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Precision Medicine and Infectious Diseases
Juan Miguel Pascale MD, MSc, PhD Facultad de Medicina, U de Panamá
Instituto Conmemorativo Gorgas [email protected]
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General concepts
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DEFINITION APPLIED TO ID
Personalized medicine builds on the concept that we all
harbor unique biological variables that orchestrate our
response to disease and leverages these differences for
the purpose of improved diagnostics and therapeutics.
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PRESENT SITUATION
While personalized medicine generally aims at interrogating the
genomic information of a patient, drug metabolism polymorphisms,
for example, to guide drug choice and dosage, personalized medicine
concepts are applicable in infectious diseases for the (rapid)
identification of a disease-causing microbe and determination of its
antimicrobial resistance profile, to guide an appropriate antimicrobial
treatment for the proper management of the patient.
Bissonnette L and Bergeron M. J. Pers. Med. 2012, 2, 50-70; doi:10.3390/jpm2020050
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HIV and Precision Medicine
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EXAMPLES: HIV
1. HLA
2. CCR5 and other polymorphisms
3. Drug resistance and transmitted diseases
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HLA: protection and progression
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CTL response exerts evolutionary pressure on HIV
selecting for HLA-associated immune escape mutations
Modied from Goulder & Watkins, Nat Rev 2008
Viral epitope
Lysis
WT virus
Infected CD4+ T cell
Specific
CTL
HLA
TCR
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HLA alleles and slower or faster rates of disease progression
Modified from Goulder and Walker, Immunity, 2012
B*57:01/57:03 B*27:05 B*14:02 B*42:01 B*52:01 A*25:01 A*32:01 A*74:01
B clade HIV-1
Protective HLA I Alleles
- Low pVL setpoint - High CD4+ T cell counts - Slow disease progression
B*35:01/35:02/35:03
B*07:02 B*08:01 B*53:01
B clade HIV-1
Risk HLA I Alleles
- High pVL setpoint - Low CD4+ T cell counts - Fast disease progression
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Humberto Valenzuela-Ponce NATURE SCIENTIFICREpoRTS | (2018) 8:6111 | DOI:10.1038/s41598-018-23849-7
Using univariable and multivariable analyses
we evaluated HLA associations with five HIV clinical
parameters in 3,213 HIV clade B-infected, ARTnaïve
individuals from Mexico and Central America
(MEX/CAM cohort).
Novel protective and risk
HLA alleles in
populations with
Amerindian ancestry
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Novel protective and risk
HLA alleles in
populations with
Amerindian ancestry
Humberto Valenzuela-Ponce NATURE SCIENTIFICREpoRTS | (2018) 8:6111 | DOI:10.1038/s41598-018-23849-7
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Novel protective and risk
HLA alleles in
populations with
Amerindian, African and
caucasoid ancestry
Humberto Valenzuela-Ponce NATURE SCIENTIFICREpoRTS | (2018) 8:6111 | DOI:10.1038/s41598-018-23849-7
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HLA and response to Rilpivirine
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7,772 naïve pacients, 16 cohorts, 43 countries, 5 continents. RT-E138X mutation was associated to HLA-B∗ 18 It is an scape mutation thad conferes resistance to Rilpivirina. This is important since Rilpivirine is use in first line squemes and for PrEP.
Gatanaga H et al AIDS. 31(14):1935–1943, SEPTEMBER 10, 2017
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• Identificación de nuevos alelos del HLA clase 1 asociados a progreso (B*35, B*39 y C*03) o protección (B*15) en población amerindia en Meosoamérica. Es la primera vez que se obtiene esta información en Amerindios en la región.
• En Panamá se encontró un posible nuevo alelo de origen africano HLA A*33.o1 asociado a progreso rápido y mayor susceptibilidad a la infección con el VIH.
• Estudios de HLA usando secuenciación de segunda generación se iniciarán le próximo año usando el sistema Illumina.
16
CONCLUSION
• New HLA clase 1 alleles were associated with progression (B*35,
B*39 and C*03) o protection (B*15) in Amerindian population in
Mesoamerica.
• In Panama, a new allele HLA A*33.o1 associated with fast
progression in africanamerican descendant.
• Despite observed HLA-B∗ 18, resistance to rilpivirine in Panama is
low but the situation needs to monitored.
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CCR5: usage and deletion
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Ciclo del VIH
LT CD4
CD4 CCR5
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Marker or progression
CD4 and co-receptors (CCR5, CXCR4, CCR2)
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CCR5-wt
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CCR5-32
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Timothy Brown Road to a Cure for HIV
HIV+ Acute Myeloid Leukemia
Patient
Identification of HLA-identical,
CCR5Δ32 homozygous bone
marrow donor
Chemo- and Radiotherapy
Conditioning
Allogeneic stem cell transplant
6 years later: remains cured
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RESULTADOS
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P= 0.0066 Polimorfismo tiene un efecto
protector 70%
P= 0.0185 Polimorfismo tiene un efecto
protector 60%
Zaldivar Y et al. AIDS 2010
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Gene Therapy in blood cells
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Therapeutic HIV protection gene
Gene Therapy in blood cells
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Gene Therapy in blood cells
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Gene Therapy in blood cells
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Therapeutic HIV protection gene
Gene Therapy in blood cells
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Gene edition with CRISPR
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Pacient
Ex Vivo Gene Therapy
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Pacient
Mobilización
Leucoféresis
O
Cosecha de médula
ósea
Ex Vivo Gene Therapy
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Pacient
Transferencia mediada por virus de Gen Terapéutico
OBJETIVO: Células modificadas
autotransplantadas corrigen o curan la
enfermedad
- Cáncer
- Enfermedades genéticas
- Enfermedades infecciosas
Ex Vivo Gene Therapy
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Paciente
Reinfusión
Ex Vivo Gene Therapy
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Modulación inmune CAR
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Another cure example When luck is with you
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INDIVIDUAL IMMUNE RESPONSE AND PM
Through deeper understanding of host immunity, not only will we be able to
1) Identify those at higher risk for infection,
2) Predict individuals who will have poorer outcomes with immune
modulating therapy, and
3) Determine who is destined for therapeutic failure therefore allowing
healthcare providers to adjust therapy in time, but we may also see the rise
of immunotherapeutics tailored specifically for infectious diseases.
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INDIVIDUAL IMMUNE RESPONSE AND PM
Maha A. Al-Mozaini and Michael K. Mansour. Saudi Med J 2016; Vol. 37 (12)
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HANTAVIRUS
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Choclo
Único virus asociado a enfermedad
Pulmón: Neumonitis intersticial, con acumulación de plasma en alveolos.
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0
50
100
150
200
250
300
350
400
450
TNF IL-6 IL-1 IL-8
Cyt
oki
ne
leve
ls p
g/m
l
Cytokines by severity of symptoms
SEVEREMILD
p=0.013
p=0.002
p=0.449
p=0.118
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0
500
1000
1500
2000
2500
3000
3500
4000
4500
SEVERE MILD/MOD SER POS SER NEG
Cyt
oki
ne
leve
ls p
g/m
l
IL-2R by severity of disease
p=0.008
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0
100
200
300
400
500
600
TNF IL-6 IL-1 IL-8
Niv
eles
de
cito
cin
a p
g/m
l
SPH y Letalidad
MUERTO VIVO
p=0.016
p=<0.001
p=0.006
p=0.161
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CAN PRECISION MEDICINE REDUCE AMR?
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www.gorgas.gob.pa Lasalvia L and Merges R. Journal of Precision Medicine | Volume 5 | Issue 3 | August 2019
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PRESENT SITUATION
The traditional diagnostic paradigm is to send off diagnostic test after diagnostic test
– and still have no solid diagnosis, and treat patients empirically based on our best
guess.
Infectious diseases are rarely considered as model applications of personalized
medicine, however, this perception is slowly changing as the utility of biomarkers
linked to the immune response, infectious disease susceptibility, host-microbiota
interactions, or hypersensitivity to antimicrobial drug treatment is being
demonstrated
Bissonnette L and Bergeron M. J. Pers. Med. 2012, 2, 50-70; doi:10.3390/jpm2020050
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EXAMPLES: Reduce AMR The empiric management of infections is a clinical practice recognized to have induced an overuse
of broad-spectrum antibiotics that
1. Increased the selective pressure on microorganisms which in return evolved and/or transmitted
antimicrobial resistance mechanisms and genes that threaten the efficiency of the last weapons
available to combat "superbugs" such as vancomycin,
2. Contributed to the emergence of drug-resistant hospital-acquired infections which
unnecessarily claim hundreds of thousands of lives annually, and
3. Are responsible for severe complications like allergy or disturbance of the normal microbiota
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The right treatment, at the right dose, at the right time for the right patient
The trick now is to find cost-effective ways to scale up this potential
game changer so its transformative power can be unleashed on a
larger scale.
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Lasalvia L and Merges R. Journal of Precision Medicine | Volume 5 | Issue 3 | August 2019
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EXAMPLES: Reduce AMR
McGeer A et al showed that shown that 89% of patients with laboratory-confirmed
flu diagnostics had received unnecessary (and not effective) antibacterial
therapy upon admission in a Canadian hospital.
In the daily practice of medicine, if the result of a microbial identification test performed on a very
symptomatic patient would be available within an hour or two, the physician
would dispose of highly useful information to initiate an appropriate therapy.
McGeer A et al. Toronto Invasive Bacterial Diseases Network. Antiviral Therapy and Outcomes of Influenza Requiring Hospitalization in Ontario, Canada. Clin. Infect. Dis. 2007, 45, 1568–1575.
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PRECISION MEDICINE AND OUTBREAKS
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Emergent pathogens introduction and globalization
- Septiember 2016: a migrant arrived to Panama through Darien from Nepal with fever, jaundice, and vomiting
- We have to discard Yellow Fever since he has been traveling through Brasil and Colombia. Final Dg was Hepatitis E.
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PRECISION MEDICINE AND VACCINES
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The 4 P: Predictive, Preventive, Participatory, Personalized
Doherty/Di Pasquale/Michel/Del Giudice. Gerontology. November 26, 2019
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GRACIAS
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¿PREGUNTAS?
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A potentially life-threatening hypersensitive reaction occurs in association with initiation of HIV
nucleoside analogue abacavir therapy in 4 to 8% of patients. Preliminary studies appear to confirm
the role of the immune system in abacavir hypersensitivity. The reaction is possibly the result of
presentation of drug peptides onto HLA, that may induce a pathogenic T-cell response.
Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701
allele and prospective HLA-B*5701 genetic screening has now been instituted in clinical practice to
reduce the risk of hypersensitivity reaction.
HLA and HLA-B*5701