Review
Combination therapy for visceral leishmaniasis

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Summary

Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. We reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens. The first phase 2 results of combination regimens are promising, and have identified effective and safe regimens as short as 8 days. Several phase 3 trials are underway or planned in the Indian subcontinent and east Africa. The limited data available suggest that combination therapy is more cost-effective and reduces indirect costs for patients. Additional advantages are reduced treatment duration (8–17 days), with potentially better patient compliance and lesser burden on the health system. Only limited data are available on how best to prevent acquired resistance. Patients who are coinfected with visceral leishmaniasis and HIV could be a reservoir for development and spread of drug-resistant strains, calling for special precautions. The identification of a short, cheap, well-tolerated combination regimen that can be given in ambulatory care and needs minimal clinical monitoring will most likely have important public health implications. Effective monitoring systems and close regulations and policy will be needed to ensure effective implementation. Whether combination therapy could indeed help delay resistance, and how this is best achieved, will only be known in the long term.

Introduction

Visceral leishmaniasis, also known as kala-azar, is a disseminated protozoan infection caused by the Leishmania donovani complex and transmitted via phlebotomine sandflies.1 The zoonotic form, for which dogs are the main reservoir, is present in the Mediterranean basin, China, the Middle East, and South America, and is caused by Leishmania infantum or Leishmania chagasi. The anthroponotic form (human reservoir) is caused by L donovani and is prevalent in east Africa and the Indian subcontinent.1, 2 Although the disease is endemic in more than 60 countries, with 200 million people at risk, 90% of the 500 000 cases every year happen in five countries: India, Bangladesh, Nepal, Sudan, and Brazil (figure 1).1, 3, 4, 5

For most of the past 70 years, the therapeutic armoury for treatment of visceral leishmaniasis has been extremely limited.6 Pentavalent antimonials were introduced in the 1940s, and include sodium stibogluconate and meglumine antimoniate. Use of amphotericin B followed after a few decades, and was later joined by paromomycin, a cheap and effective parenteral drug with an acceptable toxicity profile that can easily be given by intramuscular injection.7 The development of miltefosine, the only drug at present that can be given orally for visceral-leishmaniasis treatment, has been a major breakthrough.8, 9 This drug is the mainstay of the recently launched visceral-leishmaniasis elimination plan in the Indian subcontinent,10 and benefits from a preferential pricing scheme that puts it at the same price as generic pentavalent antimonials if large quantities are purchased. Finally, different lipid formulations of amphotericin B (ie, liposomal amphotericin B) have been developed, which are similar to amphotericin B in efficacy but with fewer toxic effects (table 1).11 Although these formulations were initially prohibitively expensive, the preferential price now offered to governments of endemic countries, WHO, and non-governmental organisations make them an option for low-income and middle-income countries. Although other compounds are being developed, these drugs are likely to constitute the main therapeutic options for visceral leishmaniasis in the years to come.6, 12 These drugs belong to chemically unrelated classes and are thought to have distinct targets. All of them have several important disadvantages (table 1).

There are several reasons why consensus has grown over the past few years towards the use of combination regimens in visceral leishmaniasis.6, 13, 14, 15, 16, 17 First, combining drugs from different chemical classes could reduce treatment duration or total drug doses, resulting in fewer toxic effects, higher compliance, and less burden on the health system. This could also reduce the overall costs (direct and indirect) and provide a more cost-effective option. Increasing reports of treatment failure with pentavalent antimonials from the Indian subcontinent have raised the issue of acquired drug resistance.14, 18, 19 This concern now extends to miltefosine, because of its long half-life and susceptibility to develop resistance with a single point mutation.20, 21, 22 Combination therapy might help to delay the emergence of resistance and increase the therapeutic lifespan of the respective drugs, as has been seen for diseases like malaria, tuberculosis, and HIV.13 Finally, combination therapy could improve treatment efficacy for complicated cases, such as patients coinfected with HIV, for whom treatment outcomes with monotherapy have been consistently poor.23

We review the evidence and explore the potential of combination therapy for visceral leishmaniasis in areas of anthroponotic transmission—in particular, the Indian subcontinent and east Africa. Given the anthroponotic pattern, these areas have the highest threat of drug resistance and bear the highest burden of visceral leishmaniasis. We will discuss the evidence and the criteria for a rational design of such combination regimens that focus on the parallel or sequential administration of separate drugs (co-administration), and are not co-formulations as used for tuberculosis or malaria.

Section snippets

Preclinical data

Few preclinical data on the efficacy and safety of combination therapies for visceral leishmaniasis are available. An early study looked at interactions between sodium stibogluconate and paromomycin.24 Whereas a marked potentiation was reported against L donovani in vitro, a less-pronounced, additive effect of the antimonial drug was noted in mice.24 Another study specifically focused on interactions in efficacy between miltefosine and sodium stibogluconate, amphotericin B, paromomycin, and

Access to and capacity of health systems

At present, major barriers exist in terms of access to diagnosis and care for visceral leishmaniasis, monitoring of treatment, and quality assurance of care. A recent study assessed the use of care by patients and delays in diagnosis and treatment in four endemic districts in India, Nepal, and Bangladesh.46 In India, even poor people prefer to see a private medical practitioner for treatment of visceral leishmaniasis. In Bangladesh and Nepal, most patients rely on the public-health-care sector,

Prevention of drug resistance

The problem of drug resistance in visceral leishmaniasis has been extensively reviewed elsewhere.14 Treatment failure can manifest as initial treatment failure (failure to clear parasites at the end of the treatment course) or relapse (reappearance of parasites after initial cure, usually within 6 months of follow-up). Although pentavalent antimonials have been successfully used throughout the world for decades, poor treatment response (mainly due to initial treatment failure) has increasingly

Special populations: HIV coinfection

In east Africa, coinfection with HIV is a major challenge in the treatment of visceral leishmaniasis, with up to 30% of cases infected with HIV in some regions.15, 23, 96 This problem also seems to be on the increase in the Indian subcontinent.97, 98 Because asymptomatic leishmania infections are thought to outnumber symptomatic infections,1, 4 the dramatically increased risk of progression to visceral leishmaniasis after infection with HIV could lead to increased disease burden,23 as has also

Future perspectives

Although the principle of combination therapy is generally accepted, the rationale for the choice of the drugs in such combination regimens is still under debate.13, 14, 15 Several combinations have been taken forward in clinical studies, which will most likely provide us with several efficacious treatment options in the near future. However, it remains to be defined what exactly we should expect from combination therapy, and which factors will be important in selecting a specific therapy

Key questions and challenges

Trial data of several combination therapies will become available over the next few years, and should address some of the issues that have been discussed. However, many questions and challenges remain (panel). Whereas combination therapy aims to increase the lifespan of available drugs, this could also lead to rapid loss of two therapeutic options, if not applied in a controlled and regulated way. Care should be taken to ensure that the increased complexity of the logistics of combination

Search strategy and selection criteria

Articles cited in this Review were obtained through searches of PubMed or Medline for papers published up to June 1, 2009, with terms including, but not restricted to, the following combinations: “visceral leishmaniasis”, “treatment”, “combination therapy”, “safety”, “efficacy”, “cost”, “cost-effectiveness”, “resistance”, “compliance”, “health system”, and “human immunodeficiency virus”. The search was limited to English. Reference lists of these articles were then searched to identify

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