A single injection of amphotericin B liposome (AmBisome) cures more than 90% of kala azar (leishmaniasis), according to a study conducted in India.
Kala azar (leishmaniasis) is one of the major infectious diseases in India as 90% of patients with visceral leishmaniasis (kala-azar) in the country and nearly 50% of patients worldwide live in the northeastern Indian state of Bihar.
Treatment with liposomal amphotericin B is effective in regimens as brief as 5 days while offering other antileishmanial agents needs a prolonged duration of treatment.
Liposomal amphotericin B in a single infusion of 5 or 7.5 mg per kilogram of body weight could still reduce the treatment time.
The study was conducted as an open-label study at Muzaffarpur of Kala-Azar Medical Research Center at Banaras Hindu University in Varanasi during the period February 2008 through March 2009.
Patients between the ages of 2 and 65 years with symptoms and signs of leishmaniasis (e.g., fever, weight loss, and splenomegaly) and if parasites were shown on microscopy of a splenic aspirate smear were recruited for the study.
Patients who were seropositive for the human immunodeficiency virus (HIV) or who had a serious concurrent infection, such as tuberculosis or bacterial pneumonia, were excluded.
To compare responses to liposomal amphotericin B versus amphotericin B deoxycholate, the researchers used a 3:1 ratio for random assignment to treatment, aiming to assign 300 patients to receive liposomal amphotericin B (liposomal-therapy group) and 100 to receive amphotericin B deoxycholate (conventional-therapy group). 412 patients were enrolled and underwent randomization.
Results from the study showed that liposomal amphotericin B (AmBisome) cured all 304 patients with leishmaniasis within 30 days, compared to 98 percent of 108 volunteers in a comparison group who received 29 days of in-hospital treatment with a different form of amphotericin.
Usually amphotericin B deoxycholate or antimony are given 30 days of therapy. This long duration may produce prominent adverse reactions, as compared with the liposomal regimen.
The use of a single-dose liposomal amphotericin B regimen removes any concern about compliance with treatment.
A 28-day regimen of oral miltefosine and 21 days of once-daily intramuscular injections of paromomycin are also effective treatments in Bihar, producing cure rates of 94 to 95%,.
However, completing 28 days of treatment may be difficult, and miltefosine cannot be used in pregnant women (adequate birth control is also required in women of child-bearing age during and for 3 months after treatment), and initial gastrointestinal reactions are common.
Although not yet available for distribution in India, paromomycin is a promising therapy against kala azar (leishmaniasis).
The pharmacokinetic properties of liposomal amphotericin B and its tissue macrophage-targeting formulation provide some assurance of high and persistent drug levels after a single infusion of 10 mg per kilogram, researchers wrote.
Miltefosine is included in National Kala-Azar Elimination Programme to eradicate the disease from India.
However, concerns about compliance and resistance-engendering effects of partial treatment have already led to suggestions for directly observed therapy and for testing of miltefosine in combination with a second agent (e.g., single-dose liposomal amphotericin B at a dose of 5 mg per kilogram).
Miltefosine-amphotericin combo which could shorten treatment time to 7 to 15 days, is now being studied in additional trials in Bihar. The combination therapy will also diminish the future of likelihood that drug resistance, it is hoped.
Liposomal amphotericin B is available at $20 per 50-mg vial through the Gilead Sciences AmBisome Access Program, in India.
The preferential pricing of the liposomal amphotericin B in India and other developing countries in which leishmaniasis is endemic, along with a single day of ospitalization, according to an agreement with the World Health Organization and Gilead Sciences on March 14, 20078, makes a single infusion of the liposomal preparation less expensive than 15 alternate-day doses of the deoxycholate preparation.
The retail cost of amphotericin B deoxycholate is approximately $6.50 per 50-mg vial. The total cost of a single infusion of 10 mg of liposomal amphotericin B per kilogram for a 35-kg patient in Bihar would be $162 ($140 for the drug plus $22 for 1 day of in-hospital care); outpatient treatment would cost $148.
For a similar patient, 15 alternate-day infusions of 1 mg of amphotericin B deoxycholate per kilogram during a 30-day hospital stay would cost $436 ($68 for the drug plus $368 for hospitalization and laboratory monitoring).
In addition, A similar analysis that was applied to pentavalent antimony (a traditional therapy still active in India outside of Bihar, administered at 20 mg per kilogram per day for 30 days1) yielded the same conclusion. Although generic pentavalent antimony in India is inexpensive ($32 per course for a 35-kg patient), the estimated total cost of parenteral treatment in a hospitalized patient is nevertheless high ($37614).
In this study, the group decided to try a high dose, which was administered over an hour, after the subsidized price of the drug dropped from $200 per vial down to $20 per vial in developing countries.
They found no evidence that the one-day treatment was less effective than the multiple treatments. In addition, AmBisome “was not associated with any safety concerns in adults or children, and compliance was guaranteed,” they reported.
With a one-dose, one-hour treatment, “you can treat 40 to 50 times more patients,” Sundar said in a telephone interview.
At $20 per vial, the drug is more expensive than the established treatment with amphotericin B deoxycholate. But the one-time infusion made overall treatment less expensive because a long hospital stay and laboratory monitoring was avoided.
Other drugs, such as oral miltefosine, are effective against the condition as well, but they must also be given over many weeks.
Kala azar or visceral leishmaniasis is a deadly disease caused by parasitic protozoa Leishmania donovani, transmitted to humans by the bite of infected female sandfly, Phlebotomus argentipes.
Kala azar lowers immunity, causes persistant fever, anemia, liver and spleen enlargement, and if left untreated, it kills.
The sandfly thrives in cracks and crevices of mud plastered houses, poor housing conditions, heaps of cow dung, in rat burrows, in bushes and vegetations around the houses.
Kala azar is endemic in three countries of WHO’s SEA Region –Bangladesh, India and Nepal. Approximately 200 million people in the Region are “at risk” from the disease, according to WHO estimates.
Kala azar is now being reported in 45 districts in Bangladesh, 52 in India and 12 I Neplal. The total number of districts reporting kala-azar exceeds 109.
Of the estimated 500,000 people in the world infected each year, nearly 100,000 are estimated to occur in the region.