Visceral leishmaniasis can be cured with a single drug dose

25 Feb 2010

Paul Chinnock

Source: New England Journal of Medicine (see original article or PDF)

Comments | Related Articles

Citation: Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW (2010). Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl; 362(6):504-512.

Bihar, northeastern India. Half of the world's cases of visceral leishmaniasis are believed to occur in this one State. [Credit: Carol Mitchell.]

Visceral leishmaniasis (VL) – also known as kala azar – is the most serious form of leishmaniasis, a disease caused by a sandfly-borne protozoan parasite. VL causes bouts of fever, substantial weight loss, swelling of the spleen and liver, and anaemia. If left untreated, the fatality rate can be as high as 100% within two years. Although VL is found in many tropical countries and its range seems to be spreading, it is thought that about half of the 500,000 new cases that occur each year are in Bihar, a state in northeastern India. A clinical trial conducted in Bihar has now provided evidence that a single dose of the drug amphotericin B may be adequate to cure the disease.

VL has for many years been treated with drugs known as pentavalent antimonials, such as sodium stibogluconate and meglumine antimoniate. These drugs have side effects and resistance to them is now common in India. The treatment of choice for VL in India is now amphotericin B. The form in which this drug is usually given, however, involves admission to hospital for one month with infusions given on alternate days. (A 28-day regimen of oral miltefosine and 21 days of once-daily intramuscular injections of paromomycin are also known to be effective as treatments for VL in Bihar. However, completing 28 days of treatment is difficult for some patients, and miltefosine cannot be given to pregnant women).

Is one dose enough?

Researchers at the Kala-Azar Medical Research Center, Banaras Hindu University set out to determine whether a single infusion of amphotericin B, given at a higher dose, would prove to be of equally effective or inferior to the standard treatment regimen for this drug.

In an open-label trial, they randomly assigned 412 patients in a 3:1 ratio to receive either liposomal amphotericin B (liposomal-therapy group) or amphotericin B deoxycholate (conventional-therapy group). The liposomal-therapy group were given amphotericin B once (at a dose of 10mg per kilogram of body weight), and patients were sent home 24 hours later. The conventional-therapy group received B amphotericin deoxycholate, administered in 15 infusions of 1mg/kg and given every other day during 29-days spent in hospital.

The researchers determined the cure rate six months after treatment. (Cure was assessed by examination of splenic aspirate for the presence of parasites.) No patients were lost to follow-up. All 304 patients in the liposomal-therapy group were cured, as were 106 of the 108 who received conventional therapy.

A common adverse effect in both groups was, as anticipated, fevers or rigors during administration of the drug – 40% with liposomal and 64% with conventional therapy. But no serious adverse effects were reported from either group.

Previous trials using a single infusion of amphotericin have employed lower doses of the drug (5 or 7.5mg/kg) and achieved cure rates of only around 90%. The findings in this trial with the 10mg/kg single infusion are therefore to be welcomed. As the authors say, “The use of a single-dose regimen removes any concern about compliance with treatment, and its simplicity makes it amenable for use at peripheral health facilities”. They speculate that the overnight hospital stay that was part of the treatment in the trial may in fact not be necessary for most patients.

This approach to treatment should also save costs. Study leader Shyam Sundar has said that health services will be able to treat 40 to 50 times more patients using the single-dose regimen.

Limitations

The authors point out that their trial was conducted in an urban referral centre in a well-controlled setting and that exclusion criteria precluded the enrolment of patients with certain conditions or markedly abnormal laboratory results. Further research would therefore be advisable.

In addition, since VL is thought to be more treatment-responsive in India than in other endemic regions the findings may not necessarily apply elsewhere.

The study report ends with a cautionary note regarding the development of drug resistance, which is established as a problem in VL treatment. Treatment regimens involving a combination of drugs are known to reduce the likelihood of resistance developing, so the use of one drug only carries some concerns. As the authors say, “...if this single-dose regimen becomes widespread in India, it will be critical to detect as early as possible any evidence suggesting that treatment failures are associated with drug resistance”.

2010 Massachusetts Medical Society

Source

Title:
Single-dose liposomal amphotericin B for visceral leishmaniasis in India.

Authors:
Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW

References:
N. Engl. J. Med. 11 Feb 2010: Vol. 362 no. 6, pp. 504-12

Abstract:
Some 50% of patients with visceral leishmaniasis (kala-azar) worldwide live in the Indian state of Bihar. Liposomal amphotericin B is an effective treatment when administered in short courses. We wanted to determine whether the efficacy of a single infusion of liposomal amphotericin B was inferior to conventional parenteral therapy, consisting of 15 alternate-day infusions of amphotericin B deoxycholate.In this open-label study, we randomly assigned 412 patients in a 3:1 ratio to receive either liposomal amphotericin B (liposomal-therapy group) or amphotericin B deoxycholate (conventional-therapy group). Liposomal amphotericin B (at a dose of 10 mg per kilogram of body weight) was given once, and patients were discharged home 24 hours later. Amphotericin B deoxycholate, which was administered in 15 infusions of 1 mg per kilogram, was given every other day during a 29-day hospitalization. We determined the cure rate 6 months after treatment.A total of 410 patients--304 of 304 patients (100%) in the liposomal-therapy group and 106 of 108 patients (98%) in the conventional-therapy group--had apparent cure responses at day 30. Cure rates at 6 months were similar in the two groups: 95.7% (95% confidence interval [CI], 93.4 to 97.9) in the liposomal-therapy group and 96.3% (95% CI, 92.6 to 99.9) in the conventional-therapy group. Adverse events in the liposomal-therapy group were infusion-related fever or rigors (in 40%) and increased anemia or thrombocytopenia (in 2%); such events in the conventional-therapy group were fever or rigors (in 64%), increased anemia (in 19%), and hypokalemia (in 2%). Nephrotoxicity or hepatotoxicity developed in no more than 1% of patients in each group.A single infusion of liposomal amphotericin B was not inferior to and was less expensive than conventional therapy with amphotericin B deoxycholate. (ClinicalTrials.gov number, NCT00628719.)2010 Massachusetts Medical Society

PMID: 20147716
Full text: HTML

Comments | Related Articles