Injectable paromomycin for Visceral leishmaniasis in India.
BACKGROUND
Visceral leishmaniasis (kala-azar) affects large, rural, resource-poor populations in South Asia, Africa, and Brazil. Safe, effective, and affordable new therapies are needed. We conducted a randomized, controlled, phase 3 open-label study comparing paromomycin, an aminoglycoside, with amphotericin B, the present standard of care in Bihar, India.


METHODS
In four treatment centers for visceral leishmaniasis, 667 patients between 5 and 55 years of age who were negative for the human immunodeficiency virus and had parasitologically confirmed visceral leishmaniasis were randomly assigned in a 3:1 ratio to receive paromomycin (502 patients) at a dose of 11 mg per kilogram of body weight intramuscularly daily for 21 days or amphotericin B (165 patients) at a dose of 1 mg per kilogram intravenously every other day for 30 days. Final cure was assessed 6 months after the end of treatment; safety assessments included daily clinical evaluations and weekly laboratory and audiometric evaluations. Noninferiority testing was used to compare 6-month cure rates, with a chosen margin of noninferiority of 10 percentage points.


RESULTS
Paromomycin was shown to be noninferior to amphotericin B (final cure rate, 94.6% vs. 98.8%; difference, 4.2 percentage points; upper bound of the 97.5% confidence interval, 6.9; P<0.001). Mortality rates in the two groups were less than 1%. Adverse events, which were more common among patients receiving paromomycin than among those receiving amphotericin B (6% vs. 2%, P=0.02), included transient elevation of aspartate aminotransferase levels (>3 times the upper limit of the normal range); transient reversible ototoxicity (2% vs. 0, P=0.20); and injection-site pain (55% vs. 0, P<0.001); and in patients receiving amphotericin B, as compared with those receiving paromomycin, nephrotoxicity (4% vs. 0, P<0.001), fevers (57% vs. 3%), rigors (24% vs. 0, P<0.001), and vomiting (10% vs. <1%, P<0.001).


CONCLUSIONS
Paromomycin was shown to be noninferior to amphotericin B for the treatment of visceral leishmaniasis in India. (ClinicalTrials.gov number, NCT00216346.)
Sundar
Shyam
S
Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. drshyamsundar@hotmail.com
Jha
T K
TK
Thakur
Chandreshwar P
CP
Sinha
Prabhat K
PK
Bhattacharya
Sujit K
SK
D000293:Adolescent; D000328:Adult; D000666:Amphotericin B / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001299:Audiometry; D002648:Child; D002675:Child, Preschool; D004197:Disease Reservoirs; D005260:Female; D006311:Hearing Disorders / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D007194:India; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007674:Kidney Diseases / Q000139:chemically induced; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010303:Paromomycin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D016896:Treatment Outcome
D000981:Antiprotozoal Agents; D010303:Paromomycin; D000666:Amphotericin B