ANIS RASSI HOSPITAL

Sixth International Conference on Preventive Cardio logyFoz do Iguaçu - Brazil

May 21-25, 2005

Sixth International Conference on Preventive Cardio logyFoz do Iguaçu - Brazil

May 21-25, 2005

Anis Rassi Junior, MD, PhD, FACP, FACC, FAHAScientific Director, Anis Rassi Hospital

Goiânia (GO) - BRAZIL

Anis Rassi Junior, MD, PhD, FACP, FACC, FAHAScientific Director, Anis Rassi Hospital

Goiânia (GO) - BRAZIL

e-mail: arassijr@terra.com.br NO COMPETING INTERESTSNO COMPETING INTERESTS

Achievements in Preventing Chagas` Disease in Brazil

Achievements in Preventing Chagas` Disease in Brazil

ANIS RASSI HOSPITAL

Chagas: endemic countries

Chagas`DiseaseChagas`DiseaseAmerican Trypanosomiasis (zoonosis)•Impact: 10-12 million people infected (16 countries of Latin America)•Incidence: 200,000 new cases per year•Agent: Trypanosoma cruzi (I and II)•Hosts: all mammal species•Vector: Triatominae bugs (138 sp)•Morbidity of human Chagas`disease:20% to 43% develop cardiac and/or digestive disease•Control: Three multi-national control programs (Southern Cone, Andean Pact, and Central American)

American Trypanosomiasis (zoonosis)•Impact: 10-12 million people infected (16 countries of Latin America)•Incidence: 200,000 new cases per year•Agent: Trypanosoma cruzi (I and II)•Hosts: all mammal species•Vector: Triatominae bugs (138 sp)•Morbidity of human Chagas`disease:20% to 43% develop cardiac and/or digestive disease•Control: Three multi-national control programs (Southern Cone, Andean Pact, and Central American)

1909

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Initial acute phase•asymptomatic•symptomatic

Chronic phase•indeterminate

form

Chronic phase•determinate forms

(cardiac and/or digestive)

Deathor major

permanentdamage

T. cruzi infection

Tertiaryprevention

Prevention ofmorbidity and

mortality

Prevention ofmorbidity and

mortality

Secondaryprevention

Secondaryprevention

Preventionor

inhibitionof diseasein cases

whereinfection

has occured

Preventionor

inhibitionof diseasein cases

whereinfection

has occured

Primaryprevention

Prevention oftransmissionPrevention oftransmissionLEVELS OF

PREVENTIONIN CHAGAS`

DISEASE

LEVELS OFPREVENTIONIN CHAGAS`

DISEASE

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Chagas` DiseaseChagas` DiseasePrimary PreventionPrimary Prevention

Interventions designed to prevent the transmission of the disease

✓

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Chagas` DiseaseTransmission

Chagas` DiseaseTransmission

> 80%

16%

2%

< 1%

�Vector-borne transmission

�Blood transfusion

�Congenital

�Other mechanisms: (i.e. oral, organ transplant, laboratory accident)

AB+blood

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TRANSMISSION MECHANISMS OF HUMAN CHAGAS DISEASE and AVAILABLE PREVENTION TOOLS

TRANSMISSION MECHANISMS OF HUMAN CHAGAS DISEASE and AVAILABLE PREVENTION TOOLS

I : PRINCIPAL MECHANISMS

• Vector Transmission: insecticide, house improvement , education

• Blood Transfusion: donor selection, chemoprophilaxi s

• Congenital: early detection & treatment

II: OTHER MECHANISMS:

• Laboratory Accident: education, protection, chemopr ophilaxis

• Organ Transplantation: pre-selection, chemoprophila xis

• Oral Route: education, protection

No vaccine availableDIAS JCP

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R. prolixus

T. dimidiata

T. infestans

T. sordida

T. brasiliensis

P. megistus

R. prolixusR. prolixus

T. dimidiataT. dimidiata

P. megistusP. megistus

Geographical distribution of the triatomine vector species of major epidemiological importance in Chagas´ diseaseGeographical distribution of the triatomine vector species of major epidemiological importance in Chagas´ disease

•Most important vector

•Strictly domiciliated

•Higher infection rate

with T. cruzi

T. infestansT. infestans

V

E

C

T

O

R

T

R

A

N

S

M

I

S

S

I

O

N

V

E

C

T

O

R

T

R

A

N

S

M

I

S

S

I

O

N

ANIS RASSI HOSPITAL

•Spraying with insecticides

•Housing improvements

•Health education

Elimination of T.infestans

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INSECTICIDESYEARYEAR INSECTICIDESINSECTICIDES COMMENTSCOMMENTS

1975

1980

1950

MALATHION &FENTHION(Organophosphates)

DELTAMETHRIN(Pyrethroid)

HCH (BHC) &DIELDRIN(Organochlorines)

Strong and unpleasent smell;

not accepted by the

population

Residual effect of 12 months; applied just once; no smell; donot mark the house walls; lowanimal and human toxicity

Residual effect of short duration

(1 to 6 months); two sucessive

applications are needed

Ideal insecticide: low cost, easy manipulation, rapid onset of action, residual effect, no induction of resistance, and nontoxicIdeal insecticide: low cost, easy manipulation, rapid onset of action, residual effect, no induction of resistance, and nontoxic

ANIS RASSI HOSPITAL

Active Control Program to EliminateVector-Borne Transmission

Active Control Program to EliminateVector-Borne Transmission

a) Preparatory phase- mapping: number of species present, their dispersi on and infestation rates

- programming activities- estimation of resources

b) Attack phase- massive insecticide spraying of houses- second spraying 6 to 12 months later- selective re-spraying of re-infested homes

c) Surveillance phase- detection of residual foci of triatomines (involve ment of the community) – decentralized operations

MAP, SPRAY and PLACE UNDER COMMUNITY - BASED VIGILANCEMAP, SPRAY and PLACE UNDER COMMUNITY - BASED VIGILANCE

Moncayo A. Mem Inst Oswaldo Cruz 2003;98:577-591

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Achievements in Eliminating T. infestans in Brazila) Regional Initiative: State of São Paulo (1965-198 9)

- executed by SUCEN- large scale spraying with BHC- complete eradication of the main vector, T. infest ans (first region in Latin America)

b) Brazilian National Campaign (1983-1986)- planned and executed by staff of SUCAM- spraying initially with BHC; progressively replace d with pyrethroids

- partially successfully: 75% of the geographic obje ctives had been attained (assigned to a secondary place in 1986 with the return of Aedes aegypti and risk of dengue)

c) The Southern Cone Initiative (1991-2000)- joint agreement between the governments of six countries (Argentina, Bolivia, Brazil, Chile, Paragu ay, and Uruguay) to eliminate T. infestans from its entire geographic distribution

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No. of Municipalities Positive for Triatoma infestans in BrazilFollowing House Spraying Campaigns

No. of Municipalities Positive for Triatoma infestans in BrazilFollowing House Spraying Campaigns

XIIIa. Reunión Intergubernamental INCOSUR/Chagas, B s.As., Argentina, Marzo de 2004OPS/DPC/CD/308/04

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Infestedareas byT. infestans ,Brazil, 1975/2000

Infestedareas byT. infestans ,Brazil, 1975/2000

363

53109

721

No. of positive municipalities

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100

10

1

0.1

1985 1990 1995 20001980

Inci

denc

e ra

te (

%)

Year

UruguayBrazil ChileArgentinaParaguay

SOUTHERN CONE INITIATIVE(House Infestations by Triatomines)

SOUTHERN CONE INITIATIVE(House Infestations by Triatomines)

4.8%4.8%

26.0%26.0%

Source: National Chagas` disease control programmes

ANIS RASSI HOSPITAL

Serological Survey 100

10

1

0.1

0.011985 1990 1995 20001980

Inci

denc

e ra

te (

%)

Year

Uruguay (< 12 years)Brazil (7-14 years)Chile (< 10 years)Argentina (18 years)Paraguay (18 years)

SOUTHERN CONE INITIATIVE(Incidence of Infection)

SOUTHERN CONE INITIATIVE(Incidence of Infection)

0.2%0.2%

18.5%18.5%

Source: National Chagas` disease control programmes

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HOUSINGIMPROVEMENTS

HOUSINGIMPROVEMENTS

POSSE (GOIÁS)Owner: LFS

(1998)

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Transfusion -transmitted Chagas`diseaseTransfusion -transmitted Chagas`disease•Second main route of T. cruzi infection•Potential problem in non-endemic countries

INFECTIVITY RISK (for a 500-ml transfusion unit): 1 2% to 49%INFECTIVITY RISK (for a 500-ml transfusion unit): 1 2% to 49%

Risk depends on:

1) Prevalence of the infection in blood donors

2) Type and number of T. cruzi infected blood products transfused

3) Parasite concentration in the infected unit trans fused

4) Virulence of the parasite strain

5) Immunological status of the transfused recipient

Risk depends on:

1) Prevalence of the infection in blood donors

2) Type and number of T. cruzi infected blood products transfused

3) Parasite concentration in the infected unit trans fused

4) Virulence of the parasite strain

5) Immunological status of the transfused recipientMoraes-Souza H, Bordin JO, Langhi Jr. D. Control of blood transfusion transmission of American Trypano somiases. In:Maudlin I, Holmes PH, Miles MA (eds). The Trypanosomiases. CABI Publishing - UK, 2004, pp 479-490

ANIS RASSI HOSPITAL

Reduction in the Prevalence of InfectedBlood Donors in Brazil (1949 -1999)1,2

7,33

2,182,8

0

1

2

3

4

5

6

7

8

1949-1979 1980-1989 1999

T. cruziinfection rate

amongblood recipients

(x 100)

2. Moncayo A. Mem Inst Oswaldo Cruz 2003; 98:577-591

1. Moraes-Souza H, Bordin JO, Langhi Jr. D. Control of blood transfusion transmission of American Tryp anosomiases. In:Maudlin I, Holmes PH, Miles MA (eds). The Trypanosomiases. CABI Publishing - UK, 2004, pp 479-490

ANIS RASSI HOSPITAL

Downward Trend in Chagas` Disease Seroprevalence

Reasons…

1) Progressive reduction in the number of infected p eople entering the age for blood donation (successful con trol of vector-borne transmission)

2) Mandatory screening of blood donors for Chagas´ di sease in Brazil and discard of blood units reactive to serolo gic assays

3) Increase in the proportion of altruistic donation s and decrease in the proportion of paid/replacement donors

4) Implementation and implantation of hemo-therapy s ervices

5) Use of autologous blood transfusion

ANIS RASSI HOSPITAL

Mem Inst Oswaldo Cruz 2003; 98 :577-591

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Preventing T. cruzi TransmissionThrough Blood Tranfusion

1) Donor education

2) Identification of high-risk infectious blood dono rs by their history

3) Mandatory serology screening using at least two s erological tests

4) Elimination of all units of blood potentially inf ected, even those with nondiagnostic titers

5) Promotion of altruistic donations

6) Implementation of programs of quality control for serology

7) Treatment of the collected blood with gentian vio let in areas of high endemicity when serological tests cannot be pe rformed or when blood with positive serology cannot be disc arded

ANIS RASSI HOSPITAL

Oral Transmission of Chagas`DiseaseOral Transmission of Chagas`DiseaseIn the past: considered speculative

More recently: supported by 4 outbreaks of acute Ch agas` disease in Brazil, unequivocally related to the inge stion of contaminated food with T. cruzi . Associated with an unusual high number of fatal cases

RS (Teutônia)

PB (Catolé da Rocha)

AP (Igarapé da Fortaleza)

SC (roadside kiosk) Sugar cane juice

17

26

27

46

Regular meals and vegetables

Sugar cane juice and other foodstuff

Assai palm fruit juice

Local members of the community and tourists

Members of a farming community

Members of a wedding anniversary part

Local members of the community

6

2

???

6

1965

1986

2005

2005

Contaminatedfood

Year Locality No.deaths

Affected people No. acutecases

✓

✓

CONTAMINATION: 1) Feces of triatomines; 2) Marsupia l secretion;3) Crushed triatomine vector insects

ANIS RASSI HOSPITAL

Congenital Infection with T. cruziStrategies for Diagnosis and Control

Transmission rate: 1% to 12% (depends on the charac teristics from the infecting parasites, and the immunological , genetical and nutritional status of the mother)

Control: Etiological treatment of the newborn child (the sooner the best)

Diagnosis:

a) Mother: serological testing if positive history. Ideal: universal maternal serological testing

b) Children of mothers with positive Chagas serology :- At birth: parasitological tests (direct or indirec t)- After birth: conventional serological testing betw een 9 and 12 months of age

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Southern Cone Initiative for Chagas Control (INCOSUR)

Southern Cone Initiative for Chagas Control (INCOSUR)

Created and approved in 1991,during the 3 rd Meeting ofMinistries of Health of theSouthern Cone, Brasilia,Resolution 04-3-CS.

Objectives1. Elimination of T.

infestans.2. Reduction of the

domestic infestation by other vectors.

3. Elimination of transmission by blood transfusion.

Interruption of T. cruzi transmissionin following countries:• 1997: Uruguay

Vectorial, transfusional• 1999: Chile

Vectorial• 2000: Brazil

Vectorial, 10 of 12 endemic states• 2001: Argentina

Vectorial, 12 of 19 provinces• 2002: Paraguay

Department of Amabay, working on rest of endemic area• 2002: Bolivia

Start of activities, IDB/PAHO/UNDP support

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Area certified as havinginterrupted vectorial transmission

Infested Area

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Chagas` DiseaseChagas` DiseaseSecondary PreventionSecondary Prevention

Interventions designed to reduce the chance of developing clinical illness (i.e. to prevent or inhibit disease in cases where infection has occurred)

✓

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Chronic Chagas Heart DiseasePathologic Findings

Presence of T. cruzi antigens (arrows)Moderate myocarditis - no T. cruzi

Immunoperoxidase techniqueHematoxylin-eosin stain x 200

Bellotti et al . In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas’ heart disease. Am Heart J 1996;131:301

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BENZNIDAZOLE- More effective than Nifurtimox in Brazil. Similar efficacy in Argentina

- Dermopathy*- Peripheral sensitive polyneuropathy*- Dose of 10 mg/kg daily x 60 days: excellent tolerance and efficacy in children

NIFURTIMOX- commercialization discontinued- 2nd option (therapeutic failure or intolerance to Benznidazole)

✓

✓

*more frequent during treatment of patients in the c hronic phase

Etiological Treatment

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Chagas` Disease

Indications for Etiological Treatment

ANTIPARASITIC DRUGS:- Nifurtimox- Benznidazole Acute Chagas Disease

Recently acquired infection (children)

Reactivation of the infection following treatment by immunosuppresive drugs

Organ transplantation procedures

Indeterminate form and mild chronic cardiac form (investigational)

✓

✓

✓

✓

✓

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Trypanocidal Drugs for Chronic AsymptomaticT. Cruzi Infection

Meta-analysis of 5 randomized studies (n=756)

0,41 (0,09-1,85)

10,91 (6,07-19,58)*

5,37 (3,34-8,64)*

0,54 (0,31-0,84)*

OR (IC 95%)Outcome

ECG abnormalities

Negative seroconversion

Negative xenodiagnosis

Reduction of antibody titers

2/99

61/102

40/42

-

Placebo

5/99

6/98

21/43

-

Active

*p<0,01

Expressive results, particularly with the nitroimid azole derivatives (BZD & NFTMX)

Villar JC et al. The Cochrane Library, Issue 2, 200 3. OxfordVillar JC et al. The Cochrane Library, Issue 2, 200 3. Oxford

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ETIOLOGICAL TREATMENT OF CHAGAS DISEASEWITH BENZNIDAZOLE IN THE CHRONIC PHASE

Adults (n=171)*

Adults (n=33)

Ad. & Ch (n=120)

Adults (n=201)

Adults (n=120)

Children (n=129)

8.8%

0.0%

63.6%

30.0%

14.3%

6.9%

Macedo et al, 1987

Ianni et al, 1993

Miranda et al, 1994

Viotti et al, 1994

Fragata F o et al, 1995

Andrade et al, 1996

7

8

10-16

8

7-8

3

6.7%

13.3%

10.5%

4.2%

7.0%

1.7%

Control/Placebo

Development of Cardiopathy (ECG)

Authors DrugFollow up

(years)Population

* Includes cases treated with Nifurtimox

Long term follow up and evolution to cardiopathy

Rassi A. Arq Bras Cardiol 1998;71:643-6.

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ETIOLOGICAL TREATMENT OF CHAGAS DISEASE

0

10

20

30

40

50

60

70

80

Recent ChronicPhase

Acute Phase

60%70%

%CURE

CURE*

Negativation of xenodiagnosisNegativation of serological testsChange in the natural course of the disease

*

Rassi A. Unpublished data

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Chagas` DiseaseChagas` DiseaseTertiary PreventionTertiary Prevention

Interventions designed to limit human incapacity and to prevent morbidity and mortality, once disease has occurred

✓

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Chagas’ Heart DiseaseClinical Syndromes

• Arrhythmias- Tachyarrhythmias- Bradyarrhythmias

• Congestive Heart Failure- Biventricular (right > left)

• Thromboembolism- Systemic- Pulmonary

DEATHDEATH

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ACE inhibitors

DiureticsDigitalis

K repletion/K sparing diureticsNitratesHigh doses of loop diuretics; combination of diuretics/IV; B-adrenergic agonistsBeta-blocking agents (low dose)

AmiodaroneOral anticoagulation

Aspirin

Heparin and/or thrombolitic agentsSpironolactone

Asymptomatic LV dysfunction; symptomatic heart failureVolume overloadCardiomegaly; S3 gallop; Low EF; AF with rapid ventricular responseDiuretic-induced hypokalemiaPersistent congestive symptomsResistant CHF

Refractory CHF with persistent sinus tachycardia

Complex ventricular arrhythmiasDocumented intracavitary thrombus; previous thromboembolic phenomena; chronic AFApical aneurysm; severe ventricular dysfunctionAcute thromboembolic phenomenaSymptomatic heart failure (NYHA class III/IV)

++

CHRONIC CHAGASIC CARDIOMYOPATHY - DRUG THERAPY

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Cardiac transplantation

Intra-Aortic ballon pump

LV aneurysmectomy

Cardiac pacemaker

Catheter or surgical ablation

Automatic implantable defibrillator

Biventricular pacing

Catheter embolectomy

Refractory CHF, age < 55, NYHA class IV, PVR < 4 Wood units

To support patients until cardiac transplantation

Refractory CHF; multiple thromboembolic phenomena; refractory VT originating in regions adjacent to the aneurysm

Symptomatic SSS; 2nd degree AV block (MII); high grade AV block; 3rd degree AV block; AF with slow ventricular response

Drug refractory, hemodynamically stable and inducible VT

Refractory VF; drug refractory VT, not inducible or inducible but hemodynamically poor tolerated

CHF class II/III and ventricular desynchronism

Peripheral emboli

CHRONIC CHAGASIC CARDIOMYOPATHY - NONDRUG THERAPY

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BENEFIT

BENEFIT

Antiparasitic clinical trialDrug: benznidazole

Population: Chagas’ heart disease

• International• Multicentre• Prospective• Randomized• Double -blind• Placebo -controlled

“ BENznidazole Evaluation For Interrupting Trypanosomiasis”

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Coordination Steering Committee(Blinded)

Independent Data Safety Monitoring Board (DSMB)

50-70 clinical centers in 6 countries

BENEFIT: Study OrganizationBENEFIT: Study Organization

POPULATION HEALTHRESEARCH INSTITUTE

McMaster UniversityHamilton, Canada

National Coordinators(Blinded)

Co-Principal InvestigatorsJA Marin Neto (Brazil)

Carlos Morillo (Canada)

MembersÁlvaro Avezum Jr.

Stuart ConnolyRaul Espinosa

Fernando RosasSosa-Estani

Carlos MorilloAnis Rassi Jr.

Juan Carlos VillarAlberto Gianella

Alberto Laguna Torres

Anis Rassi Jr. (Brazil)

Sosa-Estani (Argentina)

Raul Espinosa (Venezuela)

Fernando Rosas (Colombia)

Alberto Gianella (Bolívia)

Victor Alberto LagunaTorres (Peru)

Co-ChairsSalim Yusuf

JA Marin Neto

PHRI

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BENEFITTrial

1,500 patientsPLACEBO

3,000 patientschronic Chagas`heart disease

1,500 patientsBENZNIDAZOLE

RExclude severe disease

PRIMARY ENDPOINTcombination of death, cardiac arrest resuscitation, sustained ventricular tachyarrhythmias, need for

pacemaker or defibrillator implant, thromboembolic phenomena or hospitalization for CHF

mean follow up: 5 years

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2 31

Inflammatorycells in

apoptosis

Cardiomyocyte Damagedcardiomyocyte

T. cruziamastigotes

Inflammatorycells

Bonemarrow

cells

Fibrosis

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Heart of chronic chagasic mice transplanted with transgenic GFP - BMC (15 days)

Anti GFP + Anti Miosin

GFP- BMC Ribeiro-dos-Santos e cols (unpublished data).

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Protocol• Prospective, single-center, open label, non-randomized, phase 1 clinical trial

• Feasibility, safety and potential efficacy

• 30 patients with advanced HF due to Chagas’ disease

• 180 days follow-up

Inclusion criteria:- Previous diagnosis of heart failure due to Chagas’ disease.- Stable (> 1 month) NYHA FC III and IV- Standard HF therapy- LVEF < 40% on echocardiogram (Simpson’s rule)- Both genders- Ages between 18 and 70 years.

Bone marrow cell transplantation in Chagas’ disease HF

Vilas Boas F

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p = 0.057

Left ventricular ejection fraction on Echo (Simpson)

Left

vent

ricul

ar e

ject

ion

frac

tion

(%)

TimeN = 10Friedman testBars represent mean ± 1 SE

Bone marrow cell transplantation in Chagas’ disease HF

Time (months)4210 6

Vilas Boas F

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Randomized Multicenter Study of Stem Cell Therapy i n Chagas` Heart Disease(EMRTCC)

•300 patients with CHF (age 18-75 years)•NYHA class III or IV; LVEF < 35%•No ICD; no Sust. VT; creatinine < 2,5 mg/dL•Optimized drug therapy

150 patientsSTEM CELL THERAPY

150 patientsPLACEBO (Saline)

Primary end point: - increase in LVEF (> 5% on avera ge)

Secondary end points: - total mortality- hospitalization- functional class- quality of life

randomization

Follow-up12 mo

sponsorsponsor

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• To maintain political will and a governmental agenda in endemic countries;• To maintain the minimum technical personnel for control activities and

programme administration;

• To improve (or to start) control actions in some Countries and in new areas: agricultural frontiers, Amazon, urban spaces;

• To improve and to maintain a sustainable surveillance in yet controlled areas;

• To improve vector control techniques and tools for the peri-domestic cycle;• To develop new and more effective drugs for specific treatment;• To provide medical attention for infected individuals in all endemic area,

mainly in early stages of chronic disease; • To develop better drugs and procedures concerning heart failure and

fibrosis management

THE FUTURE: CHALLENGES AND PRIORITIES FORCHAGAS`DISEASE CONTROL AND RESEARCH

DIAS JCP

ANIS RASSI HOSPITAL

SCD

Thromboembolism

CHF

- ACEI, espironolactone- Amiodarone, PACE, ICD- Oral anticoagulant- Etiological treatment??- Bone marrow transplant??

AB+blood

CHAGASAcute

Chronicindeterminate

- Elimination of vectorial transmission- Prophylaxis of transfusionaltransmission

CHAGASChronic

Determinate

- Etiological treatment(BZD)