Visceral Leishmaniasis and HIV Coinfection

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Visceral Leishmaniasis and HIV Co-infection

• Felipe, Josy, Leo, Michelle Ricky
• 
  
  (Source BBC)?

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

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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)

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Global Burden

• Source World Health Organization. 
  Leishmaniasis/HIV coinfection.  
• http//www.who.int/leishmaniasis/leishmaniasis_map
  s/en/index1.html

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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 117-28.
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The Spread of VL/HIV Co-infection

• VL is a common infection for advanced HIV
• -77-90 of patients CD-4 count lt 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.

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Age Distribution in Brazil (2003)?

• Source Rabello A, Orsini M, Disch J. 
  Leishmania/HIV co-infection in Brazil an
  appraisal.  Ann Trop Medical Parasitol.   2003
  Oct 97 Suppl 117-28.

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Araçatuba Co-infection by Age

• Source Dr. Adriana Lopes Cavalcanti, GVE XI
  Aracatuba

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Clinical Characteristics of VL in Araçatuba,
1999-2007
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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)?

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Modes of Transmission

• Source Cruz et al. Leishmania/HIV co-infections
  in the second decade. Indian J Med Res 2006
  March 123 357-388.

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Brazil Modes of Transmission

• Source Rabello A, Orsini M, Disch J. 
  Leishmania/HIV co-infection in Brazil an
  appraisal.  Ann Trop Medical Parasitol.   2003
  Oct 97 Suppl 117-28.

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Diagnosis and Treatment
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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

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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
  

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Main Methods of Treatment

• Pentavalent Antimonials
• Amphotericin B
• Liposomal Amphotericin B
• Pentamidine
• Paramomycin
• Miltefosine

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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 lt 10 yrs.,
  adults gt50 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

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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.

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Our Study Design

• 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 (gt18 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
• 
  

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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

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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

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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

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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

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Recent Developments

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

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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

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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 19962145-6. 
• 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.
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• Laguna F.  Treatment of leishmaniasis in
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• Laguna F, et al. Amphotericin B Complex versus
  Meglumine Antimodiate in the treatment of
  Vicsceral 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.
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  Efficacy of liposomal amphotericin B for
  secondary prophylaxis of visceral leishmaniasis
  in HIV-infected patients. Journal of
  Antimicrobial Chemotherapy (2007) 60, 837842.

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References cont.

• Murray HW. Treatment of visceral leishmaniasis
  (kala-azar) A decade of progress and future
  approaches. International Journal of Infectious
  Diseases 20004158-77.
• Pintado V, Martín-Rabadán P, Rivera ML, Moreno S,
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  Leishmania HIV Mediterreanean Co-operative Group.
  European Journal of Clinical Microbiology
  Infectious Diseases. 2005 Jun24(6)411-8
• Rabello A, Orsini M, Disch J.  Leishmania/HIV
  co-infection in Brazil an appraisal.  Ann Trop
  Medical Parasitol.   2003 Oct97 Suppl 117-28.
• Sinha, PK. Pandey, K. Bhattacharya, SK. Diagnosis
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  Indian Journal of Medical Research. 2005
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• Sundar S, Jha TK, Thakur CP, at al. Oral
  miltefosine for Indian visceral leishmaniasis.
  New England Journal of Medicine 20023471739-46
  
• World Health Organization.  Leishmaniasis and HIV
  coinfection.   http//www.who.int/leishmaniasis/bu
  rden/hiv_coinfection/burden_hiv_coinfection/en/ind
  ex.html

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