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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 49, Num. 1, 2003, pp. 61-68

Journal of Postgraduate Medicine, Vol. 49, No. 1, Jan-March, 2003, pp. 61-68

Symposium

Recent Understanding in the Treatment of Visceral Leishmaniasis

Rosenthal E, Marty P*

Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Nice, Groupe de Recherche en Immunopathologie de la Leishmaniose (GRIPL), Faculté de Médecine, Université de Nice-Sophia-Antipolis, and *Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Nice, France
Address for Correspondence: Eric Rosenthal, Service d'Hématologie Clinique, Hôpital l'Archet, Centre Hospitalier Universitaire de Nice, 06202 Nice cédex 02, France E-mail : rosenthal.e@chu-nice.fr

Code Number: jp03012

Abstract:

Visceral leishmaniasis (VL) is a severe disease associated with infection of the reticuloendothelial system by Leishmania species. The infection is acquired through sandfly bites. Recent large scale epidemics of VL in east Africa and India and the emergence of a HIV epidemic make VL a priority for the World Health Organization. Pentavalent antimonials have been cornerstone of treatment for the last six decades. The appearance of antimonial-resistance and the development of lipid formulations of amphotericin B have changed the pattern of VL treatment. Within the past five years, miltefosine has been demonstrated as the first effective and safe oral treatment against VL. The price of miltefosine is yet to be determined. However, miltefosine will certainly be cheaper than lipid formulations of amphotericin B, which are beyond the financial capacity of the poor countries. Because it can be administered orally, miltefosine is suited for the treatment of large number of patients who get affected during epidemics, particularly in regions where the parasites are resistant to the currently used agents. Here, we recommend different treatment schedules according to the resistance pattern and the region-specific socio-economical and cultural factors. (J Postgrad Med 2003;49:61-68)

Key Words: Drug resistance; HIV; developing countries; liposomal amphotericin B; amphotericin B; pentavalent antimonials; miltefosine.

Visceral leishmaniasis (VL) is a disseminated protozoal infection transmitted by sandfly bites. The disease, affecting both children and adults, typically presents with fever, hepato-splenomegaly, and pancytopenia. Once established, the clinical course of untreated VL leads to death in a majority of patients, generally because of intercurrent infections. Although VL is endemic in more than 60 countries, nearly all of the 500, 000 new cases of symptomatic VL occur each year in the rural areas of just five countries: India, Nepal, Bangladesh, Brazil, and Sudan.1 Anthroponotic VL occurs in east Africa and the Indian subcontinent. An epidemic appeared in western Upper Nile region of southern Sudan in 1984, causing 100, 000 deaths among a population just under 1 million.2 In the Indian subcontinent, where 50% of reported VL cases occur, many factors led to low compliance to the therapy, including a lack of resources and health education. Premature interruptions of the therapy led to emergence and progression of resistance to first-line drug. In contrast, in Latin America, China and the Mediterranean basin, VL is a zoonotic disease. In the mid-1980s the first cases of VL have been reported in southern Europe in patients infected with human immunodeficiency virus (HIV). To date, Leishmania-HIV co-infection has been reported from 33 countries,3 with most of the cases located in southern Europe. In this region, 25-70% of adult patients with VL are co-infected with HIV and it is estimated that 1.5-9% of patients with AIDS will develop leishmaniasis.4 Although not recognised as an AIDS-defining criterion, VL constitutes an opportunistic disease in HIV-infected patients. Several studies have demonstrated that HIV/AIDS patients living in Leishmania-endemic areas are at a greater risk of developing VL5 and that dual infection accelerates the clinical course of HIV disease.6 Clinical presentations are often atypical, with unusual parasite localisations and frequent relapses.7 The introduction of highly active anti-retroviral therapy (HAART) as a standard treatment for HIV has resulted in a significant decrease in the incidence of VL in HIV-infected individuals in southern Europe.8 Another cause for concern is the increase in the number of co-infection cases in eastern Africa, Brazil and Indian subcontinent, owing to the simultaneous spread and geographical overlap of both diseases as well as the periodic occurrence of epidemics of VL.3 Currently, however, accessibility and affordability of HAART in these areas remain limited.

Today, treatment of VL constitutes a difficult challenge. The most recent complicating difficulties are co-infection with HIV and resistance to penta-valent antimonials. These problems join the long-standing list of obstacles that have undermined the measures to control VL: inadequate vector control, poverty and malnutrition, migration of non-immune refugees, insufficient diagnosis tools and unavailable or unaffordable drugs.

Available Drugs

A: Classical Agents

1. Pentavalent Antimony
Organic salts of pentavalent antimony have been the cornerstone of treatment for all forms of leishmaniasis for more than 60 years.9 Antimonials are thought to act by inhibiting the enzymes of glycolysis and other metabolic pathways.10 Two major pentavalent antimonials are currently used: Sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantime®). Sodium stibogluconate contains antimony 100 mg/ml and is primarily used in English-speaking countries. The closely related compound meglumine antimoniate (Glucantime®) contains antimony 85 mg/ml and is primarily used in French-speaking areas. The drugs are given intravenously or intramuscularly (i.m.), and they are equal in efficacy when used in equivalent doses. The recommended regimen consists of once-daily injection of full-dose drug (20 mg/kg) for 30 days. While active elsewhere in India, antimonials are no longer useful in north eastern state of Bihar, where as many as 65% of the previously untreated patients fail to respond to or promptly relapse after therapy with antimonial compounds.11 Disadvantages of antimonials include the parenteral mode of administration, the long duration of therapy and the adverse reactions. Systemic toxicity normally relates to total dose administrated. Secondary effects (such as fatigue, bodyache, electro-cardiographic abnormalities, raised aminotransferase levels and chemical pancreatitis) are frequent, albeit usually reversible. Severe adverse events remain rare. However, sudden death due to arrhythmia has been reported in a patient receiving high doses for a prolonged period.12 Acute pancreatitis with a fatal evolution has been reported in HIV-infected patients.13

Cheaper generic formulations of sodium stibogluconate are available. They were recently compared in field conditions in east Africa and were found to be equally safe and as effective as their branded counterparts.14-16 However, the poor quality of some generic antimonials led to serious toxicity in some of the recipients in India.17 Efforts to develop lipid formulations of antimonials are on. A novel liposome-based meglumine antimoniate formulation appears to be promising as a pharmaceutical product for the treatment of VL.18

2. Diamidine
Pentamidine isothienate (4 mg/kg im, thrice- weekly for six weeks) was used in the treatment of antimonial-resistant VL. However, side effects such as myalgia, nausea, headache and hypoglycaemia were common at this dose, with an exceptional risk of developing irreversible diabetes. Besides, the drug achieves poor response rates (around 75%) when used as a second-line drug in antimonial-resistant areas. This is a major factor limiting interest in pentamidine.19, 20

3. Paromomycin
Aminosidine is an aminoglycosidic antibiotic identical to paromomycin sulfate and is administered once daily, usually by the intra-muscular route. Combined with antimonials, aminosidine (12-18mg/kg for 21 days) allows a reduction in the duration of the therapy 21 and may be more efficient than antimonials alone in areas with high levels of antimonial resistance.22 Aminosidine also appears to be active in India when used alone.23 However, its potential for causing ototoxicity and nephrotoxicity needs further evaluation.24

4. Allopurinol
At the beginning of the 1980s, non-randomised trials showed that a combination of antimonials and allopurinol (15 mg/day) was efficacious in treating VL.25-28 Recently, a randomised trial in patients with antimonial-unresponsive VL, suggested that combined therapy with allopurinol plus pentamidine provided higher cure rate than with pentamidine alone.20 At the present, allopurinol is not used in monotherapy in India.

B: Recent Advances in VL Therapy

Amphotericin B and Lpid-associated Formulations
The anti-fungal agent amphotericin B has long been recognised as a powerful leishmanicidal drug. It probably intercalates with the parasite episterol precursors of ergosterol. It owes its popularity as an effective agent for treatment of VL largely to the decline and fall of antimonials in India and the failure of pentamidine as satisfactory substitute in such cases.19

Amphotericin B Desoxycholate
In India, 98% of long-term cure was obtained in both antimonial-unresponsive and previously untreated patients, with conventional amphotericin B desoxycholate (Fungizone®).19, 29 However, infusion-related side effects (fever, chills, bone pain) and renal toxicity of conventional amphotericin B are still major problems. Despite manufacturers recommendations against mixing, short-course treatment with amphotericin B-fat emulsion (five alternate-day infusions of 2 mg/kg) has been evaluated in an uncontrolled study in India. Definitive cure was reported in 93% of antimonial-unresponsive patients. Although debatable, this could represent a cost-effective treatment for patients with VL, including those with antimonial-unresponsive infection.30

Lipid Formulations of Amphotericin B
First used in antimonial-resitant VL by Davidson et al 31 in 1991, lipid formulations of amphotericin B have been proven to increase the efficacy and to limit the toxicity of conventional amphotericin B.32-34 These formulations allow administration of considerably higher daily doses and simultaneously appear to target infected tissue macrophages via enhanced phagocytic uptake.24 Three lipid formulations are available: Ambisome®, which is a formulation using spherical, unilamellar liposomes that are less than 100 nm in size; Amphocil®, which is a dispersion with cholesterol sulfate in 1:1 molar ratio; Abelcet®, which is a ribbon-like lipid structure using a phospholipid matrix. A five days long regimen consisting of daily infusion or a 10-day regimen consisting of infusions on days 1-5 and day 10 are considered to be remarkably active.32-35 There are regional differences in responsiveness to the lipid formulations. In Mediterranean VL, Ambisome® 18-24 mg/kg total dose is efficient compared to Ambisome® 6-14 mg/kg in India.36-38 In HIV-co-infected patients and in recipients of organ transplants, higher dosages and prolonged treatment are needed.39-41 Recently, a comparative trial evaluated the efficacy of a single dose of liposomal amphotericin B (5mg/kg) versus once-daily infusion of 1 mg/kg for 5 days in Indian VL. Definive cure rates were not different between the groups (91% versus 93%), warranting further testing of the single-dose regimen.42

Miltefosine
Hexadecylphosphocholine (miltefosine) is one of a series of alkylphosphocholines. It has been developed as an anti-neoplastic agent and is now used topically in dermal metasatases of breast cancer. Administered orally, miltefosine has a long half-life ranging between 150 and 200 hours. It was first identified to have in vitro and in vivo activity against L. donovani.43 Other studies showed that oral miltefosine had activity in mice against VL caused by L. donovani and L. infantum.44-46 The mechanisms of action of miltefosine against Leishmania have not yet been well defined. Miltefosine has been shown to block the proliferation of Leishmania and to alter phospholipid and sterol composition.47 The anti-leishmanial activity of miltefosine is not only related to a direct cytotoxic effect on the parasite but is also related to the activation of cellular immunity, which in turn, takes care of the parasitic infection.48-50

The first phase clinical trial of oral miltefosine was performed in patients with Kala-azar in India to evaluate safety, tolerance and efficacy.51 Oral doses of miltefosine were given to six groups of five Indian men (50 mg every second day to 250 mg/day for 28 days). Vomiting and diarrhoea were observed in 22 of 30 patients. Twenty-one patients were apparently cured by day 14. One patient developed severe diarrhoea and renal insufficiency and died on day 21. At the end of four weeks, 29 of 30 patients were apparently cured, and by 8 months, 18 of 19 patients treated daily appeared to be cured. Half of these patients had previously failed to show response to therapy with pentavalent antimony. The authors concluded that treatment with orally administered miltefosine at 100-150 mg/day for 4 weeks holds promise as an effective treatment of Indian VL, including antimonial-resistant VL. Other clinical trials seem to confirm the efficacy of the drug.52-54 Dosing 100 mg (2.5mg/kg/day) over days 21-28 days appeared efficient both in untreated VL and in antimony-resistant VL. More recently, an open-label randomised trial compared the efficacy of oral miltefosine (in the dose of 50 or 100 mg, approximately 2.5 mg per kilogram of body weight daily for 28 days) in 299 patients with that of intravenous amphotericin B (in the dose of 1 mg per kilogram every other day for a total of 15 injections) in 99 patients.55 At the end of treatment, the initial cure rate was 100% in both the groups. By 6 months after the completion of the treatment, 94% and 97% of patients in miltefosine and amphotericin B groups respectively, had not had a relapse and were classified as cured. The side effects of miltefosine were generally tolerable and compare favourably with those of all agents other than liposomal amphotericin B. Vomiting and diarrhoea are the most frequent side effects, occurring in about 40% and 20%, respectively. Approximately three quarters of the gastrointestinal events last one to two days per patient and occur once on each of these days. Miltefosine has toxic effects on reproductive capacity in female animals, and pregnancy should be strictly avoided while on the drug and for two months after completion of therapy.

C: Other Drugs

Numerous oral agents have been tested as stand-alone agents or as agents for combination therapy for treatment of VL. Most of them including ketoconazole, itraconazole, fluconazole, terbinafine and metronidazole have been discarded.56-58 Sitamaquine (WR6026), an 8 amino-quinoline, first reported in 1994, may constitute a promising oral drug. Sitamaquine (1 mg/kg/day for 4 weeks) when administrated to 8 patients provided a 50% cure rate.59 More recently, a phase 2 dose-escalating trial was performed in Brazil. Cure rates for patients treated for 28 days were 0% and 67% at 1 mg/kg/day and 2 mg/kg/day, respectively.60 Further studies are needed to determine the efficacy and toxicity profile of this agent.

D: Immunotherapy

Interferon gamma is a potent macrophage activator with synergistic activity with antimonials in mice.61 Interferon gamma alone has limited efficacy in human VL.62 Adjunctive interferon gamma therapy may accelerate or improve the response to antimonial therapy in some difficult cases.63, 64 However, this approach may offer, at best, a marginal benefit in settings with high level resistance to antimonial compounds 64 and has been used sparingly since the advent of amphotericin B lipid formulations.40 The high cost of interferon gamma precludes its widespread use in the developing world.

Factors Influencing the Choice of Therapy

Many factors must be taken in account while choosing the most appropriate agent for the therapeutic management of VL. These include not only medical factors but also socio-economical and cultural factors. One should know about the endemicity of Leishmania strains, the immune and nutritional status of the population, level and pattern of parasite resistance to drugs and obviously the cost of the drugs.

In Mediterranean L. infantum area, VL is a sporadic disease with a limited number of cases. In North Africa, VL remains a disease primarily affecting children in poor families. In these areas children account for as many as 90% of the cases with no clinical resistance to antimonial compounds.65

The epidemiological situation is quite similar in Brazilian L. chagasi focus. On the European coast of the Mediterranean basin (Italy, France, Spain, Portugal), where the socio-economical conditions are better, the annual number of VL cases in children remains stable. However, adults represent 60-70% of burden of VL cases.66 In immunosuppressed HIV-infected patients, representing half of the adults infected with L. infantum, VL is an emerging opportunistic disease.5, 67, 68 In these patients, the major problems are frequent relapses and need for secondary chemoprophylaxis depending on CD4 cell count.69, 70

In African and Indian areas with L. donovani infection, VL is a hyperendemic disease with a high rate of transmission. Most of the areas where VL is rampant there is lack of basic sanitary infrastructure. 2, 71 About half a million cases are reported annually, mostly in extremely poor and malnourished individuals. In many of these areas, HIV epidemic is shaping up and it is feared that Leishmania-HIV co-infection may explode in the future.1

The total cost of the treatment depends both on the price of the drug (Table 1) and the cost of hospitalisation. The cost can be 14 times more expensive for a branded drug compared to a generic one.15 For the same drug, the price could vary depending on the distributor and the client (Bryceson, personal communication). Different local price scales may be offered and actual acquisition costs may be around 30 to 40% lower in certain circumstances.24 Hospitalisation costs also need to be taken into consideration while determining the cost of regimen. The exorbitantly high price of amphotericin B lipid formulations makes them inaccessible in developing countries. Although hospital costs can be appreciably reduced by short courses and especially by single-dose-regimens, the savings do not offset the cost of the drug in countries such as India, where hospital charges are low. Drug companies will have to cut prices for the potential benefits to be realised.45

Recommendations for Treatment of Visceral Leishmaniasis

Current best practices in the treatment of VL may be differentiated according to the different settings.

1. Mediterranean VL due to Leishmania Infantum 

Immunocompetent Patients
In 1995, the WHO agreed that four first-line regimens were acceptable for the management of VL in immunocompetent patients:72

  1. Organic pentavalent antimonials in the form of sodium stibogluconate or meglumine antimoniate solutions. The recommended dose of antimony is 20 mg/kg/day for 20-28 days,
  2. Antimonials (20 mg/kg/day) in combination with allopurinol (15mg/kg/day) for 20-28 days,
  3. Liposomal amphotericin B (Ambisome®) at 3 mg/kg/day on days 0,1,2,3,4 and 10, giving a total dose of 18 mg/kg,
  4. Aminosidine was considered an acceptable first-line drug, but dose and treatment duration were not defined. It was used alone or in combination with pentavalent antimonials at 12-16 mg/kg for 14-63 days.

However, although acceptable, to our knowledge regimens 2 and 4 have are not commonly used in the treatment mediterranean VL.

Patients of VL with HIV co-infection
In 2001, the fourth WHO joint meeting on Leishmania-HIV co-infection held in Catania (Italy) examined the therapeutic options.73 The treatment of Leishmania-HIV co-infected patients remained controversial. The use of pentavalent antimonials or amphotericin B desoxycholate, although useful, has a significant toxicity and the therapy is of long duration.74 New Amphotericin B lipid formulation have a better tolerability and can be used as short-course treatment. However, there are no reports of large-scale studies involving use of lipid amphotericin B in these patients.

HIV-infected patients, including those on HAART demonstrate relapse of VL after successful therapy. This is not a common occurrence and it is likely to occur at lower CD4 counts.69, 70 In the absence of controlled study, there is no agreement about the indication and choice of secondary prophylaxis. The relapse-free period between patients treated with lipid amphotericin B (Abelcet® 3 mg/kg every 3 weeks) versus no treatment has been evaluated: after one year follow-up, 50% and 22% respectively, had no relapses. However, the figures were not statistically different (Laguna, data not published). Recipients of organ transplant constitute another group of immunocompromised individuals and this group may face the prospect of VL occurring as an opportunistic infection in them as well. It is possible that this group may have to tackle issues similar to those faced by patients with HIV-Leishmania co-infection.45

American VL due to Leishmania chagasi
American VL due to Leishmania chagasi and Mediterranean VL due to Leishmania infantum do not differ from the parasitological and epidemiological points of view. The treatment practices are quite similar in both diseases. A multi-centre trial in India, Kenya and Brazil suggested that Ambisome® 2 mg/kg on days 1-10 constitutes an effective therapy for patients with Mediterranean VL.75

Anthroponotic VL due to Leishmania donovani
The first-line treatment remains antimonial pentavalent compounds with a minimum dose of 20 mg/kg/day for 28 days. Sub-optimal doses, incomplete treatment and sub-standard drugs may lead to clinical resistance. Until recently, amphotericin B desoxycholate was the only other available alternative drug in these areas. The availability of new oral anti-leishmanial drug, miltefosine could change the situation in near future and it may become a preferred first-line drug. Miltefosine is now registered in India. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains too expensive for most patients.76

Discussion

Socio-economic and cultural conditions have a tremendous bearing not only on the prevalence of VL but also on the choice of therapeutic option.77 Taking into consideration the 1995 WHO recommendations, liposomal amphotericin B should be considered the preferred first line drug.72 This drug provides spectacular cure rates at an extremely rapid pace, especially in children, and is associated with low potential for toxicity. It constitutes a cost-effective regimen in comparison to antimonials, if one takes into account the hospitalisation costs. The recommendation could change once an effective orally administered agent becomes available. There is nor running away from the fact that several issues regarding treatment of VL in HIV-infected patients remain unresolved. These are related to the duration of therapy and exact indications for institution and stoppage of prophylactic regimens. Liposomal amphotericin B constitutes the first-line therapy, but we cannot recommend a precise duration of treatment. Secondary prophylaxis can probably be interrupted, when CD4 cell counts exceed 300 per mm.3,70 In HIV-infected people living in endemic areas and asymptomatic carriers of Leishmania, HAART probably prevents overt VL.8

In developing countries, the cost of lipid formulations of amphotericin B precludes their use. Miltefosine is an affordable drug, which appears as an effective and safe agent for use in regions with high level of antimonial resistance. Under these conditions, it may constitute the first-line therapy. However, due to the long half-life, sub-therapeutic levels of miltefosine may be encouraged for a few weeks after a 4-week course. It is feared that this characteristic might encourage the emergence of resistance in future. The risk of emergence of secondary resistance must be evaluated and the possible use of combination therapies needs to be explored to forestall it.78 In areas without antimonial resistance, antimonial compounds may remain the first-line choice. However, considering its striking advantages in terms of safety, ease of oral administration and affordability, miltefosine may soon become an alternative choice.

The issue of treatment of VL in developing countries is no longer an issue limited to an individual patient. It is a public health problem considering the fact that inadequate and ineffective therapy is fraught with emergence of secondary resistance. The issue of controlling VL also goes beyond development of new effective drugs and therapies and implementation of vector control measures. The world has to face the problem of high costs of therapy squarely as control of VL cannot wait till the economic situation improves and social and cultural issues tackled.

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