in the second decade of the 21st century , visceral leishmaniasis ( vl ) continues to challenge public health authorities around the world . the world health organization ( who ) estimates yearly incidence of 500,000 cases , with a case - fatality ratio of approximately 10% [ 1 , 2 ] . : india , bangladesh , sudan , south sudan , ethiopia , and brazil [ 1 , 3 ] . brazil is by far the most affected country , with more than 3,000 reported cases per year and case - fatality ratio of 5.8% in the period from 2005 through 2009 . brazilian picture is worsened by the progressive territorial expansion and urbanization of lv . up to the early 1980s , the disease was mainly restricted to rural areas in northeastern brazil . in the turn of that decade , a southward expansion was also noticed , and the proportion of cases reported outside northeast region increased from 15% in 1998 to 44% in 2005 . the changing epidemiology of visceral leishmaniasis posed new challenges for health protection of the residents of the affected areas . in the first place measures directed to the canine reservoirs ( dog culling , vaccination ) or to the vector ( environmental intervention , insect repellents ) are often impractical in large urban centers . besides , they were not proved to be definitely effective [ 7 , 8 ] this is a relevant issue , since case - fatality ratio is generally higher in newly affected regions . the pooled case - fatality ratio for 19992012 was 8.7% , and it was especially higher ( 11.5% ) in the first five years . delay in the diagnosis and institution of appropriate therapy is a possible explanation for those data . the purpose of our review is to discuss the therapeutic options for vl in brazil and public policies to ensure access throughout the country . the universal and free access to health care is predicted in the brazilian constitution and is provided through the unified health system ( sus , an acronym for the portuguese  sistema nico de sade  ) . presently there are three therapeutic options for vl available in the sus : meglumine antimoniate ( glucantime ) , amphotericin b deoxycholate , and liposomal amphotericin b ( ambisome ) . pentavalent antimonials ( meglumine antimoniate and sodium stibogluconate ) were the first - line treatment for vl for many decades . besides leishmanicidal activity , antimonials have been shown to induce proinflammatory responses ( e.g. , enhancement of phagocytosis and production of tnf - alpha ) , which may play a role in controlling vl progression [ 1113 ] . recently , the use of this class was limited in india due to extensive parasite resistance  up to 60% . however , there is no evidence of significant resistance to meglumine antimoniate in brazil . on the contrary , reports from observational studies point out to high efficacy . a recent study focusing on a cohort of children treated with antimonials reported efficacy of 96% in mild - to - moderate cases , and over 60% in severe cases . the same study found rates above 15% for cardiac , hepatic , and pancreatic toxicity . toxicity is indeed a major concern , and severe cases ( sometimes leading to death ) have been reported , mostly in patients above 50 years of age . . there is also concern about failures and relapses in special groups , such as those with aids - vl coinfection and other immune - suppressed patients . the recommended dosing regimen for glucantime is 20  mg / kg / day of antimoniate ( up to 1215  mg / day , which represent three vials ) , for 2040 days . amphotericin b deoxycholate ( abd ) was introduced as second - line therapy for vl in the 1960s . this drug has excellent leishmanicidal activity , with cure rates of 90%95% in studies from endemic countries . similar to antimonials , abd ( as well as lipid formulations ) was also shown to have immune modulatory effects , including regulation of t - cell proliferation and enhancement of pro - inflammatory cytokines production [ 2022 ] . . the administration must be slow in order to avoid infusion - related adverse effects . brazilian guidelines for treatment of severe vl recommended the choice of amphotericin b deoxycholate for patients in extremes of age ( over 65 years or under 6 months ) , with signs of malnourishment or significant comorbidities . the recommended posology is 1  mg / kg / day ( maximum 50  mg / day ) for 1421 days . a recent document from brazilian health ministry ( september 2013 ) updated that recommendation . in the revised guidelines , the lipid formulations of amphotericin b greatly increased the safety in the therapy of systemic mycosis and vl . presently there are three formulations in the market : amphotericin lipid complex ( abelcet ) , amphotericin colloidal dispersion ( amphocil ) , and liposomal amphotericin ( ambisome ) . though they are not bioequivalent ( and probably not therapeutically equivalent ) , all of them allow the administration of doses above 5  mg / kg / day . this formulation is also the only one that has been extensively studied in the therapy of vl . several dosing schemes of liposomal amphotericin have been studied for vl in different countries , ranging from single doses of 10  mg / kg   to a total of 1821  mg / kg / day distributed over 57 days ( i.e. , 35  mg / kg / day ) . recommended doses are 3 - 4  mg / kg / day for 57 days ( ministry of health ) [ 18 , 24 , 25 ] and 35  mg / kg / day for 5 days ( so paulo state health department ) . the major limitation for the use of liposomal amphotericin is its price , and this fact has weighed negatively on cost - effectiveness analysis . however , this has been overcome by an agreement with the producing industry ( gilead ) , which allowed brazilian health ministry to purchase ambisome at prices much lower than those prevailing in the market . the brazilian health ministry recommendations for severe vl favor the use of liposomal amphotericin b. the evidence for this choice is not strong . it is based on the opinion of experts and on analogy from clinical trials mostly conducted in india . while the urgent need for reducing case - fatality rates justifies decisions based on incomplete evidence , some major questions remain . four recent studies focusing on predictors of death in vl patients showed agreement in most findings [ 10 , 3436 ] . briefly , delay in the diagnosis , age above 60 years , hemorrhagic manifestations , jaundice , suspected or confirmed bacterial infection , neutropenia , low platelet counts , and aids coinfection were associated with worse outcomes . all those factors , alongside with anemia , renal failure , malnourishment , and low serum albumin ( < 2.5  mg / dl ) , are listed as severity markers in the most recent governmental recommendations for treatment of severe vl [ 24 , 25 ] . although this document does not indicate unequivocally the use of amphotericin b ( deoxycholate or liposomal ) for patients in this condition , it determines the availability and logistics to supply these drugs throughout the country . given the country continental extent and the disparities in social / economic development among regions  which have an impact on patients access to health services  this commitment is of foremost importance . trends in vl reemergence ( urbanization ) and aids epidemiology ( interiorization , i.e. , progress towards cities in inner brazil ) made covered areas of the two diseases intertwine . thus , similar to what had happened in europe and africa , co - infection became epidemiologically and clinically relevant . in 2007 - 2008 , approximately 4% of vl cases in brazil were coinfections . a comprehensive account of specificities of aids / vl co - infection is beyond the objectives of this review . still , some of the major challenges are worth citing : ( a ) atypical and severe presentations , which hinder diagnosis and impact unfavorably on outcomes [ 40 , 41 ] ; ( b ) failure of therapy with antimonials ; and ( c ) frequent relapses and the need for long - term suppressive therapy . given the unfavorable outcomes of co - infected patients , brazilian health ministry revised therapeutic guidelines in year 2013 , including hiv co - infection as an indication for therapy with liposomal amphotericin . the beneficial effect of highly active antiretroviral therapy ( haart ) in the prevention of symptomatic vl or of relapses is still not clear , both in brazil or in a worldwide perspective . this is an important issue , since patients with vl / aids co - infection may benefit from the universal access to antiretrovirals provided by the brazilian aids program . at this point , making a brief description of the governmental approach of vl therapy in the state of so paulo is worth . this is the most populous and economically developed among the 26 states in brazil . as discussed earlier , the first autochthonous case of vl , pooled case - fatality ratio was 11.5%about two times the value for brazil . in an effort to lower death rates , the state expedited guidelines in 2006 , recommending therapy with liposomal amphotericin for all children up to 10 years of age and adults over 50 years . vl / aids co - infection , pregnancy , and relapses were also defined as indications for liposomal amphotericin . those recommendations were considerably wider than those proposed by the brazilian health ministry at that time . in years that followed the expedition of the state guideline ( 20062012 ) , the case - fatality ratio was 7.8% ( rr = 0.67 ; 95% ci , 0.500.91 , p = 0.01 ) . of course , many issues may account for this finding ( including improvement in diagnosis and access to health system ) . still , a more refined analysis of the database for notifiable diseases may throw some light on the possible beneficial effect of the change in so paulo state therapeutic recommendations . they relate to the difficulties of providing free health care throughout the territory of a huge developing country . it is worth remembering that , especially in the amazon region , vl patients may have difficulty in transportation to centers where treatment is available . in this sense , the public health system has sought empowerment of regional centers for the care of vl cases . we emphasized previously how much the current recommendations are based on expert opinion and the analogy with clinical trials that focused on indian or african vl . here , too , the ministry of health of brazil has undertaken significant effort . through its department of science and technology ( decit ) and the brazilian innovation agency ( finep ) , two multicenter clinical trials were funded , with the aim of comparing the efficacy and safety of the available therapeutic options . one of those trials is also assessing combination therapy with different drugs , a strategy that proved useful in other countries [ 29 , 44 ] . when available , data from those trials will provide valuable data to guide definite governmental recommendations . since the effect of preventive strategies is not established , timely diagnosis and adequate therapy may be the most important goals to avoid vl - related deaths . the development and validation of a unified severity score could help in guiding therapeutic choice . a thorough approach to data from epidemiologic surveillance files may also be of help in providing information on the effectiveness of vl therapy in a  real - life  setting . while many questions remain on the efficacy and cost - effectiveness of vl therapeutic options in brazil , it is certain that the country is making great progress toward an evidence - based approach to this potentially life - threatening disease .
over 3,000 yearly cases of visceral leishmaniasis ( vl ) are reported in brazil . 
 brazilian public health system provides universal free access to antileishmania therapeutic options : meglumine antimoniate , amphotericin b deoxycholate , and liposomal amphotericin b. even though amphotericin formulations have been advised for severe disease , this recommendation is mostly based on the opinion of experts and on analogy with studies conducted in other countries . presently , there are two ongoing multicenter clinical trials comparing the efficacy and safety of the available therapeutic options . 
 some other issues require further clarification , such as severity markers and the approach to vl / aids coinfection . 
 brazil is facing the challenge of providing access to diagnosis and adequate treatment , in order to avoid vl - related deaths .