precision medicine and infectious diseases...2020/01/11  · available to combat...

Precision Medicine and Infectious Diseases

Juan Miguel Pascale MD, MSc, PhD Facultad de Medicina, U de Panamá

Instituto Conmemorativo Gorgas jmpascale@gorgas.gob.pa

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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

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

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

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

• 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

Gene Therapy in blood cells

Therapeutic HIV protection gene

Gene Therapy in blood cells

Gene Therapy in blood cells

Gene Therapy in blood cells

Therapeutic HIV protection gene

Gene Therapy in blood cells

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Gene edition with CRISPR

Pacient

Ex Vivo Gene Therapy

Pacient

Mobilización

Leucoféresis

O

Cosecha de médula

ósea

Ex Vivo Gene Therapy

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

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.

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

Choclo

Único virus asociado a enfermedad

Pulmón: Neumonitis intersticial, con acumulación de plasma en alveolos.

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

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

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?

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.

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

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