Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial.
BACKGROUND
Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India.


METHODS
Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5-60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969.


RESULTS
Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5-96·3) for amphotericin B, 156 (97·5%; 93·3-99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24-99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1-99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment.


CONCLUSIONS
Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites.


BACKGROUND
Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.
Kala-Azar Medical Research Center, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. drshyamsundar@hotmail.com
Shyam
S
Sundar
Prabhat Kumar
PK
Sinha
Madhukar
M
Rai
Deepak Kumar
DK
Verma
Kumar
K
Nawin
Shanawwaj
S
Alam
Jaya
J
Chakravarty
Michel
M
Vaillant
Neena
N
Verma
Krishna
K
Pandey
Poonam
P
Kumari
Chandra Shekhar
CS
Lal
Rakesh
R
Arora
Bhawna
B
Sharma
Sally
S
Ellis
Nathalie
N
Strub-Wourgaft
Manica
M
Balasegaram
Piero
P
Olliaro
Pradeep
P
Das
Farrokh
F
Modabber
D000293:Adolescent; D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007194:India; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008099:Liver / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D010303:Paromomycin / Q000008:administration & dosage* / Q000009:adverse effects; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D012008:Recurrence; D055815:Young Adult
D000981:Antiprotozoal Agents; D006454:Hemoglobins; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D010303:Paromomycin; D000666:Amphotericin B; D003404:Creatinine