Antimonial Resistance & Combination therapy in Indian Visceral Leishmaniasis. Shyam Sundar Banaras Hindu University Varanasi, India

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1 Antimonial Resistance & Combination therapy in Indian Visceral Leishmaniasis Shyam Sundar Banaras Hindu University Varanasi, India

2 History of the Current Epidemic in India & Antimony Resistance

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6 6 Official Reporting of Leishmaniasis in India ( times underreporting in India) Year No. of Patients

7 Sodium Stibogluconate in 70s Antimony, 10 mg/kg for 6-10 days, was successful in curing most of the patients During late seventies several unconfirmed reports of unresponsiveness appeared and up to 30% resistance to this regimen noted

8 Declining Efficacy of Antimony in India Year Authors Daily dose Duration (Days) 1980 Sen Gupta 600 mg 10 & Thakur 600 mg Thakur 20 mg/kg Cure Rate Jha 20 mg/kg Sundar 20 mg/kg Sundar 20 mg/kg Thakur 20 mg/kg Sundar 20 mg/kg (Bihar) 89 (UP) 2004 Thakur 20 mg/kg 30 38

9 Efficacy of SSG 20mg/kg/d in Bihar, India during Sundar & Olliaro

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11 Treatment Seeking Behaviour of Patients with Kala-azar Qualifed 27% Quakes 73% 30 Days <30 Days First contact Duration of Treatment Irregular 42% Regular 58% Regularity of Treatment Inadeq uate 74% Adequ ate 26% Dose & Duration

12 IN VITRO SENSITIVITY TO Sb Clinical Response ED 50 (μg/ml) Promastigotes ED 50 (μg/ml) Amastigotes ED 90 (μg/ml) Amastigotes Amastigotes/ 100 untreated macrophages Antimony Responsive (n=9) Antimony Unresponsive (n = 15)

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14 Sb Resistance & importance

15 Impact of Sb Resistance Sb was the only affordable drug in India (Cost for 50 kg 20$) Very few can afford anything priced higher Delayed or no cure leading to build up of reservoir and spread of the disease

16 Amphotericin B

17 Lipid Amphotericin B - Conclusions Total dose most important determinant in the outcome Total dose requirement 15 mg/kg for Asia 3.75 mg cured 89% (Duration 5 day) 5 mg cured >90% (Single dose) AmBisome is now available for US$ 20/vial of 50 mg for VL Still just the drug cost for a 35 kg adult will be US$

18 Paramomycin This aminoglycoside is now approved in India Monotherapy with aminoglycosides readily induces resistance in microorganisms It is probably safest second only to AmBisome Produced in India & available at a price of $ for an entire course for an adult

19 Miltefosine Long Halflife (~7 days) Relapse rate doubled in phase IV study Cure rate 84% in Nepal Cannot be used in pregnant females [teratogenic], and those refusing contraception (for the treatment period and another two months) Over the counter availability No Directly Observed therapy in place

20 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 use them in combination Shorten duration Better compliance Less chances of development of drug resistance Single dose of AmBisome (5 mg/kg) cured 91% patients Two weeks of miltefosine cured 89% patients These findings suggest that short course multidrug treatment is a feasibility

21 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 combination therapy AmBisome + Miltefosine AmBisome + Paromomycin Paromomycin + Miltefosine

22 New Treatment Approach in Indian Visceral Leishmaniasis: Single-Dose Liposomal Amphotericin B Combined with Short-Course Oral Miltefosine

23 Dose Regimens A - AmBisome, 5 mg/kg, once B - AmBisome, 5 mg/kg, plus milt for 10 days C - AmBisome, 5 mg/kg, plus milt for 14 days D - AmBisome, 3.75 mg/kg, plus milt for 14 days ` After initial post-treatment assessments on day 16 showed apparent cure responses in all subjects, the protocol was amended to include a fifth group of 45 subjects (Group E) using the same inclusion and exclusion criteria. These nonrandomized subjects received E - AmBisome, 5 mg/kg, followed by milt for 7 days.

24 Evaluation After baseline screening, treatment was started within 72 hours Vital signs were recorded several times a day Repeat assessment of weight, spleen size, laboratory parameters were done on day 8, 16 and six months. Post treatment parasitological evaluation was done on day 16 (a repeat was done 4 weeks later if scanty parasites present)

25 Safety Except of grade 1-2 hepatic or nephrotoxi city in 12% in almost every group, no serious adverse event was noted Only exception was one patient in group 3, who developed grade 3 rise in hepatic on day 8 but by day 16 he developed clinical hepatitis with 5.66 mg% biliurbin and enzymes >2000.

26 Parasitological Cure None of the patients in the five group had detectable parasite at the end of treatment During six month follow up, 3 patients in Group A, 1, 2, 2 and 1 in group B, C, D & E, respectively 1 patient in group A contracted severe gastroenteritis after being well for 5.5 months at home (time of severe flooding), and died

27 Final Cure Rates AmBisome 5mg/kg single dose Ambisome 5mg/kg + Miltefosine 10 days Ambisome 5mg/kg + Miltefosine 14 days Ambisome 3.75mg/kg + Miltefosine 14 days Ambisome 5mg/kg + Miltefosine 7 days N Final Cure Efficacy % [95% CIs] % [78-97] % [87-100] % [84-99] % [84-99] % [87-100]

28 Conclusions Sequential administration of AmBisome & miltefosine was well tolerated All AEs except one were of gr patient on day 16 developed gr 4 hepatotoxicity Every patient became parasite free at the end of treatment Final cure rate in this small study ranged between % These results calls for bigger studies to confirm these findings and should also involve drugs approved recently. Multidrug therapy appears the only way to protect very clinically available antileihsmanial drug and almost none in pipeline.