overview of neglected tropical diseases and their impact on hiv: chagas disease, leishmaniasis and...
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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: [email protected] 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: [email protected])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