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Koert RitmeijerMédecins sans Frontières
(MSF-Holland), Amsterdam
MSF and VL Control in East Africa: Operational Challenges
LeishRisk Workshop, ITM, Antwerp, 13 November 2007
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VL endemic areas in East Africa
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VL cases treated by MSF in East Africa, and outcomes, 1989-2006
Admissions Cure rate Death rate
Northern Sudan 33,467 92.2% 6.6%
Southern Sudan 36,018 90.1% 8.3%
Ethiopia 11,197 88.1% 10.1%
Uganda 2,437 96.3% 2.7%
Somalia 1,671 93.2% 7.6%
TOTAL 84,790 90.9% 7.6%
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Hospital (Humera, north-west Ethiopia)
Field Hospital (Um-el-Kher, eastern Sudan)
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Under the trees (southern Sudan)
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Characteristics of VL-endemic areas in East Africa
• Extremely remote and isolated areas
• Lack or absence of health infrastructure
• Lack of infrastructure • Poor access during rainy season • Active conflict or insecurity
Poor access to diagnosis & treatment facilitiesOnly an estimated 50% of VL patients can access treatmentCollin S. et al. 2006
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Primary Kala-azar Cure Rates 1998-2007
70
75
80
85
90
95
100
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
North SudanSouth SudanEthiopia
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Diagnosis of Visceral leishmaniasis
Clinical Case definition:• Fever (>2 weeks) excluding
malaria, with splenomegaly orlymphadenopathy, and wasting(Prior-probability in Sudan: ~50%)
Laboratory Confirmation Required:• Microscopy (spleen or
lymphnode aspirate)• Direct Agglutination Test (DAT)• Rapid serological strip test
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lymph node aspirate spleen aspirate
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Simple field labExperienced technicians
Direct Agglutination Test (DAT)
Borderline concept:High titer (≥ 1:6400) : positiveLow titer (≤ 1:400) : negativeIntermediate titer : aspirate
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DiaMed-IT-Leish® rapid diagnostic test based on rK39 antigen
• Sudan: 90% sensitivity, 99% specificity Ritmeijer K. et al. 2006
• Uganda: 97% sensitivity, 99% specificityChappuis F. et al. 2005
rK39: Simple, rapid, cheap “under the tree” diagnostic test
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Primary VL Diagnostic Algorithm
Borderline1/800 – 1/3200
spleen or lymphnode aspiration
Non kala-azar→ search otherdiagnosis + treat
kala-azar→ treatment
Kala-azar suspect : fever > 2 wks + splenomegaly + wasting
Direct Agglutination Test (DAT)
Negative< 1/400
Positive> 1/6400
- +
rK39 RDT +-
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Diagnostic Algorithm (future?)
Seek alternativediagnosis
Treat forKala-azar
Kala-azar suspect : fever > 2 wks + splenomegaly + wasting
High Specific rK39 Rapid Diagnostic Test
- +
High Sensitive rK39 Rapid Screening Test
+-
No alternativediagnosis found
Aspirate- +
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SSG (sodium stibogluconate):
Still very effective in African VL,
Cheap generic drug:($ 22 per patient vs. branded SSG (Pentostam): $ 200 per patient)
But:
• 30 days of daily painful injections
• SSG is toxic, especially in very sick patients, and those with HIV infection
high mortality
TREATMENT
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Risk Factors for Death
“Severe Kala-azar”
Odds of Death
BMI <13 11.0Hb <8 g/dl 4.0
Age <5 yrs 5.4Age >45 yrs 4.6
Collin S. et al. 2004Treatment of severe VL with AmBisome under
field conditions
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Essential management of complications:
Intercurrentinfections
Malnutrition
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Primary Kala-azar Death Rates 1998-2007
0%
5%
10%
15%
20%
25%
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
North SudanSouth SudanEthiopia
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Operational Strategies for VL control in East Africa
• No big gains to be expected from further medicalimprovements: difficult to further reduce mortality.
• Major gains to be expected from public health approach: increase access and coverage by further decentralisation of diagnostic and treatment services.
• Requires very simple diagnostic and treatment protocols in peripheral health units:
Dipstick + SSG
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Khartoum
Um-el-Kher
Nimne
Nile
White
Nile
Blue
Nile
Lankien
Humera2000
Access to treatment:
Decentralised services
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Khartoum
Malakal
Um-el-Kher
Nimne
Ler
Nile
White
Nile
Blue
Nile
Pieri
HumeraMycadra
Abdurafi
Sobat Sites (7)
2005
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Primary VL Admissions and Mortality, North-West Ethiopia (1997 - 2007)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
1997 1998 1999 2000 2001 2002 2003 2004 2005 20060%
5%
10%
15%
20%
25%
30%
AdmissionsMortality
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Primary Kala-azar Admissions, Lankien, South Sudan, 1999-2003
050
100150200250300350400450500
Jul
Aug Sep OctNovDec Ja
nFe
bMar AprMay Ju
n1999-20002000-20012001-20022002-2003
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Short Course Combination Therapy – Neglected Research
• SSG + Paromomycin (17 days)Good experience in epidemic circumstancesMelaku Y. et al. 2007
Currently studied in East Africa by DNDi
• SSG + AmBisome ?• AmBisome + Miltefosine ?• AmBisome + Paromomycin ?• Miltefosine + Paromomycin ?
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Bednet Distribution Gedaref State, Eastern Sudan
• Epidemic situation 1997-1999; treatment capacity overwhelmed (>4,500 cases per year)
• 357,000 nets distributed (1999 – 2001)
• ITN, jersey polyester 300 mesh (sandfly-proof)
• 155 villages
• Community education campaigns
Ritmeijer K. et al. 2007
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• 94% distribution coverage
• 2 years post-distribution 44% of nets were still present and reasonably intact
• main reason for use: mosquito nuisance
• bednet utilisation during dry hot season <10%, increasing during rainy season
• net utilisation April: 1%
May: 10%
June: 55%
• bednets were put up between 9 and 11 p.m.
Operational EvaluationCoverage, Utilisation
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Epidemiological EvaluationProtective Effect
• simulation model comparing actual and predicted VL incidence per village and per month
• 1,060 cases prevented between June 1999 and January 2001
• calculated protective effect: 27%
• protective effect increased with time, with greatest effect 17-20 months post-intervention: 59% (C.I. 25-78%)
• Potentially strong reduction in VL incidence following a community distribution of ITNs.
• Effectiveness of ITNs depends on behavioural factors, which differ between communities
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• HIV co-infection rates in VL patients in East Africa:Humera / Northern Ethiopia:
1998-1999: 19%1999-2000: 23%2003-2004: 29%2006: 34%
Um-el-Kher / Eastern Sudan2005: 9%
Upper Nile / Southern Sudan2002: 0.4% (rural)2005: 5% (urban)
HIV/VL co-infectionDiagnostic and Treatment Challenges
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HIV / VL co-infection in Ethiopia
• VL is main OI in HIV• >30% of VL patients are HIV co-infected• >30% of HIV patients have a history of VL
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HIV testing:
HIV positive: 34.4%(95% CI: 26.2 – 43.3%)
Cross-sectional diagnostic accuracy study in Humera, Ethiopia (2006-2007)
(n=699 clinical suspects)
Parasitology: splenic aspirate
rK39: DiaMed-IT-Leish®
DAT: quantitative titre assessment
Field evaluation of serological tests for diagnosis of visceral leishmaniasis in a population with
high HIV prevalence
Good performance of rK39 and DAT in non-HIV-infected VL in
East Africa
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Preliminary study results
• rK39 specificity in clinical suspects: 92%• rK39 specificity in endemic controls: 99%• rK39 can be implemented at every level of care• DAT requires established basic laboratory
+
SensitivityrK39
DiaMed-IT-LeishDAT
(titre ≥1:6400)rK39 + DATCombination
HIV-Negative 86.9% 86.9% 98.8%
HIV-Positive 77.3% 75.0% 90.9%
Recommended diagnostic algorithm:
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Antimonial (SSG) treatment outcome and HIV status
(SSG vs. Pentostam study, Humera, 1999)
HIV neg HIV pos
# Treated 112
3.6%
92.1%
27
Death rate during treatment 33.3%
Final Cure Rate(6m follow-up)
43.5%
Ritmeijer K. et al. 2001
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Miltefosine vs. Sodium Stibogluconate for Treatment of Visceral Leishmaniasis in an
Ethiopian Population with High HIV prevalence
Study design: randomised open studyn = 580 adult men with VL
sodium stibogluconate(SSG)
20 mg/kg/day x 30 days IM
Miltefosine
100 mg/day x 28 days oral
HIV status:HIV positive: 28.5%
Ritmeijer K. et al. 2006
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Miltefosine vs. SSGfor treatment of VL in a population with
high HIV prevalence
• 6-fold higher odds of mortality associated with SSG treatment, as compared with miltefosine in those with positive or unknown HIV status (P=0.0003).
• Indication that much of the mortality in HIV co-infected is cause by SSG itself.
• Miltefosine is less effective (higher initial parasitological failure and relapse rates), but safer (lower mortality) than SSG in treating VL in a population with high HIV prevalence
• Miltefosine is safe and effective in HIV-negative VL patients
• The safer profile of Miltefosine makes it a preferential drug over SSG in HIV co-infected patients, as it may prolong survival
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Treatment of VL in HIV co-infected: HAART
• Patients relapse 3-6 months; successive relapses become less typical and less acute, but more frequent
• Patients get less responsive to treatment with each relapse, andeventually become unresponsive to all drugs Can HAART protect against relapse?
• VL itself causes low CD4 counts• Baseline CD4 lower in HIV co-infected VL patients than in HIV-negative
patients• Increment of CD4 count at completion of treatment much lower in HIV-
positive patientsCan HAART improve CD4 count?
Prospective study of 356 HIV/VL co-infected patients, Includes almost 600 episodes of VL
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CD4 trends on HAART; patients with relapse vs. patients without relapse on HAART
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Relapse probability curve – lowest CD4 and previous VL episodes
010
2030
4050
60P
roba
bilit
y of
rela
pse
(%)
<100 100-199 200+Lowest CD4 count during follow-up (cells/mm3)
None or primary VLOne relapseTwo or more relapses
VL history prior to HAART initiation
Probability of VL relapse within 12 months of HAART initiation
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Impact of HAART on relapse
HAART has only partial protective effect against relapseHazard ratio 0.46 (95% CI: 0.26-0.82)
Yet 28% of first VL relapses occurred despite CD4 >200
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Conclusion: Main Research Priorities
Diagnostics:• Simple “point of care” field diagnostic antigen test
(for primary VL, relapse VL, test-of-cure)• Improved rK39 dipstick tests: combination of highly sensitive
screening test and highly specific diagnostic test
Treatment:• Evaluation of short-course combination therapies
HIV/VL co-infection:• Evaluation of combination drugs in HIV/VL co-infected
(AmBisome, Miltefosine)• Efficacy and tolerability of secondary prophylaxis / maintenance
therapy in preventing relapse