyte Activation Associated with Cognitive
Impairment during ART
Burdo, AIDS 2013 (see also Letendre, CROI 2012, #82; Lyons, JAIDS, 2011; Ancuta PLoS One, 2012)
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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
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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
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¿tenemos biomarcadores
útiles?
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Papel de los Biomarcadores en la Clínica
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The “Inflammatory Soup” In treated HIV infection immunological predictors of disease progression are
linked but poorly correlated
Serrano-Villar. Datos no publicados
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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
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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
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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
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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
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Lancet Infect Dis 2015
CID 2013 Hayle, JAMA Intern Med 2013
Ahn. JAIDS 2015
¿Es Necesario Monitorizar los CD4 en un paciente en TAR?
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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
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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
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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
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• 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
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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
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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
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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
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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
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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
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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
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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
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Serrano-Villar & Deeks. Lancet HIV 2015
The CD4/CD8 ratio: an Emerging Biomarker
for HIV
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Serrano-Villar & Deeks. Lancet HIV 2015
The CD4/CD8 ratio: an Emerging Biomarker
for HIV
Está justificado monitorizar este marcador en la práctica clínica
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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
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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
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Searching for the cause of genital inflammation
and vulnerability to HIV in African Women
Anahtar. Immunity 2015
Cervicovaginal Microbiota: Simpler is Better!
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Abundance of Penile Anaerobes, IL-8, and the Risk of HIV
Acquisition, Uganda
Liu. mBio 2013 Liu. CROI 2017. Abstract 87
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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
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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
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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