1. Efficacy and Safety outcomes: Liposomal Amphotericin B (Ambisome) treatment for Visceral Leishmaniasis (VL) under routine programme conditions in Bihar, India. Jitendra Gupta MSF- Spain

2. Facts about VL A major neglected disease. Worldwide around 500,000 new cases/ year. Only 5 countries have more than 90% of cases (India, Bangladesh, Nepal, Sudan and Brazil). Leishmania donovani, Kala-Azar in Indian subcontinent. Fever, weight loss and enlarged spleen. If untreated, anemia and wasting, fatal illnesses in 95% of cases.

3. INDIA

4. Bihar background Second poorest state of the country. Around 60 – 75% VL cases of India are in Bihar alone.

5. Available Treatment Options Sodium Stibogluconate (SSG) Pentamidine Isethionate Paromomysin (also called Aminosidine) Miltefosine Amphotericin B Liposomal Amphotericin B

6. Liposomal Amphotericin B (Ambisome) Safest available drug for VL treatment. First line treatment for VL in resource rich settings. Phase II studies showed: – High efficacy (89-100%). – Low safety risk. No phase III or IV study data available. High cost of the drug.

7. MSF-Spain VL project in Bihar

8. Objectives To evaluate effectiveness of first line AmBisome, at a total dose of 20mg/kg body weight. To evaluate tolerability and safety of first line AmBisome treatment, at above dosage, under routine programme conditions.

9. Methodology Prospectively monitored and evaluated a cohort of VL patients. Ambisome 20 mg/kg body weight on day 0, 1, 4 & 9 (WHO recommended, 2005). Inclusion: The first 250 patients diagnosed with primary VL. Clinically & Rk 39 dipsticks positive. Exclusion: Patients previously treated with Ambisome. Patients with relapse, <2 years, HIV or TB co-infected.

10. Continued… Safety monitoring: – Clinical assessment – Hemoglobin, Weight End points: – At the end of treatment (day 10). – 3-months after the treatment. – Final cure at 6-months. Clinically well If clinically suspected, parasitological clearance

11. Characteristics on Admission: Total (N) 250 Age (years) Median (range)* M: F ratio 15 (2 – 65) 1.4 : 1 (145/105) Spleen Size (cm)* Hemoglobin (gm/dl)* 6 (0 – 17) 7.7 (3.6 – 14.5) Severe malnourished** Moderate malnourished*** 23 (9.2%) 52 (20.8%) Musahar cast N (%)28 (11.2%) Respiratory infections Gastro-intestinal 40 (43%) 33 (36%) *For age, spleen & HB: Median (range) **Severe malnourished: BMI > 16kg/m 2 or W/H <70% ***Moderate malnourished: BMI 16- 18kg/m 2 or W/H 70-80%

12. Main Adverse Events GradeAdverse eventNumber MildNausea, vomiting, chills, rigor, fever 41 (16.4%) ModerateIncreased tendency to bleed 3 (1.2%) Increased back pain4 (1.6%) Generalized itching and swelling 5 (2%) SevereProgressive lip swelling (Hypersensitivity) 3 (1.2%) No clinical or laboratory findings of Cardiac, Hepatic, Nephro and Oto-toxicities.

13. Outcomes At the end of Treatment (250) At 3-months FU 248 (98%) At 6-months FU 222 (89%) Stopped treatment due to ADR 30(3)* Defaulters20(2)* Loss to follow up02219(41)* Died012(3)* No. of patients remain in the follow up 245222201 Intention to treat (%)98%89%81% Cure Rate% (CI)**98% (0.96-0.99%)97% (0.94–0.99%)96% (0.93-0.98%) Accumulative numbers **Confidence interval (CI 95%)

14. Clinical Markers for Improvement At the end of Treatment At 3-months FUAt 6-months FU HB gain (gm/dl) Median (range) 0.7 (-2.7 to 3.8)3.1 (-1 to 9.4)3.3 (-1 to 4.2) Spleen size regression (cm)- 5 (-1 to -14)0*0*0 Weight gain (kg)  15 years 0.64 (-3 to 7)2 (-5 to 10)2 (-3 to 7) BMI (kg/m 2 )  16 years 0.2 (-0.4 to 0.7)1.6 (-0.5 to 3.2)1.5 (-1.2 to 4.3) Severe malnourished 20/23 (87%)4/23 (17%)2/23 (8.7%) *at 3-months follow up time, 15 patients presented with palpable spleen but clinically free from VL and 8/15 were splenic aspiration negative.

15. Odds Ratio (Intention to Treat) Odds Ratio (95% CI)P value HB < 7 gm/dl2.40 (1.02 – 5.71).02 Musahar & Unknown cast8.5 (1.9 – 33).005 Severe malnutrition (BMI <16 & W/H <70%) 2.25 (0.6 – 8.2)NS * NS: non significant

16. Conclusion Ambisome (20 mg/kg bw) shows high effectiveness (96%), under routine programme conditions. Extremely safe: only 0.23 adverse event per treatment. High tolerability.

17. Key Issues & Recommendations High drug cost. New implementation programmes with Ambisome 15 mg and closely monitored under field conditions should be undertaken. Further combination studies with Ambisome as the main drug, to be combined with other drugs, should be urgently explored.

18. Acknowledgements Thank you!! MSF Spain MSF Spain, India, Hajipur RMRI, Patna Manica Balasgaram