Overview of Neglected tropical diseases and their impact on HIV: Chagas disease, Leishmaniasis and Endemic Mycoses

XIX International Aids Conference, 2012Washington, USA

Maria Aparecida Shikanai YasudaInfection on Immunosupressed Host Committee

Chagas disease Out patient clinicLaboratory of Clinical Investigation in Immunology

Hospital das Clínicas, Faculdade de MedicinaUniversity of São Paulo

WHO Technical Group IVb on Prevention and Control of Transmission of Chagas Diseaseand Case Management of Non- Congenital Infection

email: masyasuda@yahoo.com.brPhone 55 11 3061 7047/7048

CONFLICT OF INTEREST DISCLOSURE: NO CONFLICTS OF INTERESTS

HIV - parasite/host interactions: bi-directional influences I. Reactivation of parasitic disease in aids patients:Leishmania (M) and T. cruzi: blood and

tissues (ID mice)

.II HIV replication by the parasite: Stimulus on lymphocytes by Leishmania LPG: Promastigote Lipophosphoglycan (surface) and Upregulation of HIV gene expression by NF-B HIV load Chagas disease reactivation but experimental data in restricted systems: HIV replication by T. cruzi at placenta level/in human M culture

III. Changes in the immunopathology/ response to therapy

1. rate of reactivation of chronic iinfection (co-infecton without React)

2. Higher severity of the Reactvation: meningoencephallitis 75%, myo-

carditis 15% in Chagas disease reactivation, dissemination of

dermotropic Leishmnania to visceral organs ....

3. Decreased therapeutic sucess (more recidives, lower % of cure)

Increased lethality

III. Changes in the natural history of both HIV and parasite infection

1. Progress in the evolution of parasite disease: severe involvement of organs/ death

2. HIV progression (?): aids and occurrence of opportunistic infection

IV. Expansion of the HIV epidemic around the world + globalization of parasite infection: impact on parasite/HIV coinfections)

Andreani et al, 2009, PLoS ONE 4(12): e8246, Olivier et al, An. Trop. Med. Par 2003, ,97 (S 1): S79, Da Cruz et al., .S Br.Med.Trop 39(SIII) :75, 2006

HIV (a)/Trypanosoma cruzi (b), Leishmaniasis (d) co-infections

Andreani et al, Curr OpHiv Aids7:276, 2012

Epidemiology Chagas disease 1990 2000 2006____________________________________________Deaths (year) > 45000 21000 12500Human infection 106 cases) 30 18 15 (8) Annual Incidence 700 000 200 000 41200Population under risk (106) 100 40 28Distribution (countries) 21 19 18 ___________________________________________

Source: TDR/WHO, PAHO

T. cruzi and HIV co-infectionTH2 response: Parasitemia as cofactor for

reactivation1. A. Trypanosoma cruzi:

CD4< 200/μL in Chagas disease: 80% reactivated pt and IL4/IF ratio – co-infection SCID mice T. cruzi infected and IF : parasites with low levels of myocardial inflammation

but early mortality (Silva et al, 1993, Michailowsky et al, 2001).

parasites placental cultures Tc/HIV: ↓IL6,IL8, IP10 and MCP 1 (cytokines: downmodulate T. cruzi replication)

2. Higher parasitemia in coinfected T. cruzi/HIV without React. lead to > chance of reactivation (5 year prospective study)

Major chance of transmission by bood and derivatives Major chance vertical transmission (1-13.8% immunocompetents vs > 50% in co-infection) No polimorfisms or innate immunity have been analyzed.

3. Mortality up to 100% on dependence of early therapy, clinical severity Usually less than 20% with 60 days of treatment

Freitas et al, PLOS Neg. Trop. Dis, 2011; 5(8) e1277, Sartori et al. Ann. Trop. Med. Parasitol. 101:31-50, 2007,Scappelato et al, Rev. Soc. Bras. Med. Trop. 42:107, 2009; Freilij & Altchech 1995, 2:;551,

Nisida et al, Rev. Soc. Bras. Med. Trop 41:305, 1999 Recomendações, Rev. Soc.Bras.Med.Trop., 39:392- 2006

1) prevalence of T. cruzi/HIV coinfection (1.5%) (multicenter)/incidence Chagas disease reactivation(10-15%);2) active screening to imonitor T.cruzi/HIV coinfection before the reactivation of parasitic disease (underestimate: < 300 reported cases),3) predictive factors for disease reactivation (CD4 + parasitemia + HIV load);

Ramos Jr et al. J Infect Dev Ctries 2010; 4:682, Freitas et al, PLOS Neg. Trop. Dis, 2011; 5(8) e1277, Sartori et al. Ann. Trop. Med. Parasitol. 101:31-50, 200

Brazilian (International) Network for Attention and Studies on T.cruzi/HIV coinfection (10000-15000 co-infected patients in Brazil)

4) new drugs or drugs combination: > efficacy parasitological cure, < toxicity; % of recurrence after therapy;5) efficacy of secondary prophylaxis and its relationship with CD4+ T lymphocyte levels, HIV viral load and HAART therapy; 6) Monitoring of parasitemia and immunosupression (qPCR - pre-emptive therapy; 7) % of congenital transmission, and the morbidity-mortality rate among newborns, perinatal deaths/intervention;

8) Influence of genetic diversity of parasite (and HIV) and innate/acquired immunity in the co-infection and reactivation

Source: MoH /SVS -Brazil.

VL-HIV co-infection cases (%) reported in Brazil and % of co-infection

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Year

N V

L/H

IV

%V

L/H

IV

Cure 60-67% (glucantime/Amph B)Failures 34-40%Relapses 21-61%

Lethality 17,2% (mean) Variable from 0 - 30.7%

• HIV 100-2320X chance of VL endemic areas•In 2001 ~ 0.5% VL cases • In 2010 ~ 6.5% VL cases• Co-infection: •Cutaneous leishmaniasis 0.1% x 2% VL

Guidelines for Leishmania/ HIV-AIDS coinfection: Recommendations for diagnosis, treatment and follow-up of the patients – Secretaria de Vigilância em Saúde, Health Ministry, Brazil,

Olivier et al, An. Trop. Med. Parasitol.. 2003, 97 (S 1): S79, Da Cruz et al., Rev. Soc. Bras. Med. Trop. 39(SIII) :75, 2006, Cota et al, PLOS Neg.Trop Dis 5(6):e1153, 2011

} co-infections

Co-infection: ↓ CD4/μL, decreased IL15 (linked to TH1 response ) TH2Dendritic cell as Leishmania reservoirs: infected by HIV bind to DC-SIGN, enhanced entry)CD8 T cells more activated in Leishmania co-infected than HIV + patients

Brazilian Network of Leishmania/HIV co-infection GAPS in Co-infection HIV/Leishmania

• Immunopathogenesis– Recovery of immune response against Leishmania is related to CD4 and CD8?– Differential immune response in visceral and tegumentary leishmaniasis ?

• Genotyping of Leishmania X Pathogenesis

• Diagnosis: better serologic methods for antibody detection in co-infection(Recommendation: HIV serology to all VL patients (Brazilian Health Ministry)

• Sensitivity• Specificity

• Response to the treatment– Different drugs– Drugs association. Doses

José Angelo Lauletta Lindoso* (email: jlindoso@usp.br)Coordinator of the Brazilian Network of Leishmania/HIV co-infection

Paracoccidoides brasiliensis complex

Analysis of 65 isolates (8 regions in 5 nuclear loci)Matute et al. Mol. Biol. Evol. 23:65-73, 2006

S1 – 38 isolates: Argentina, Paraguai,Peru, Brazil, Venezuela

PS3: 21 Colombia

PS2- 5 Brazil 1 Venezuela

Richini-Pereira et al. , Mem Inst O Cruz 104: 636, 2009, Takayama et al, Med Mycology, 2009; 1: 9

A new species: Paracoccidioides lutzii :Main challenges for diagnosis, and clinical management

Paracoccidioides lutzii: divergent from S1, PS2 e PS3 Rondonia (North West egion) and Mato Grosso (Central West region): Secreted Antigens

from other regions: 26-45% Sensitivity X 92.3% com P. lutzii Biological differences, clinical expression and drug susceptibility?? Role in Immunocompetent and Immunosupressed patients (HIV)

Teixeira et al, Mol. Phylog. Evol. 2009; 52:273,Batista et al, ;Mycoses, 53:176, 2009, Morejon et al, Am..J Trop Med. Hyg. 2009, 80:359

1. HIV/Pbm Patients a. 1.5- 5% Paracoccidioidomycosis endemic area are HIV +b. are younger than immunocompetent patients, drug users. c. CD4 < 200/d l (> 80%)d. irregular anti-retroviral therapy (Viral load >= 30 000/l in 90%))

2. Clinical expression: lung + lymphohematogenic dissemination: Skin,bones, liver, spleen, lymphnodes

Immunosupressed patient: Chronic form + phagocytic mononuclear system dissemination - IMMUNE PROFILE UNKNOWN

Paracoccidioidomycosis/Histoplasmosis: hypergammaglobulinemia/polyclonal activation of Blymphocytes Immunocompetents: TH1 associated with protection, IF by M

Paracoccidioidomycosis and HIV infection

Opportunistic disease that changes the natural history of the infection with P. brasiliensis: should be considered as condition that defines AIDS

Early diagnosis and treatment

3. Treatment Co-infection % Pbmycosis % period (months)

Remission or improvement 63 93.4 24Relapses 18.5 2.3 24 (p<0.05)Deaths (pbmycosis) 12.2 6.0 06Deaths (other causes) 14/45 6.0

Data from a Reference center – early diagnosis

Morejon et al, Amer. J. Trop. Med. Hyg. 2009, 80:359; Marques & Shikanai-Yasuda, 1994

Histoplasmosis and HIV/aids infection

In red:

Histoplasmosis/HIV, Ferreira & Borges, Rev Soc. Bras, Med.Trop. 2009, 42:192

Without HIV:Endemic in AmericaLess common: Europe and Asia

1.3 – 5% histoplasmosis in patients with HIV infection

Zerbe & Holland, CID 41:38, 2005,Goldman et al, CID 38:1485, 2004, Lee et al, Arth. Rheum. 46:2565, 2002

Histoplasmosis and aids:different clinical expressions due to genetic diversity?

Variable clinical expression and high lethality in intensive care units (30%)

Mortality is variable according to early diagnosis (?visceral forms:CNS) and therapeutic intervention

Influence of genetic diversity in the clinical expression and outcomes of the disease?

Data (%) Mora Unis Daher Chang Panamá* Badlley*____________________________________________________________________Skin 43.5 44.3 10.0 16.7 17.3 06.5Mucosa 08.8 14.3 1.9>3xHepatic Enzyme 94.7 62.5Pancytopenia 59.6 (mean SD) 34.6 (median)

CD4<100/dl 94.3 104179 80.0 16(2-450)

Hepato/Espl 66.7 35.7 34/18 40.0 42.3 10.9XR Ret.Dif.Inf. 61.4 32.9 48.0 (pneum) 52.3Fungemia 24.3 35.7 50.0Dissemination 83.3 93.5Lymphadenopathy 3.0 36.7

Mortality 23.0 38.6 32.0 40.0 12.5 12.0

Unis et al, 2004, Rev SBMT 30:463,De Francesco Daher et al Trop.Med. Int. Hlth 2007,12:118, Chang et al, 2007, Rev SBMT.49:37, Mora et al, 2008, Mycoses 51:136, Balley et al,D. Mic Inf Dis 2008,62:151

Major challenges

Chagas disease, Leishmaniasis, Paracoccidioidomycosis, Histoplasmosis

Analysis of the Prevalence of co-infection in different countries, including population of

major risk for transmission of both infections and reactivation of parasitic disease:

(clinical regional aspects)

Look for accessible screening sensitive methods for early diagnosis of the co-infection

and reactivation to guarantee

Best therapeutic approach and prophylaxis directed to special risks population

(and/or preemptive therapy)

Look for more efficient and less toxic drugs and drugs combination

Analysis of the role of genetic diversity of parasites, and innate and acquired immunityin

the clinical expression and outocmes of the disease

Laboratório de Imunologia

LIM-48 HC-FMUSP

Vera Lúcia Teixeira de Freitas

Sheila Cristina Vicente da Silva

Célia Regina Furuchó

Paula Keiko Sato

SEAP/HIV Clínica Moléstias Infecciosas e Parasitárias

Ana Marli C. Sartori

Maria Christina Gallafrio

Noêmia Barbosa Carvalho

Laboratório de Parasitologia LIM-46 HC-FMUSP

Rita Cristina Bezerra

Erika Gakya

Instituto de Ciências Biomédicas – USP

Marta M. G. Teixeira

Instituto Adolfo Lutz - Setor Parasitoses Sistêmicas

Elisabeth V. Nunes

Osvaldo Silva

Thank you!

Fundação de Amparo à PesquisaEstado de São Paulo FAPESP

Conselho Nacional de DesenvolvimentoCientífico e Tecnológico CNPq

Ambulatório de Micoses SistêmicasAdriana Kono

Márcia Yoshida

International Network for Attention and Studies on HIV/T. cruzi co-infection

Brazilian Network of Leishmanaia/HIV co-infection