Oral Therapy for Kala-azar
Abstract & Commentary
Synopsis: Visceral leishmaniasis (kala-azar) is caused by the intracellular parasite Leishmania donovani that is transmitted to humans via the bite of the sand fly. The parasite infects the reticuloendothelial system of the liver, spleen, and bone marrow. There are approximately 500,000 cases per year in Asia, South America, and East Africa, with India, Brazil, and Sudan accounting for the most cases in these regions. Scattered cases occur in southern Europe. The incidence is rising with the increasing prevalence of AIDS. Patients with kala-azar present with hepatosplenomegaly and pancytopenia and, if left untreated, more than 90% will die.
Source: Jha TK, et al. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 1999;341:1795-1800.
There is currently no effective orally administered medication for any leishmania infection. Jha and colleagues describe a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis that can be administered orally to patients for the treatment of Indian visceral leishmaniasis (kala-azar). The study used an escalating dose, open-label phase 2 trial of four regimens that were tested at three clinical centers in India in 120 patients with a diagnosis of visceral leishmaniasis (VL). Eligible patients had signs and symptoms of VL (fever, loss of appetite, enlarged spleen) and at least "2+ leishmania" on splenic aspiration performed one week before the first dose of drug. Severe cases of VL with peripheral white cell count (WBC) less than 2000 cells per mm3 and platelet count less than 75,000 per mm3, Hgb less than 6.5 g/dL, or patients with HIV infection were excluded. A second splenic aspirate, obtained two weeks after completion of therapy, determined either parasitologic cure or failure of therapy. Cure was defined as parasitologic cure and clinical cure (loss of fever, 33% drop in spleen size, improvement of cytopenias and albumin level). Four cohorts, containing 30 persons in each, received 50, 100, or 150 mg of miltefosine per day for 4-6 weeks and in all 120 patients there was an initial parasitologic cure. Only six patients had clinical and parasitologic relapse six months after treatment. With the 100-mg dose for four weeks, 97% of patients were cured. Adverse effects noted were mild nausea and occasional vomiting soon after medication ingestion. Asymptomatic reversible hepatotoxicity and nephrotoxicity were observed in a few patients.
Comment by Michele Barry, MD, and wendy thanassi, md
This trial looks quite promising. Current treatment modalities for visceral leishmaniasis are largely impractical for the developing world. Liposomal amphotericin B, while 95% effective, is only available parenterally and costs a prohibitive $5000. Standard amphotericin is also 95% effective but frequently causes renal dysfunction and requires IV injections for 2-3 weeks. Other pentavalent antimonials have a clinical failure rate of 40% in some parts of India and are associated with a high incidence of pancreatitis and other adverse effects.
Miltefosine was originally developed as a treatment for cancer, and its exact mechanism of cytotoxicity with respect to the parasite is unknown. The recommended regimen from this trial was 100 mg/d orally (approximately 2.5 mg/kg) for four weeks, with a maximum dose of 4 mg/kg/d. The main side effect was a relatively minor gastroenteritis. Miltefosine’s cost is unknown, but it is predicted to be "acceptable," as it is easily synthesized. This phase 2 trial is an encouraging step toward the establishment of an effective oral agent that could reduce mortality from this severe disease. We await more information on a phase 3 trial in VL and its efficacy in children and in persons with HIV. How broadly applicable miltefosine therapy is for the other leishmanial clinical syndromes (caused by 21 species in 88 countries) is unknown at this time. (Dr. Thanassi is a Resident, Yale University School of Medicine.)
Miltefosine is a new, potentially useful antiparasitic agent found to:
a. be effective in treatment of cutaneous and visceral leishmaniasis.
b. have irreversible and fatal hepatotoxicity in a few cases.
c. cause both parasitologic cure and clinical cure of visceral leishmaniasis.
d. interfere with mitochondrial metabolic pathways of leishmania.
e. be useful in consolidation therapy for chronic trypanosomal disease in Africa.
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