New Treatment Approach for Indian Visceral Leishmaniasis

Abstract & Commentary

By Michele Barry, MD, FACP

Dr. Barry is a Professor of Medicine and Public Health; Director of International Health Program, Department of Medicine, Yale University School of Medicine, New Haven, CT.

Dr. Barry reports no financial relationships relevant to this study.

Synopsis: A new treatment approach to visceral leishmaniasis, or kala-azar, using single-dose liposomal amphotericin B followed by short-course oral miltefosine has been demonstrated in the Bihar area of India where 90% of India's cases, and 45% of the world's cases, occur.

Source: Sundar S, Rai M, Chakravarty J, et al. New treatment approach in Indian visceral leishmaniasis: Single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis 2008;47:1000-1006.

Bihar, India, is the source of nearly one-half of the world's burden of visceral leishmaniasis and, unfortunately, drug resistance has ended the usefulness of pentavalent antimony (Sb) therapy. Early reports of miltefosine resistance have prompted investigation of alternative, cost-effective, practical regimens. This group postulated that a single infusion of IV liposomal ampho-tericin B (L-AmB) could be curative and, if followed by short-course oral miltefosine, potentially could prevent future drug resistance. They randomized 181 subjects to treatment of 5 mg/kg L-AmB alone (group A: 45 subjects), 5 mg/kg L-AmB followed by miltefosine for 10 days (group B: 46 subjects) or 14 days (group C: 45 subjects), or lower dose L-AmB 3.75 mg/kg followed by oral miltefosine for 14 days (group D: 45 subjects), and L-AmB 5.0 mg/kg followed by oral miltefosine for 7 days (group E: 45 subjects). (See Table.) Patients were eligible if they were older than 12 years of age with symptoms and signs of kala-azar (e.g., fever, weight loss, and splenomegaly) and parasites demonstrated by microscopic examination of splenic aspirate smear at time of diagnosis. Pregnant or breast-feeding women and individuals who were seropositive for HIV were excluded. Patients with severe pancytopenia (wbc < 1000, plts < 40,000, hgb < 3.5 g/dL) or liver or renal insufficiency were excluded.

Each regimen was satisfactorily tolerated, and all 226 subjects showed initial cure responses with negative splenic aspirates at 16 days. Nine months after treatment, final cure rates (defined as feeling healthy without signs or symptoms of relapse) were similar; group A, 91% (95% confidence interval [CI], 78%-97%]; group B, 98% (95% CI, 87%-100%); group C, 96% (95% CI, 84%-99%]; group D, 96% (95% CI, 84%-99%); and group E, 98% (95% CI, 87%-100%).

A single dose of intravenous liposomal amphotericin B (L-AmB) was tested, as was intravenous L-AmB followed by several randomized treatment regimens of short-term oral miltefosine therapy. All randomized regimens in this pilot study resulted in 100% parasite-free splenic aspirates at 16 days and symptom-free patients at 9-month follow-up. The authors postulate that potential advantage of 2-drug combination therapy includes lowered toxicity, better compliance, and less likelihood of developing drug resistance that has made traditional first-line monotherapy with pentavalent antimony obsolete in this part of the world.

These results suggest that treatment with single-dose L-AmB as well as single dose L-AmB followed by 7, 10, or 14 days of miltefosine is active against Indian visceral leishmaniasis or kala-azar. The authors postulate a short-course, sequential regimen has the benefit of preventing drug resistance in areas where miltefosine resistance is already beginning to be reported.

Commentary

Leishmaniasis, spread by the bite of the female sandfly, is caused by a heterogeneous group of protozoan parasites belonging to the genus Leishmania. Leishmaniasis, also known as kala-azar or black fever, is caused by three parasite species of L. donovani complex; L. donovani, L. infantum, and L. chagasi. In 1903, Leishman and Donovan separately described Leishmania donovani in splenic tissue from patients in India with a life threatening disease called visceral leishmaniasis. Unfortunately, almost a century later epidemics of this sandfly-borne disease persist and pentavalent antimony (Sb) therapy has now been made obsolete due to drug resistance in this part of India.1 In India and Bangladesh, L. donovani has no animal reservoir, and humans serve as both the natural reservoir and host for infection. Kala-azar means "black sickness" and refers to the earthen-gray skin color that is common among infected individuals in India. Most patients do not recall a primary cutaneous lesion from the vector bite, but present with five characteristic hallmark features:

  • hepatosplenomegaly;
  • fever;
  • cachexia;
  • pancytopenia; and
  • hypergammaglobulinemia.

Examination often reveals massive splenomegaly and moderate hepatomegaly. Concomitant HIV infection can produce unusual features in kala-azar with involvement of the central nervous system, respiratory tract, and gastrointestinal tract.

The results of this pilot study indicate the feasibility and cost-effectiveness of combination therapy in Indian kala-azar. A single intravenous dose L-AmB followed by oral miltefosine mitigates the cost of traditionally longer and more expensive regimens. A 28-day cost of the traditional course of oral miltefosine remains fairly expensive, even at the discounted price offered to the World Health Organization (US $84 for a patient weighing > 25 kg). Although inexpensive, paromomycin requires 21 days of intramuscular injection. Inpatient 5-day course L-AmB (total dose 15 mg/kg) is also expensive despite its discounted price, and treatment with intravenous amphotericin B deoxycholate usually requires 30 days in the hospital. Thus, the simplified regimens reported in this study could encourage drug compliance and be cost saving.

It is important to note that this trial was not designed to identify whether addition of miltefosine meaningfully improves the over 90% cure rate of single dose L-AmB alone or whether any of the tested combinations are as effective as the traditional 28-day oral course of miltefosine alone. It is also important to note all HIV-infected patients were excluded from this study. However, this pilot suggests outpatient single infusion of L-AmB followed by brief self-administered miltefosine may produce high cure rates inexpensively and might theoretically prevent drug resistance, although that was not proven in this study. Future confirmatory studies are eagerly awaited.