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Diseases Leishmaniasis Current Treatments
Diseases Leishmaniasis Current Treatments
Current Treatments
Current Treatments
| The number of treatments has increased in the past decade, but there are numerous drawbacks to each, such as difficulty in administration, length of treatment, toxicity, cost, and increasing parasitic resistance. Pentavalent antimonials remain the first-line treatment in most parts of the world, except in Bihar State, India where there is a high level of resistance. However, there has been significant improvement in the number of treatments available for VL during the past decade, with both new drugs and new formulations of old drugs either recently approved or in clinical trials (see table below). These new treatments include: AmBisome™, an amphotericin B liposome formulation, which was registered for VL in the USA and Europe in the 1990s and has significant activity, even as a single dose treatment, in India; oral miltefosine registered in India in 2002 and now in Phase IV trials; and a low cost parenteral (intramuscular) formulation of paromomycin that has completed Phase III clinical trials and was registered in India (www.oneworldhealt.org) in 2006, and is in phase III in East Africa. Unfortunately, all of these drugs suffer from significant drawbacks of either parenteral route of administration, length of treatment (21 to 28 days), toxicity or cost, which limit their use in disease-endemic areas. Parasitic resistance to pentavalent antimonial drugs in India could also develop in other regions of S. Asia and in Africa. Both of the new therapeutic agents, miltefosine and paromomycin, have been shown to rapidly select for resistance in laboratory studies; they are expected to have only a short effective ‘life’ in clinical use unless strategies to minimise resistance are put in place. |
| Drugs | Pentavalent Antimonials | Amphotericin B | Liposomal Amphotericin B | Miltefosine | Paromomycin sulphate |
| Regimen | 20 mg/kg daily for 20-30 days (depends on geographic area) | 1 mg/kg e.o.d. for up to 30 days (15mg/Kg total dose) | 5-20 mg/kg total dose in 4-10 doses over 10-20 days | 1.5-2.5 mg daily over 28 days (India only) | 15mg/kg/ for 21 days (India only) |
| Marketing authorisation holder | Albert David (SSG) GSK (Pentostam) Sanofi Aventis(Glucantime) | Bristol Meyers Squibb (Fungizone) Generic companies | Gilead (AmBisome®) | Paladin (Impavido) | Gland Pharma / OWH |
| Administration | iv or im | iv | iv | oral | im |
| Clinical efficacy Asia Africa South America | 35-95% (depending on geographic area) | > 97% all regions | > 97%; single dose: 91% Not fully established; Not fully established | 94-97% (India); Not established; Not established | 94%(India) In evaluation Assumed to be limited |
| Resistance | As high as 60% (Bihar, India) | Not documented | Not documented | Lab isolates | Lab isolates |
| Toxicity | +++ Cardiac toxicity, pancreatitis, nephrotoxicity hepatotoxicity | +++ Nephrotoxicity (in patient care needed) | + Some nephrotoxicity | + Gastro-intestinal (20-55% of patients, usually mild),nephrotoxicity hepatotoxicity Possible teratogenicity | + Nephrotoxicity ototoxicity hepatotoxicity (all relatively rare) |
| Approximate cost of drugs per course* USD (Euros) | SSG (AD) ~$50 (37€) Glucantime (SA)~ $70 (52 €)(Based on 30 day course) | Generic price: ~ $117 (87€) | Preferential price: $280 (207€) (for 20mg/kg total dose) Commercial price: ~10x above costs | Preferential price: ~ $74 ( 54 €) (can be obtained at 46€ if buying>75 000 packs) Commercial price: ~ $150 | ~ $10 (7.3 €) |
| Issues | Quality control Availability Length of treatment Painful injection Toxicity Resistance in India | Need for slow iv infusion; Dose-limiting nephrotoxicity; Heat stability | Price; Need for slow iv infusion; Heat stability (Stored <25° C) | Price; Possible teratogenicity; Potential for resistance; Patient compliance | Efficacy variable between and within regions |
| Resistance to amphotericin B (only shown in laboratory so far) and AmBisome has not yet been a clinical problem, but this may be due to the extremely limited use of these two drugs, based on cost of treatment and the nephrotoxicity of the first, and the prohibitive cost of the second. The increasing numbers of patients with HIV / VL co-infection, particularly in Ethiopia, who require repeated courses of treatment for parasite control and to prevent relapse, represents another major challenge for the development of new safe and affordable treatments. Data from one MSF treatment centre in northern Ethiopia (Humera) indicate that miltefosine may be more efficacious and better tolerated than SSG in HIV/VL co-infected patients. These data need to be confirmed. |
Leishmaniasis
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