*
India
Nepal
Bangladesh
N
EW
S
Kala-azar Endemic Districts of WHO SEA Region,
1995-2000KALA-AZAR ENDEMIC DISTRICTS
*
*
Increasing Devastation of Leishmaniasis
human leishmaniasis is on the increase worldwide
including India
– Reports from non-endemic regions – MP, Gujrat,
Uttarakhand, Himachal, Kashmir, Kerala
– Increase in the number of cases in VL
0
10000
20000
30000
40000
50000
60000
70000
80000
No.
of
Cas
es
77 79 81 83 85 87 89 91 93 95 97 99 1 3 5
Official reports from India
*
Diagnosis of VL
*
*
DIAGNOSIS OF KALA-AZAR
Serology: ELISA, IFAT, CIEP – GOOD
Expensive, equipment
Electricity, Expertise Field applicability poor
Not popular or in use
Aledehyde Test –
Highly nonspecific and should
be abandoned
Direct Agglutination Test –
Excellent results, but Cumbersome,
limited field applicability
*
39 AMINO ACID ANTIGEN ENCODED BY 117 bp GENE IN KINESINE REGION OF AMASTIGOTES (LD) IN L chagasi
K39 ELISA – ~100% SENSITIVE & SPECIFIC NOT PRACTICAL FOR THE FIELD USE
RAPID STRIP TEST DEVELOPED USING IMMUNOCHROMATOGRAPHIC STRIPS
K39 IS FIXED ON THE STRIP WITH PROTEIN A/ COLLOIDAL GOLD FIXED FOR DETECTION
AB BASED TEST, SO OF NO USE AS TOC OR IN RELAPSES OR REINFECTION
K39 IN THE DIAGNOSIS OF KALA-AZAR
*
*
Comparison of sensitivity and specificity of DAT &
rK39 strip test in patients with VL and controls
(Sundar et al, Lancet 98, TRSTMH, 06)
Patients
Category
n
DAT (FD)
Positive
No. (%)
DAT (AQ)
Positive
No. (%)
rK39 Strip
test
Positive
No. (%)
Confirmed VL 150 144 (96) 146 (97) 149 (99)
Healthy non-
endemic controls 100 0 (0) 0 (0) 0 (0)
Healthy endemic
controls 153 47 (31) 39 (25) 33 (22)
Other diseases 105 7* (7) 6# (6) 5 (5)
*Tuberculosis 3, Malaria 4; # Tuberculosis 2, Malaria 4; Tuberculosis 3, Malaria 2
*
*
Sodium Stibogluconate
Pentavalent Antimony (Sodium stibogluconate)
has been the mainstay of the treatment of all
forms of leishmaniasis all over the world for more
than seven decades
Except India where during late seventies several
reports of unresponsiveness appeared and up to
30% resistance to this regimen noted
Periodical upward revision of dosage and
duration failed to improve the situation
*
Declining Efficacy of Antimony in India Year Authors Daily dose Duration
(Days)
Cure Rate
1980 Sen Gupta 600 mg 10 & 10 96
1984 Thakur 600 mg 20 87
1988 Thakur 20 mg/kg 20
40
81
97
1991 Jha 20 mg/kg 30 64
1995 Sundar 20 mg/kg 30 60
1997 Sundar 20 mg/kg 30 36
1998 Thakur 20 mg/kg 30 58
2000 Sundar 20 mg/kg 30 35 (Bihar)
89 (UP)
2004 Thakur 20 mg/kg 30 38
*
Efficacy of SSG 20mg/kg/d in Bihar, India during 1988-2002.
0
20
40
60
80
100
1988 1990 1992 1994 1996 1998 2000 2002
Sundar & Olliaro
*
Amphotericin B
Polyene antibiotic
Dose 0.75-1.0 mg daily or alternate days
for 15-20 infusions
Infusion reactions (minimised by
paracetamol & antihistaminics),
thrombophlebitis common
Hypokalemia, myocarditis & death are
serious, but uncommon, toxicities
High Cure rates ~100%
*
*
Lipid Associated Amphotericin B in
Kala-azar
Most exciting development
Targeted delivery to macrophages
Possible to infuse high dose in short duration as
compared to 4-6 weeks of conventional treatment
Low toxicity/Improved efficacy
Highly expensive
Liposomal (AmBisome) , Lipid Complex (Abelcet),
Colloidal dispersion (Amphocil) now available
*
Total Dose
mg/kg
No. of
Patients
Treatment
Duration
Cure
Rate
Author
14 10 Day 1-6, 10 100 Thakur et al,
TRSTMH
1996 10 10 Day 1-4, 10 100
6 10 Day 1,4, 10 100
15 28 5 96 Sundar et al,
AJTMH
2002 7.5 28 5 93
3.75 28 5 89
Liposomal Amphotericin B (AmBisome) in
Refractory Indian Kala-azar
*
Total Dose
mg/kg
No. of
Patients
Treat.
Dur.
Cure Rate
5 46 1 91 ( Sundar, BMJ,2002)*
5 45 5 93
7.5 203* 1 90 (Sundar, CID, 2003)*
15 17 1 100 (Thakur, AAC, 2001)
Single Dose Liposomal Amphotericin B
(AmBisome) in Indian Kala-azar
* Multicenter
*
Lipid Amphotericin B - Conclusions Total dose – most important determinant in the
outcome – Total dose requirement 20-24 mg/kg - for Brazil and Europe
18-20 mg/kg – for Africa
10-15 mg/kg – for Asia
40 mg/kg for Immunosuppressed
AmBisome in India
3.75 mg cured 89% (Duration 5 day)
5 mg cured >90% (Single dose)
High cost is no longer a stumbling block
WHO negotiated price for 50 mg is US$ 20.00
Not much to choose in terms of efficacy
AmBisome is safest, nearly free of adverse events
High cure rates are possible with single infusion
*
Paramomycin
• An aminoglycoside (parenteral)
• Good antileishmanial activity, earlier used for bacterial &
Parasitic infections
• In several phase II studies 16 mg/kg for 3 weeks cured 93%
VL patients
• India is the first country to approve it for Tt of VL after the
Phase III trial results ( Base 11 mg/kg x 21 days)
• Safe, Good alternative to antimony as first line Tt
• Produced in India
• Could be the cheapest antileishmanial drug (400 rupees per
treatment course)
*
Paromomycin Phase III Conclusions (Sundar et al, NEJM, 2007)
Paromomycin sulfate at 15 mg/kg/day (~11 mg/kg of paromomycin base) IM for 21 days
Well-tolerated
Reversible ototoxicity (n=7, 1.6%)
No nephrotoxicity
No difference in rate of withdrawal between groups
High overall cure rates (final cure: 94.6%)
Effective in Sbv/miltefosine therapy failed patients
Very affordable
Appears to be an excellent replacement for Sbv and amphotericin B as a first line anti-leishmanial drug
Paromomycin sulfate is a safe, affordable, and effective drug for the treatment of visceral leishmaniasis
*
Miltefosine
• Hexadecylphosphocholine (alkyllphospholipid analogue)
• Developed as an oral antineoplastic agent, but GI adverse events limited its use
• Excellent antileishmanial activity in experimental animals and in vitro
• A pilot dose escalating study conducted in 1997
*
Miltefosine Phase I & II Trials – Results
(including 1 multicenter trial) Lancet, 98, N Eng J Med 99; Ann Trop Med 99; Clin Infect Dis 2000
Daily Dose
28 days
Patients
(n)
Definite
cure %
~100 mg 100 97 97
~150 mg 53 51 96
>200 mg 19 19 100
100 mg x 21
days
18 18 100
100 mg x 14
days
18 16 89
*
Miltefosine – conclusions (Sundar et al, NEJM 2002)
• Dose: 100 mg (>25 kg); 50 mg (<25 kg); Children 2.5mg/kg
• Duration: Four weeks
• Side – effects:
• Vomiting occurs in ~40%
• diarrhea in ~20%.
• Transient elevation of hepatic enzymes
• Skin allergy, nephrotoxicity are occasionally seen
• Long term cure rates 94%
• Cannot be used in pregnant females [teratogenic], and those
refusing contraception (for the treatment period and another two
months)
*
*
Dr. D. Nath
Lab: CB Singh
Dr. SK Mishra
Lab: AK Chaudhary
Dr. S Sundar
Dr. TK Jha
Dr. BB Thakur
Dr. S Kumar
Dr K Tiwari
Lab: CPN Thakur
Dr. BB Jha
Dr. S Mukherjee
Dr. AK Aditya
Dr. MP Sharma
Lab: DK Mishra
RMRIMS
CP Thakur
Lab: RMRIMS
Dr. RC Pandey
Dr. RK Singh
Lab:CN Gupta
Dr. S Rijjal PHASE IV Miltefosine–Sponsored by ICMR, monitored by
TDR/WHO
Sex All ages >12
years
<12
years
Male 724 477 247
Female 408 227 181
Total 1132 704 428
Distribution of patients by age and gender
*
Visit 0
1132 started treatment
(99.7%)
Visit 5
Initial cure assessment
1034 completed
(91.1%)
95 patients
dropped out,
3 died
63 patients
dropped out
Visit 6 (+6 mo)
Final cure assessment-
971 completed
(85.7%)
927 final cure
(95.5% PP, 81.9 ITT)
44 failure (4.5%)
FLOW CHART FOR
MILTEFOSINE PHASE IV
*
Summary: What Are the
therapeutic Options ?
Use Antimony only in responsive regions
Amphotericin B – Most important & ~100% Cure rate (Lipid Ampho B -
Cost?)
Miltefosine (Oral) –
Promising ( Cures Sb refractory patients also)
Teratogenic,
Long half life (rapid emergence of resistance)
Cost (not affordable Rs 6000.00)
Compliance in domiciliary care ? ( DOT)
Paromomycin –
Quite promising
Could be an appropriate substitute for Sb
Likely to be cheap
Combination Chemotherapy with short duration regimens?
*
What is the rationale of combination? Every drug with the exception of amphotericin B is prone to
development of resistance
No new drug in pipeline and future of sitamaquine uncertain
The only way to protect the newly developed drugs is to develop
combination chemotherapy
Shorten duration
Better compliance
Reduce costs; improve cost-effectiveness
Less chances of development of drug resistance
Reduce drug pressure; mutual protection against resistance
prolong therapeutic life-span of effective use
Single dose of AmBisome (5 mg/kg) cured 91% patients
Two weeks of miltefosine cured 89% patients
These suggest - short course multidrug therapy is a feasibility
*
Experimental Evidences of
Combinations (Siefert & Croft, 2006)
Activity enhancement indeex (AEI)
In vivo
Mkiltefosine + Ampho B – 11.3
Miltefosine + Paromomycin – 7.2
Miltefosine + SAG – 2.38
Thus, the three approved drugs for VL can
be tried for multidrug therapy AmBisome + Miltefosine
AmBisome + Paromomycin
Paromomycin + Miltefosine
*
VL Combination Toxicology Combination drug administration (DNDi/Advinus
Therapeutics, Bangalore)
Study groups Miltefosine alone
AmBisome alone
Paromomycin alone
Paromomycin + Miltefosine
AmBisome + Miltefosine (concomitant 5 days, milt alone 23 days)
AmBisome + Paromomycin (concomitant 5 days, paromo alone 23
days)
Results No significant haematological changes: alone vs combined
No significant clinical chemistry changes: alone vs combined
*
Results of a phase II combination
trial in Indian VL
Regimen n Initial
Cure
Rate (%)
Final
Cure
Rate
95%
Confidence
Interval
AmBisome (5mg/kg) 45 100 91.1 78-97
AmBi 5 + Milt 14 days 45 100 95.6 84-98
AmBi 3.75 + Milt 14 days 45 100 95.6 84-98
AmBi 5 + Milt 10 days 46 100 97.8 87-100
AmBi 5 + Milt 7 days 45 100 97.8 87-100
*
*
Post Kala-azar Dermal
Leishmaniasis
*
PKDL
<1% in India and up to 50% patients in Sudan
develop skin manifestations
Nodule
Macule
Mixed
In India it occurs 6 months to several years later
whereas in Sudan in can occur concurrently with VL
or immediately thereafter
*
*
*
*
Prevention & Vaccination
Vector control through insecticide spray
Long lasting insecticide impregnated
bednets & curtain
Insect repellants
Improvement of housing
No vaccine is available
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