Efficacy and Safety outcomes: Liposomal Amphotericin B

(Ambisome) treatment for Visceral Leishmaniasis (VL) under routine programme conditions in Bihar,

India.

Jitendra Gupta MSF- Spain

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.

INDIA

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

Available Treatment Options

• Sodium Stibogluconate (SSG) • Pentamidine Isethionate • Paromomysin (also called Aminosidine)

• Miltefosine• Amphotericin B • Liposomal Amphotericin B

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.

MSF-Spain VL project in Bihar

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.

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.

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

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 infectionsGastro-intestinal

40 (43%)33 (36%)

*For age, spleen & HB: Median (range)**Severe malnourished: BMI > 16kg/m2 or W/H <70%***Moderate malnourished: BMI 16- 18kg/m2 or W/H 70-80%

Main Adverse EventsGrade Adverse event Number

Mild Nausea, vomiting, chills, rigor, fever

41 (16.4%)

Moderate Increased tendency to bleed

3 (1.2%)

Increased back pain 4 (1.6%)

Generalized itching and swelling

5 (2%)

Severe Progressive lip swelling (Hypersensitivity)

3 (1.2%)

• No clinical or laboratory findings of Cardiac, Hepatic, Nephro and Oto-toxicities.

OutcomesAt the end of Treatment (250)

At 3-months FU248 (98%)

At 6-months FU222 (89%)

Stopped treatment due to ADR

3 0(3)* 0(3)*

Defaulters 2 0(2)* 0(2)*

Loss to follow up 0 22 19(41)*

Died 0 1 2(3)*

No. of patients remain in the follow up

245 222 201

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%)

Clinical Markers for ImprovementAt the end of Treatment

At 3-months FU At 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

Weight gain (kg) 15 years

0.64 (-3 to 7) 2 (-5 to 10) 2 (-3 to 7)

BMI (kg/m2 ) 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.

Odds Ratio (Intention to Treat)Odds Ratio (95% CI) P value

HB < 7 gm/dl 2.40 (1.02 – 5.71) .02

Musahar & Unknown cast 8.5 (1.9 – 33) .005

Severe malnutrition(BMI <16 & W/H <70%)

2.25 (0.6 – 8.2) NS

*NS: non significant

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.

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.

Acknowledgements

Thank you!!

MSF SpainMSF Spain, India, HajipurRMRI, PatnaManica Balasgaram