New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine.
BACKGROUND
In Bihar, India, home to nearly one-half of the world's burden of visceral leishmaniasis, drug resistance has ended the usefulness of pentavalent antimony, which is the traditional first-line treatment. Although monotherapy with other agents is available, the use of 2 drugs with different modes of action might increase efficacy, shorten treatment duration, enhance compliance, and/or reduce the risk of parasite resistance. To test the feasibility of a new approach to combination therapy in visceral leishmaniasis (also known a kala-azar), we treated Indian patients with a single infusion of liposomal amphotericin B (L-AmB), followed 1 day later by short-course oral miltefosine.


METHODS
We used a randomized, noncomparative, group-sequential, triangular design and assigned 181 subjects to treatment with 5 mg/kg of L-AmB alone (group A; 45 subjects), 5 mg/kg of L-AmB followed by miltefosine for 10 days (group B; 46 subjects) or 14 days (group C; 45 subjects), or 3.75 mg/kg of L-AmB followed by miltefosine for 14 days (group D; 45 subjects). When it became apparent that all regimens were effective, 45 additional, nonrandomized patients were assigned to receive 5 mg/kg of L-AmB followed by miltefosine for 7 days (group E).


RESULTS
Each regimen was satisfactorily tolerated, and all 226 subjects showed initial apparent cure responses. Nine months after treatment, final cure rates were similar: group A, 91% (95% confidence interval [CI], 78%-97%]; group B, 98% (95% CI, 87%-100%); group C, 96% (95% CI, 84%-99%]; group D, 96% (95% CI, 84%-99%); and group E, 98% (95% CI, 87%-100%).


CONCLUSIONS
These results suggest that treatment with single-dose L-AmB followed by 7-14 days of miltefosine is active against Indian kala-azar. This short-course, sequential regimen warrants additional testing in India and in those regions of endemicity where visceral leishmaniasis may be more difficult to treat.


BACKGROUND
ClinicalTrials.gov identifier: NCT00370825 .
Sundar
Shyam
S
Kala-Azar Medical Research Center, Department of Medicine, Banaras Hindu University, Institute of Medical Sciences, Varanasi, India. drshyamsundar@hotmail.com
Rai
M
M
Chakravarty
J
J
Agarwal
D
D
Agrawal
N
N
Vaillant
Michel
M
Olliaro
Piero
P
Murray
Henry W
HW
D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007194:India; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B