*

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