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Maria Aparecida Shikanai Yasuda Infection on Immunosupressed Host Committee

Overview of Neglected tropical diseases and their impact on HIV: Chagas disease , Leishmaniasis and Endemic Mycoses XIX International Aids Conference , 2012 Washington, USA. Maria Aparecida Shikanai Yasuda Infection on Immunosupressed Host Committee

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Maria Aparecida Shikanai Yasuda Infection on Immunosupressed Host Committee

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  1. Overview ofNeglected tropical diseasesandtheirimpacton HIV: Chagas disease, LeishmaniasisandEndemicMycosesXIX International Aids Conference, 2012Washington, USA Maria Aparecida ShikanaiYasuda InfectiononImmunosupressed Host Committee Chagas disease Out patientclinic LaboratoryofClinicalInvestigation in Immunology Hospital das Clínicas, Faculdade de Medicina Universityof São Paulo WHO TechnicalGroup IVb on Prevention and Control of Transmission of Chagas Disease and Case Management of Non- CongenitalInfection email: masyasuda@yahoo.com.br Phone 55 11 3061 7047/7048 CONFLICT OF INTEREST DISCLOSURE: NO CONFLICTS OF INTERESTS

  2. Reactivationofparasiticdisease in aids patients:Leishmania (M)andT. cruzi: bloodandtissues (ID mice) •  HIV replicationbythe parasite: StimulusonlymphocytesbyLeishmania LPG: • PromastigoteLipophosphoglycan (surface) andUpregulationof HIV gene expressionby NF-B •  HIV load Chagas disease reactivation but experimental data in restricted systems: •  HIV replicationbyT. cruziat placenta level/in human M culture • III. Changes in theimmunopathology/ response totherapy •  rate ofreactivationofchroniciinfection (co-infectonwithoutReact) • HigherseverityoftheReactvation: meningoencephallitis 75%, myo- • carditis 15% in Chagas diseasereactivation, disseminationof • dermotropicLeishmnaniato visceral organs .... • 3. Decreasedtherapeuticsucess (more recidives, lower % of cure) • Increasedlethality • III. Changes in the natural historyofboth HIV and parasite infection • 1. Progress in theevolutionof parasite disease: severeinvolvementoforgans/death • 2. HIV progression (?): aids and occurrence of opportunistic infection • IV. Expansion of the HIV epidemic around the world + globalization of parasite infection:impacton parasite/HIV coinfections) HIV - parasite/host interactions: bi-directionalinfluences Andreani et al, 2009, PLoS ONE 4(12): e8246, Olivier etal, An. Trop. Med. Par 2003, ,97 (S 1): S79, Da Cruz et al., .S Br.Med.Trop 39(SIII) :75, 2006

  3. HIV (a)/Trypanosoma cruzi(b), Leishmaniasis(d) co-infections Andreani et al, Curr Op HivAids7: 276, 2012 Epidemiology Chagas disease 1990 2000 2006 ____________________________________________ Deaths (year) > 45000 21000 12500 Human infection 106 cases) 30 18 15 (8) Annual Incidence 700 000 200 000 41200 Population under risk (106) 100 40 28 Distribution (countries) 21 19 18 ___________________________________________ Source: TDR/WHO, PAHO

  4. T. cruziand HIV co-infectionTH2 response: Parasitemia as cofactor for reactivation 1. A. Trypanosoma cruzi: CD4< 200/μL in Chagas disease: 80% reactivatedptand IL4/IF ratio – co-infection SCID mice T. cruziinfectedand IF :   parasites with low levels of myocardial inflammation but early mortality (Silva et al, 1993, Michailowsky et al, 2001).  parasites placentalculturesTc/HIV: ↓IL6,IL8, IP10 and MCP 1 (cytokines: downmodulateT. cruzireplication) 2. Higher parasitemiaincoinfectedT. 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% immunocompetentsvs > 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 etal, 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, Nisidaet al, Rev. Soc. Bras. Med. Trop 41:305, 1999 Recomendações, Rev. Soc.Bras.Med.Trop., 39:392- 2006

  5. Brazilian (International) Network for AttentionandStudiesonT.cruzi/HIV coinfection (10000-15000 co-infectedpatients in Brazil) 1) prevalence of T. cruzi/HIV coinfection (1.5%) (multicenter)/incidence Chagas disease reactivation(10-15%);2) active screening to imonitorT.cruzi/HIV coinfection before the reactivation of parasitic disease (underestimate: < 300 reported cases),3) predictive factors for disease reactivation (CD4 + parasitemia + HIV load); 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 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

  6. VL-HIV co-infection cases (%) reportedin Braziland % ofco-infection • 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 }co-infections Source: MoH /SVS -Brazil. • Co-infection: ↓ CD4/μL, decreased IL15 (linkedto TH1 response ) TH2 • Dendritic cell as Leishmaniareservoirs: infected by HIV bind to DC-SIGN, enhanced entry) • CD8 T cells more activated in Leishmania co-infected than HIV + patients Cure 60-67% (glucantime/AmphB) Failures 34-40% Relapses 21-61% Lethality 17,2% (mean) Variable from 0 - 30.7% Guidelines for Leishmania/ HIV-AIDS coinfection: Recommendations for diagnosis, treatment and follow-up of the patients – Secretaria de VigilânciaemSaúde, 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

  7. Brazilian Network ofLeishmania/HIV co-infectionGAPS in Co-infectionHIV/Leishmania • Immunopathogenesis • Recovery ofimmune response againstLeishmaniaisrelatedto CD4 andCD8? • Differential immune response in visceral and tegumentaryleishmaniasis ? • GenotypingofLeishmania X Pathogenesis • Diagnosis: betterserologicmethods for antibodydetection in co-infection (Recommendation: HIV serology to all VL patients (Brazilian Health Ministry) • Sensitivity • Specificity • Response to thetreatment • Differentdrugs • Drugsassociation. Doses José AngeloLaulettaLindoso* (email: jlindoso@usp.br) CoordinatoroftheBrazilian Network ofLeishmania/HIV co-infection

  8. Paracoccidoidesbrasiliensis complex S1 – 38 isolates: Argentina, Paraguai, Peru, Brazil, Venezuela Analysisof 65 isolates (8 regions in 5 nuclear loci) Matute et al. Mol. Biol. Evol. 23:65-73, 2006 PS2- 5 Brazil 1 Venezuela PS3: 21 Colombia Richini-Pereiraet al. , Mem InstO Cruz 104: 636, 2009, Takayama et al, Med Mycology, 2009; 1: 9

  9. A newspecies:Paracoccidioideslutzii :Mainchallenges for diagnosis, andclinical management Paracoccidioideslutzii: divergentfrom 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 • Biologicaldifferences, clinicalexpressionanddrugsusceptibility?? • Role in ImmunocompetentandImmunosupressedpatients (HIV) • HIV/Pbm Patients • a. 1.5- 5% Paracoccidioidomycosisendemicareaare HIV + • b. are youngerthanimmunocompetent patients, drug users. • c. CD4 < 200/d l (> 80%) • d. irregular anti-retroviral therapy (Viral load >= 30 000/l in 90%)) 2. Clinicalexpression: lung + lymphohematogenicdissemination: Skin,bones, liver, spleen, lymphnodes • Immunosupressed patient: Chronic form + phagocytic mononuclear system dissemination - IMMUNE PROFILE UNKNOWN • Paracoccidioidomycosis/Histoplasmosis: hypergammaglobulinemia/polyclonalactivationofBlymphocytes • Immunocompetents: TH1 associated with protection, IF by M Teixeira et al, Mol. Phylog. Evol. 2009; 52:273,Batista et al, ;Mycoses, 53:176, 2009, Morejonet al, Am..J Trop Med. Hyg. 2009, 80:359

  10. 3. TreatmentCo-infection % Pbmycosis % period (months) Remissionorimprovement 63 93.4 24 Relapses 18.5 2.3 24 (p<0.05) Deaths (pbmycosis) 12.2 6.0 06 Deaths (other causes) 14/45 6.0 Data from a Reference center – earlydiagnosis Paracoccidioidomycosis and HIV infection Opportunisticdiseasethatchangesthe natural historyoftheinfectionwith P. brasiliensis: shouldbeconsidered as conditionthat defines AIDS Earlydiagnosisandtreatment Morejonet al, Amer. J. Trop. Med. Hyg. 2009, 80:359; Marques & Shikanai-Yasuda, 1994

  11. Histoplasmosisand HIV/aidsinfection Without HIV: Endemic in America Lesscommon: EuropeandAsia In red: Histoplasmosis /HIV, Ferreira & Borges, RevSoc. Bras, Med.Trop. 2009, 42:192 1.3 – 5% histoplasmosis in patients with HIV infection Zerbe & Holland, CID 41:38, 2005, Goldman etal, CID 38:1485, 2004, Lee etal, Arth. Rheum. 46:2565, 2002

  12. 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 andprophylaxisdirectedtospecialriskspopulation (and/orpreemptivetherapy) • Look for more efficientandlesstoxicdrugsanddrugscombination Analysis of the role of genetic diversity of parasites, and innate and acquired immunityin the clinical expression and outocmes of the disease Variableclinicalexpressionand high lethality in intensivecareunits (30%) Mortalityis variableaccordingtoearlydiagnosis (?visceral forms:CNS) andtherapeuticintervention Influence of genetic diversity in the clinical expression and outcomes of the disease? Histoplasmosis and aids:different clinical expressions due to genetic diversity? Data (%) Mora Unis DaherChang Panamá* Badlley* ____________________________________________________________________ Skin 43.5 44.3 10.0 16.7 17.3 06.5 Mucosa 08.8 14.3 1.9 >3xHepatic Enzyme 94.7 62.5 Pancytopenia 59.6 (mean SD) 34.6 (median) CD4<100/dl 94.3 104179 80.0 16(2-450) Hepato/Espl 66.7 35.7 34/18 40.0 42.3 10.9 XR Ret.Dif.Inf. 61.4 32.9 48.0 (pneum) 52.3 Fungemia 24.3 35.7 50.0 Dissemination 83.3 93.5 Lymphadenopathy 3.0 36.7 Mortality 23.0 38.6 32.0 40.0 12.5 12.0 Unis etal, 2004, Rev SBMT 30:463,De Francesco Daheretal Trop.Med. Int. Hlth 2007,12:118, Chang etal, 2007, Rev SBMT.49:37, Mora etal, 2008, Mycoses 51:136, Balleyetal,D. MicInfDis 2008,62:151

  13. Thankyou! SEAP/HIV Clínica MoléstiasInfecciosas e Parasitárias Ana Marli C. Sartori Maria Christina Gallafrio Noêmia Barbosa Carvalho Laboratório de Imunologia LIM-48 HC-FMUSP Vera Lúcia Teixeira de Freitas Sheila Cristina Vicente da Silva Célia Regina Furuchó Paula Keiko Sato Ambulatório de Micoses Sistêmicas Adriana Kono Márcia Yoshida Laboratório de Parasitologia LIM-46 HC-FMUSP Rita Cristina Bezerra Erika Gakya Instituto Adolfo Lutz - Setor Parasitoses Sistêmicas Elisabeth V. Nunes Osvaldo Silva Fundação de Amparo à Pesquisa Estado de São Paulo FAPESP Brazilian Network ofLeishmanaia/HIV co-infection Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq Instituto de Ciências Biomédicas – USP Marta M. G. Teixeira International Network for AttentionandStudieson HIV/T. cruzico-infection

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