development partnership, drugs for neglected diseases initiative works on the development of new treatments (combination treatments and new chemical entities) for visceral leishmaniasis. the traditional treatment is with pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate. resistance is now common in india, and rates of resistance have been shown to be as high as 60% in parts of bihar, india. the treatment of choice for visceral leishmaniasis acquired in india is now amphotericin b in its various liposomal preparations. in east africa, the who recommended treatment is ssg&pm (sodium stibogluconate and paromomycin) developed by drugs for neglected diseases initiative (dndi) in 2010. miltefosine is the first oral treatment for this disease. the cure rate of miltefosine in phase iii clinical trials is 95%; studies in ethiopia show that is also effective in africa. in hiv immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment. miltefosine has received approval by the indian regulatory authorities in 2002, in germany in 2004 and in u.s.a. in 2014. it is now registered in many countries. the drug is generally better tolerated than other drugs. main side effects are gastrointestinal disturbance in the first or second day of treatment (a course of treatment is 28 days) which does not affect the efficacy. because it is available as an oral formulation, the expense and inconvenience of hospitalization is avoided, and outpatient distribution of the drug becomes an option, making miltefosine a drug of choice. however, there are some important disadvantages: 1) there is evidence of reduced efficacy after a decade of use 2) it is teratogenic and cannot be used in women of child-bearing age without anticonception during and for 4 months after treatment. incomplete treatment has been cited as a major reason of death from visceral leishmaniasis. the nonprofit institute for oneworld health has adopted the broad spectrum antibiotic paromomycin for use in treating vl; its antileishmanial properties were first identified in the 1980s. a treatment with paromomycin costs about us$15. the drug had originally been identified in the 1960s. the indian government approved paromomycin for sale and use in august 2006. prognosis protective immunity immunity to leishmania is determined by the interplay of white blood cells, cytokines, immune complexes, and genetic and environmental factors. protective immunity develops either after successful treatment of vl (cured) or after asymptomatic infections that resolve without development of vl (asymptomatic). both types of immunity are characterized by cell-mediated immunity (cmi), including skin test positivity, proliferation, and interleukin 2 (il-2), interferon gamma (ifn-γ), and interleukin 12 (il-12) secretion by peripheral blood mononuclear cells (pbmc) in response to leishmania antigens. t cells isolated from both cured and asymptomatic pbmc activate autologous macrophages to kill intracellular amastigotes. ifn-γ activates macrophages to kill intracellular parasites so its role in vl has been studied extensively and ifn-γ production is often used as a marker of protective immunity. cured pbmc generally secrete less ifn-γ and more interleukin 10 (il-10) in response to leishmania antigens than asymptomatic pbmc. il-12 is important in the development and maintenance of type 1 t helper cell responses and protective immunity so its role in vl has also been studied. addition of il-12 to some vl pbmc increases proliferation and ifn-γ secretion in response to leishmania antigens and anti-il-12 inhibits proliferation and ifn-γ secretion by some cured pbmc. other cytokines also appear to be important in immunity to leishmania but their roles are not as well characterized. leishmania antigen stimulation of pbmc from cured patients show a mixed t helper cell and regulatory t cell response. both cd4+ and cd8+ t cells contributed to ifn-γ production. studies of leishmania antigen specific t cell clones from cured patient pbmc confirm that cured patients have a mixed t cell response that involves both cd4+ helper t cells and cd4+ and cd8+ regulatory t cells. two studies of asymptomatic t cell clones show that most have type 1 profiles and secrete more ifn-γ than t cell clones from cured patients. neither study revealed the presence of type 2 or regulatory t cells. some clones secreted soluble factors that caused the death of cd8+ regulatory t cells but not cd4+ t cells from vl patients, which might explain the strong protective immunity of asymptomatic patients. non-protective immunity vl patients are unable to clear their infections because they lack cmi. this anergy may be limited to leishmania antigens or extend to mitogens and other antigens as the disease progresses. in addition to skin test negativity, vl patient pbmc do not proliferate or secrete il-2 or ifn-γ in response to leishmania antigens. memory t cells may be depleted in vl patient pbmc. since il-10 is known to suppress innate and acquired immunity and prevent ifn-γ from activating macrophages, its role in vl has been studied extensively and elevated il-10 production is often used as a marker of non-protective immunity in vl. elevated levels of il-10 in the plasma, infected tissues, and pbmc of vl patients accompany the anergy of vl. pkdl patients also have elevated il-10 levels. vl patients with the highest il-10 levels are more likely to be unresponsive to treatment and progress to pkdl. pbmc secretion of il-10 without the addition of leishmania antigen (endogenous) is inversely correlated with antigen specific ifn-γ secretion but leishmania antigen specific il-10 and ifn-γ secretion are not correlated, suggesting that endogenous secretion is more important in pathology. addition of anti-il-10 increases proliferation and ifn-γ secretion by pbmc from some patients. both cd4+ and cd8+ t cells have been shown to contribute to il-10 secretion by vl pbmc. the high level of immune complexes characteristic of vl have also been shown to increase il-10 levels. epidemiology