Vises Futuras da Leishmaniose Tegumentar Americana

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Collaborative Course on Infectious
Diseases January 2009
LECTURE 6 Visions of the Future of
Mucocutaneous Leishmaniasis Jackson M. L.
Costa Gonçalo Moniz Research Center -
FIOCRUZ jcosta_at_bahia.fiocruz.br
Harvard School of Public Health Centro de
Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz
(Fiocruz) Brazil Studies Program, DRCLAS,
Harvard University
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Mucocutaneous Leishmaniasis
It is impossible to understand the future
without understanding the past
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Objectives

• To understand Mucocutaneous Leishmaniasis in
  Brazil
• To learn about the importance of different
  clinical forms of the disease
• To discuss different factors that contribute to
  the persistence of the disease in Brazil
• To consider different options for controlling the
  disease

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Leishmaniasis (Present Visions)
According to the World Health Organization

• ? One of the 6 diseases responsible for the
  endemic diseases in the world
• ? Approximately 350 million residents in risk
  areas are infected
• ? 1 to 2 million individuals fall ill yearly
• ? Around 12 million individuals are infected
  yearly
• ? 40,000 patients yearly in Brazil
• 2nd in medical importance among diseases caused
  by protozoans
• Category 1 disease emergent and uncontrolled

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Leishmaniasis
Belongs to Tropical Neglected Diseases
? 1/3 of world population is impacted ?
Occur in poor populations ? People lack
political power low priority ? They cause
disabilities, mutilations, deaths, and
discrimination ? Low profitability for
pharmaceutical industry
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Mucocutaneous Leishmaniasis Characteristics
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Mucocutaneous leishmaniasis (MCL) or
Tegumentary leishmaniasis (TL)
? It is an infectious disease, not contagious,
caused by different protozoan species of genus
Leishmania, that occur in the skin and mucous.
Primarily, it is a zoonotic infection occurring
in other animals and then, secondarily, involving
man.
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Development of mucosal lesions in Brazil

• The lifetime risk of mucosal lesion is likely
  under 10 during the first 5-10 years after the
  primary lesions start (experience in Três Braços,
  Bahia, Brazil)
• No evidence in the literature in support of a
  non-zero protective efficacy for any Sb5 regime.

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Extension of Mucosal Lesions
Development of mucosal lesions in Brazil

• Nose
• Nasopharynx
• Palate
• Epiglottis
• Larynx
• Vocal cords
• Trachea
• Conjuntiva

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Mucocutaneous Leishmaniasis
Diffuse Cutaneous Leishmaniasis
Cutaneous Leishmaniasis
Mucosal leishmaniasis
L. Amazonensis L. mexicana
L. braziliensis L. amazonensis L. guyanensis
L. braziliensis L.Peruviana
Parasites macrophages Celular immun
- Antibodies IFN-? - IL-10
Parasites macrophages Celular immun
Antibodies IFN-???? IL-10
Parasites macrophages Celular immun
Antibodies IFN-??? IL-10
SVS - Ministério da Saúde do Brasil, 2003
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Mucocutaneous Leishmaniasis
What were the advancements?
1 Epidemiology 2 Clinical Aspects 3
Laboratorial Diagnosis 3 Therapeutics 4
Controls 5 Epidemiologic Vigilance
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Mucocutaneous Leishmaniasis
Epidemiology
1 Definitions of epidemiologic patterns 2
Characterization of the cycles of transmission in
Brazilian regions 3 Characterization of the
principal leishmanias responsible for the
disease in Brazil and other countries of
the Americas 4 Characterization of the main
vectors (phlebotomines) responsible for the
transmission of the parasite 5 Knowledge of
the importance of wild reservoirs in the
transmission cycle of the disease.
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Histophatology Culture Xenodiagnosis Pcr
Border of lesion Ganglios Blood
Direct Methods
Biopsy/Smears
Western Blots
Specific
Serology
IFI ELISA
Nonspecific
Indirect Methods
Celular immunity
Skin test (leishmanin)
SVS-Ministério da Saúde do Brasil, 2003
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MUCOCUTANEOUS LEISHMANIASIS
Therapy

• Pentavalents Antimonials (First Line)
• Meglumine Antimoniate (Glucantime)
• Sodium Stibogluconate (Pentostam).
• Pentamidines (Second Lines)
• Pentamidine Isetionate (Pentacarinat)
• Pentamidine Mesilate (Pentam)
• Amphotericin B (Second Lines)
• Desoxicolate
• Lipidics Formulations
• Aminosidine Sulphate (Alternatives drugs)
• Miltefosine

Standardized schemes aiming To avoid Refractory

Primary Resistance
SVS-Ministerio da Saude do Brasil, 2003
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Mucocutaneous Leishmaniasis
Control and Vigilance
Early treatment of the confirmed cases
Identification of the etiologic agents
circulating in the region Knowledge
of the areas of transmission
Knowledge of the spatial distribution Circuits
of production of the disease Formation of human
resources
Brazilian Health Minister, 2003
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MUCOCUTANEOUS LEISHMANIASIS
METAXENIC DISEASE
Intermediate Host Susceptible Men
Vector
Etiologic Agent
Environmental Changes
Factors
Physical
Human or social
Biological
WHO, 1990
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Current questions that need urgent answers!
Challenges for the Future

• Epidemiology
• How will we achieve effective measures of control
  in relation to
• Etiologic Agent (Leishmania)
• Vectors
• Reservoirs
• Individual measures
• Environmental balance x Development
• Vaccines

SVS-Ministerio da Saude do Brasil, 2005
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MUCOCUTANEOUS LEISHMANIASIS 4) Strategies for
vaccine development

• Strains of Leishmania reduced by deletion of
  specific genes.
• Expression of specific peptides for reduced
  agents, like the BCG.
• Vaccines of DNA.
• Powers of dendritics cells
• Imunomodulation of the host against sandfly bites

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MUCOCUTANEOUS LEISHMANIASIS Vaccines against
Leishmaniasis

• What do we want ?
• A vaccine for human and / or animal
• Act against MCL and / or Visceral Leishmaniasis
• For protection against MCL, the vaccination of
  populations or segments with exhibition is a
  sensible alternative
• In VL, considering that a dog is an important
  reservoir and s responsible for the maintenance
  of the cycle, its vaccination is relevant.

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MUCOCUTANEOUS LEISHMANIASIS
Current questions that need urgent answers!
Challenges for the Future
Clinic Early diagnosis sensitive /
specific Organization of Services (Networks of
reference and against reference) Spontaneous
cure and its meaning (When or whom to treat) New
drugs Treatment unit dose / oral route
Fonte SVS-Ministerio da Saude do Brasil, 2005
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MUCOCUTANEOUS LEISHMANIASIS
Current questions that need urgent answers!
Perspectives for the future
Early Diagnosis sensitive / specific 1 -
Serology ELISA (Detection of Antibodies IgG and
IgM through soluble antigen of L. Mexicana
strain ATCC 50157) 2 - Molecular diagnosis
Polimerase Chain Reaction (PCR)
Fonte SVS-Ministerio da Saude do Brasil, 2005
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Results of different methods for the diagnosis
between Mucous Leishmaniasis and other diseases
in the state of Acre (Brazilian Amazonian)
(S) sensitivity (sp) specificity (a)
Inflamatory Process Chronic Nonspecific IC
Confidance Interval VPP Predictive Positive
Value VPN Predictive Negative Value
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LeishmaniasIs Therapies in the Americas (Studies
without Phase III)

• Pentavalents Antimonials (Sb5)
• (Favorable results in the treatment of the
  MCL in Brazil)
• Pentamidines
• (Several side effects observed - Few trials
  realized)
• Sulphate of Aminosidine
• (Few trials realized)
• Amphotericin B Phase II in Brazil
• (Desoxicolate Results in Montes Claros for
  VL 78/80 (97.5 ) with 14 doses of 1mg/kg/dia)
• Lipidics Formulations
• (Good results with colloidal dispersion
  20/20 (100)
• Anphotericin B Sb5 in Montes Claros for VL
• (Good results)
• Miltefosine
• (Trials in progress for MCL and VL)

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Leishmaniasis Therapies
Repercussion of the Current Situation

• 1 - The Sb5 presents good results and must be
  maintained like 1st line drugs
• 2 - Must be challenged by studies of Phase III
  with Anphotericin B Desoxicolate and / or Lipidic
  Formulations
• 3 - Aminosidine sulphate and Miltefosine must be
  valued at Phase II (Miltefosine is already).

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Leishmaniasis Therapies (SUGGESTIONS)

• Trials (Phase II) for Pentamidines, Aminosidine
  and Miltefosine.
• Trials (Phase III) for Anphotericin B
  (desoxicolate and lipidics formulations) x Sb5.
• Trials for co-infection of Leishmaniasis HIV.
• Studies on factors for prognosis identification
  of targets for prevention or early intervention.

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NECESSITY OF NEW DRUGS FOR THE TREATMENT OF THE
NEGLECTED DISEASES
Global diseases
Extremely neglected diseases
Neglected Diseases
Pharmaceutical world-wide marketgt 518 bi in 2004
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Pharmaceutical world-wide market (PERCENTAGE
THAT OCCUPY THE DEVELOPING COUNTRIES)
How will we resolve these Problems?
Pharmaceutical world-wide market, 2004 Total
518 billions
WHO,2004
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INSUFFICIENT PROGRESS REGARDING NEW TOOLS FOR
IMPROVING THE HEALTH OF POOR PEOPLE

• In spite of
• Increase in the global amount of research for
  health from US 30 bi in 1986 to US 106 bi in
  2004
• (Monitoring Financial Flows for Health
  Research, Global Forum for Health Research, 2004)
• Increased levels of protection of intellectual
  property did not result in an increase of RD of
  necessary medicines for global health
• (UK Commission on Intellectual Property Rights,
  2002)

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MUCOCUTANEOUS LEISHMANIASIS
Current questions that need urgent answers!
Challenges for the Future
Clinic Mucous Lesions Earlier marker Diffuse
cutaneous leishmaniasis Markers of cure
Residual Lesions Bone deformities (Therapeutic
schemes of proved efficiency) Co-infections How
to conduct?
Minister of Health of the Brazil, 2005
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MUCOCUTANEOUS LEISHMANIASIS
Current questions that Need Urgent Answers!
Challenges for the Future
CLINIC Mucous lesions Earlier markers Use of
several protocols of RAPD (Randomly Amplified
Polymorphic DNA). (To understand the importance
of the variability intra-specifics of L.
braziliensis)
SVS-Minister of Health of the Brazil, 2005
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Criteria of Definitive Cure in Diffuse Cutaneous
Leishmaniasis (DCL) in the State of the Maranhão
Brazil (2005)
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New Challenges in Diffuse Cutaneous Leishmaniasis

Study with New Drugs 1 - Lipossomal
Anphotericine B 2 - Imunotherapics
Chemotherapics 3 - Miltefosine
Imunogenetic Study 1 - Familiar study 2 - Genic
therapy
Criteria of Definitive Cure 1 - Clinical
evolution 2 - Laboratorial Diagnosis
(Immunologic and Parasitologic) 3 - Imaging
exams
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MUCOCUTANEOUS LEISHMANIASIS
It is an aspiration that strengthens our spirit,
which brings our conscience to see the
epidemiology, the clinic, the laboratory and the
clinical observation, hand in hand, in a
profitable alliance, elevating Brazilian
medicine, which will enter us in a prosperous
route of immense conquests Carlos Chagas
Thank you
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Discussion Questions

• What is the signficance of the different clinical
  forms of Mucocutaneous Leishmaniasis?
• What are the most effective strategies for
  controlling Mucocutaneous Leishmaniasis?
• What are the most important factors that
  contribute to the persistence of Mucocutaneous
  Leishmaniasis?