Transcript Efficacy and Safety outcomes of Liposomal Amphotericin B

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.
KA cases in India & Bihar
35000
Number of new cases of KA
30000
25000
20000
India
Bihar
15000
10000
5000
0
2001
2002
2003
2004
2005
2006
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)
Age (years) Median (range)*
M: F ratio
Spleen Size (cm)*
Hemoglobin (gm/dl)*
250
15 (2 – 65)
1.4 : 1 (145/105)
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
*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%
40 (43%)
33 (36%)
Main Adverse Events
Grade
Adverse event
Mild
Nausea, vomiting, chills,
rigor, fever
Moderate
Increased tendency to
bleed
3 (1.2%)
Increased back pain
4 (1.6%)
Severe
Number
41 (16.4%)
Generalized itching and
swelling
5 (2%)
Progressive lip swelling
(Hypersensitivity)
3 (1.2%)
• No clinical or laboratory findings of Cardiac, Hepatic, Nephro and Oto-toxicities.
Outcomes
At the end of
Treatment (250)
At 3-months FU
248 (98%)
At 6-months FU
222 (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%
98% (0.96-0.99%)
97% (0.94–0.99%)
96% (0.93-0.98%)
Cure Rate% (CI)**
•Accumulative numbers
**Confidence interval (CI 95%)
Clinical Markers for Improvement
At the end of
Treatment
HB gain (gm/dl)
Median (range)
At 3-months FU
At 6-months FU
0.7 (-2.7 to 3.8)
3.1 (-1 to 9.4)
3.3 (-1 to 4.2)
- 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)
20/23 (87%)
4/23 (17%)
2/23 (8.7%)
Spleen size
regression (cm)
Severe
malnourished
*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)
HB < 7 gm/dl
Musahar & Unknown cast
Severe malnutrition
(BMI <16 & W/H <70%)
*NS: non significant
Odds Ratio (95% CI)
P value
2.40 (1.02 – 5.71)
.02
8.5 (1.9 – 33)
.005
2.25 (0.6 – 8.2)
NS
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
MSF Spain
MSF Spain, India,
Hajipur
RMRI, Patna
Manica Balasgaram
Thank you!!