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Visceral Leishmaniasis and HIV Co-infection

Felipe, Josy, Leo, Michelle & Ricky (Source: BBC) ‏. Visceral Leishmaniasis and HIV Co-infection. Q: Developing treatment protocol for VL/HIV co-infected patients to prevent high rates of relapse. Overview. Introduction Prevalance of Co-infection Age Distribution of Co-infection

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Visceral Leishmaniasis and HIV Co-infection

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  1. Felipe, Josy, Leo, Michelle & Ricky (Source: BBC)‏ Visceral Leishmaniasis and HIV Co-infection

  2. Q: Developing treatment protocol for VL/HIV co-infected patients to prevent high rates of relapse.

  3. Overview • Introduction • Prevalance of Co-infection • Age Distribution of Co-infection • Primary Infection vs. Relapse • Modes of Transmission • Diagnosis • Current Methods of Treatment • Our Study Design • Recommendations • Recent Developments

  4. Introduction World • Cases of co-infection in 34 countries -70% cases of VL/HIV co-infection in Southern Europe -100 cases in Brazil by 2003 • VL Relapse in absence of secondary prophylaxis -6 months: 60% -12 months: 90% (CDC, 2006)‏ Araçatuba (2007)‏ • 10 cases of co-infection • 3 deaths from patients with co-infection (CVE, 2007)

  5. Source: World Health Organization.  Leishmaniasis/HIV coinfection.   http://www.who.int/leishmaniasis/leishmaniasis_maps/en/index1.html Global Burden

  6. Brazil: Prevalence of Co-infection Figure: The biennial (e) and cumulative (f) numbers of Leishmania/HIV co-infection cases in Brazil Source: Rabello A, Orsini M, Disch J.  Leishmania/HIV co-infection in Brazil: an appraisal.  Ann Trop Medical Parasitol.   2003 Oct; 97 Suppl 1:17-28.

  7. The Spread of VL/HIV Co-infection • VL is a common infection for advanced HIV -77-90% of patients: CD-4 count < 200 cells/mm • HIV grows less urban while VL grows less rural -Rise of co-infection in peri-urban areas (i.e., the periphery of Araçatuba) -Higher rates of VL in older endemic areas • Burden: marginalized populations -Issues: unemployment, low levels of income, education, malnutrition, lack of access to quality healthcare, unsanitary conditions, etc.

  8. Source: Rabello A, Orsini M, Disch J.  Leishmania/HIV co-infection in Brazil: an appraisal.  Ann Trop Medical Parasitol.   2003 Oct; 97 Suppl 1:17-28. Age Distribution in Brazil (2003)‏

  9. Source: Dr. Adriana Lopes Cavalcanti, GVE XI – Aracatuba 1999 2000 2001 2002 2003 2004 2005 2006 2007 AGE M F M F M F M F M F M F M F M F M F > 1 1 1 - 4 5 - 9 10 - 14 15 - 19 20 - 29 2 1 2 1 30 - 39 1 1 1 2 3 1 1 1 2 6 40 - 49 1 2 2 1 1 1 1 1 1 1 50 - 59 1 1 > 60 1 1 TOTAL 1 1 1 5 6 4 1 3 2 6 2 8 2 Araçatuba: Co-infection by Age

  10. Clinical Characteristics of VL in Araçatuba, 1999-2007

  11. Primary Infection vs. Relapse • Primary infection due to lymphocyte decrease caused by HIV infection • Latent infection reactivated by immune system suppression (i.e. HIV, transplant patients) • Asymptomatic patients with positive skin tests formed VL symptoms after immunosuppression (Italy and France) • Mode of transmission • Europe: 60-70% of co-infected from IVDU • Rest of world: 15% of co-infected from IVDU (Alvar, 2006)‏

  12. Source: Cruz et al. Leishmania/HIV co-infections in the second decade. Indian J Med Res 2006 March; 123: 357-388. Modes of Transmission

  13. Source: Rabello A, Orsini M, Disch J.  Leishmania/HIV co-infection in Brazil: an appraisal.  Ann Trop Medical Parasitol.   2003 Oct; 97 Suppl 1:17-28. Brazil: Modes of Transmission

  14. Diagnosis and Treatment

  15. Diagnosis Parasitologic - Spleen aspirations (Sens. 94.7-96.4%, Mort. 1%), bone marrow (Sens. 67-94%), lymph node (Sens. 52.6-59%), or liver biopsy (Sens. 76.9-91%, Mort. risk)‏ Culture -64-67% sensitivity Serology -Enzyme immunoassay +ELISA +ICT -Agglutination tests (DAT)‏ PCR -72-100% sensitivity -Post-treatment monitor

  16. Problems in Diagnosis • Non-specific clinical symptoms -fever, malaise, anorexia, splenomegaly • Sensitivity of diagnostic tests - bone marrow aspirates, ELISA • Limitations of serology of VL -not used in endemic areas -20% of co-infected patients test negative • Long incubation of canine and human hosts • Personnel & cost of molecular techniques

  17. Main Methods of Treatment • Pentavalent Antimonials • Amphotericin B • Liposomal Amphotericin B • Pentamidine • Paramomycin • Miltefosine

  18. Methods of Treatment: Araçatuba · Liposomal Amphotericin B-3-5mg/kg/day for 5 consecutive days and additional dose for following 5 days -Used for: -children < 10 yrs., adults >50 yrs., HIV co-infection, immunosuppressed patients, pregnant women, failure with Antimonial Tx., and relapsed patients · Pentavalent Antimonials -20mg/kg/day for 20-30 days · Amphotericin B -0.5-1mg/kg/day for 20 days

  19. Problems with Treatment • High toxicity of Antimonials -pancreatitis -cardiac arrythmias -renal insufficiency • High toxicity of Amphotericin B -nephrotoxicity • High cost of Liposomal Amphotericin B • High rates of relapse in VL/HIV co-infected • High rates of death (25%) in advanced HIV/VL pop.

  20. Prospective non-randomized non-controlled Trial Goal:To examine methods of treatment for VL among patients with co-infection in Araçatuba Sample Size (n = 100) Duration: 2008 – 2011 Inclusion Criteria: Cases (i) Adults (>=18 years) who are HIV-infected patients with VL (ii) Any HIV patients with first infection or relapse of VL (iii) Any patients should received at least one dose of secondary prophylaxis. (iv) All patients should be under HAART. If patients were not receiving HAART when VL was diagnosed, this treatment was initiated after the fifth dose of L-AMB. (v) Patients who receive extended periods of treatment at first infection or relapse Our Study Design

  21. Experimental Methods • Forms of Secondary Prophylaxis • 1. Liposomal Amphotericin B at 5 mg/kg every 3 weeks • 2. Meglumine antimoniate at 20 mg/kg every 15 days by IV/IM. • 3. Amphotericin B at 1mg/kg/mo • Forms of Treatment by Duration • -Liposomal amphotericin B • 1. 4mg/kg for 5 consecutive days, another dose 5 days a/f • 2. 4mg/kg for 10 consecutive days, another dose 5 days a/f • 3. 4mg/kg for 20 consecutive days, another dose 5 days a/f

  22. Variables • Dependent • proportion of patients remaining relapse-free at several time points (6, 12, 24 and 36 months). • Independent • Age, Gender • Race • Levels of income (individual, household and neighborhood), education, occupation • Mode of transmission • Duration of L-AMB treatment • Types of secondary prophylaxis • CD-4 counts, viral loads, hx previous infxns • Levels of resistance to treatment

  23. Study Limitations · Drug toxicity · Resistance to drugs · Patient Compliance · Sample size · Issues with measurement (i.e, levels of resistance) · Issues with missing data (i.e., race, income) · High cost of treatment · Research funding & support

  24. Recommendations • Analyze data from Araçatuba • Observe trends in treatment and patient relapse • Examine socioeconomic conditions of patients • Income, race, education, and occupation • Goals • Improvements in diagnosis and treatment • Reduction in relapse • Consistent treatment protocol for co-infection • Decreasing drug toxicity

  25. Recent Developments • Diagnostic Tools • Direct agglutination test (DAT) • Urine antigen-detection test • Development of species-specific primers • Treatment • Miltefosine • Paramomycin • Vaccine

  26. Experimental Treatments • Miltefosine (used in India since 2002) • First oral drug • Issues:Teratogenic and Potential risk of resistance • Paramomycin (antibiotic used in India) • potential for multi-drug therapy • field experience of Médecins Sans Frontières (unpublished) • Vaccine • L. species antigenic variation rare - 1 vaccine may apply to several species • Long-term immunity (med. by Th-1 cells) • Currently in phase I clinical trial

  27. References • Alvar, Jorge et al. Leishmania and Human Immunodeficieny Virus Coinfection: the First 10 Years. Clinical Microbiology Review, April 1997, 298-319. • Arias JR, Monteiro PS, Zicker F. The reemergence of visceral leishmaniasis in Brazil. Emerg Infect Dis 1996;2:145-6.  • Cruz, I. Nieto, J. Moreno J. Canavate, C. Desjeux, P. Alvar, J. Leishmania/HIV co-infection in the second decade. Indian Journal of Medical Research.March 2006, pp 357-388. • Chappuis, F. Sundar, S. Hailu, A. Ghalib, H. Rijal, S. Peeling, RW. Alvar, J. Boelaert, M. Natural Reviews. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Microbiology. 2007 Nov;5(11):873-82. Review. • Laguna F.  Treatment of leishmaniasis in HIV-positive patients.   Ann Trop Medical Parasitol.  2003 Oct;97 Suppl 1:135-42. • Laguna F, et al. Amphotericin B Complex versus Meglumine Antimodiate in the treatment of Vic]sceral Leishmaniasis in patients infected with HIV: a Randomized Pilot Study. Journal of Antimicrobial Chemotherapy, July 2003, vol 52, pp. 464-468. • Lopes Cavalcanti, Adriana, M.D., GVE XI – Aracatuba. Lecture, January 17, 2008. • Minodier, Phillipe et al. Lipsomal Amphotericin B in the Treatment of Visceral Leishmaniasis in Immuoncompetent Patients. Fundamental & Clinical Pharmacology, 2003, vol 17, 183-188. • Molina I, Falco V, Crespo M, Riera C, Ribera E, Curran A, Carrio J, Diaz M, Villar del Saz S, Fisa R, López-Chejade P, Ocan I and Pahissa A. Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. Journal of Antimicrobial Chemotherapy (2007) 60, 837–842.

  28. References cont. • Murray HW.Treatment of visceral leishmaniasis (kala-azar): A decade of progress and future approaches. International Journal of Infectious Diseases 2000;4:158-77. • Pintado V, Martín-Rabadán P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)- infected and non-HIV-infected patients: A comparative study. Medicine 2001;80:54-73. • Pasqual F, Ena J, Sanchez R, Cuadrado JM, Amador C, Flores J, Benito C, Redondo C, Lacruz J, Abril V, Onofre J. Leishmaniasis as an opportunistic infection in HIV-infected patients: determinants of relapse and mortality in a collaborative study of 228 episodes in a Mediterreanean region. Leishmania HIV Mediterreanean Co-operative Group. European Journal of Clinical Microbiology Infectious Diseases. 2005 Jun;24(6):411-8 • Rabello A, Orsini M, Disch J.  Leishmania/HIV co-infection in Brazil: an appraisal.  Ann Trop Medical Parasitol.   2003 Oct;97 Suppl 1:17-28. • Sinha, PK. Pandey, K. Bhattacharya, SK. Diagnosis & management of leishmania/HIV co-infection. Indian Journal of Medical Research. 2005 Apr;121(4):407-14. Review. • Sundar S, Jha TK, Thakur CP, at al. Oral miltefosine for Indian visceral leishmaniasis. New England Journal of Medicine 2002;347:1739-46 • World Health Organization.  Leishmaniasis and HIV coinfection.   http://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinfection/en/index.html

  29. MUITO OBRIGADA!

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