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Leishmaniasis

treatment updates and clinical practice guidelines review

Copeland, Nathanial K.a,b; Aronson, Naomi E.a,b

Current Opinion in Infectious Diseases: October 2015 - Volume 28 - Issue 5 - p 426–437
doi: 10.1097/QCO.0000000000000194
TROPICAL AND TRAVEL-ASSOCIATED DISEASES: Edited by Joseph M. Vinetz and Yukari C. Manabe
Free

Purpose of review This review summarizes recent important and interesting articles investigating the challenging treatment of the parasitic infection, leishmaniasis. In addition, it compares and contrasts leishmaniasis clinical practice treatment guidelines.

Recent findings Studies show that, in contrast to experience in India, visceral leishmaniasis in East Africa requires higher doses of liposomal amphotericin for effective treatment results and that pentavalent antimonial drugs remain efficacious. A retrospective study of visceral leishmaniasis in organ transplant patients suggests that there may be a role for secondary prophylaxis after treatment akin to HIV coinfection recommendations. The pros and cons of oral therapy with miltefosine, which cuts across leishmaniasis syndromes in its spectrum, are discussed. Cutaneous leishmaniasis clinical practice guidelines vary, although the recent European guidelines favor species-directed therapy.

Summary Leishmaniasis remains a neglected tropical disease, with a need for additional clinical trials with better design and reported endpoints to lead evidence-based treatment recommendations – especially in cutaneous leishmaniasis and leishmaniasis in the immunocompromised host.

aWalter Reed National Military Medical Center

bUniformed Services University of the Health Sciences, Bethesda, Maryland, USA

Correspondence to Dr Naomi E. Aronson, Infectious Diseases Division, Department of Medicine, Room A3060, USUHS 4301, Jones Bridge Rd, Bethesda, MD 20814, USA. Tel: +1 301 295 3621; e-mail: Naomi.aronson@usuhs.edu

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INTRODUCTION

Leishmania parasites – comprising more than 20 species known as human pathogens – cause diverse clinical syndromes (e.g., visceral, mucosal, cutaneous) shaped by the balance between parasite factors (e.g., tropisms, virulence, resistance, species) and the host–immune response. The overall treatment priorities vary by syndrome; for visceral leishmaniasis, treatment is given to save lives, and for cutaneous leishmaniasis to prevent morbidity such as disfigurement, relapse, and, in some species, metastatic infection.

Clinical practice guidelines vary (especially for cutaneous leishmaniasis) with standardization being difficult in part because of the limitations of the evidence base for treatment. Poor study design and reporting were summarized in comments of recent Cochrane reviews as ‘there is a need for more evidence of effectiveness and safety of different anti-Leishmania drugs compared with placebo…authors also need to standardize the measurements used to judge success’ [1–3]. Results obtained in trials in one geographic area and species may not apply in other clinical situations.

To date, there is no single effective treatment for all Leishmania species and syndromes. Additionally, the current treatment modalities usually do not result in parasitologic cure; relapse in the setting of immunosuppression (i.e., HIV) is an emerging focus that requires more exploration. Recently, the details of current treatment of cutaneous leishmaniasis in US travelers have been reviewed in this journal including details of drug dosages [4]. Our review summarizes recent treatment study findings in visceral leishmaniasis and cutaneous leishmaniasis, and compares several leishmaniasis clinical practice treatment guidelines.

Box 1

Box 1

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VISCERAL LEISHMANIASIS

Treatment of visceral leishmaniasis in the immunocompetent host

The evidence basis for visceral leishmaniasis treatment in immunocompetent patients has previously been reviewed, and there are known regional treatment differences [5]. An editorial summarizes amphotericin B (AmB) treatment trials by region [6].

Liposomal amphotericin B (AmBisome, Astellas Pharma, Northbrook Illinois, USA; L-AmB) is a well studied and well tolerated option for the treatment of visceral leishmaniasis [5]. It is the WHO's treatment of choice (TOC) in the Indian subcontinent [7] and is part of India's plan for visceral leishmaniasis elimination [8]. Médecins Sans Frontières (MSF) reported results of L-AmB visceral leishmaniasis treatment in 8749 patients in India [9▪▪]. All patients received L-AmB 20 mg/kg over 4–10 days resulting in more than 99% initial clinical cure and a good safety profile [9▪▪]. Although passive follow-up was poor, parasitologically confirmed relapse was observed in 119 (1.4%) patients with the median time to relapse being 10.1 (interquartile range, 7.1–13.8) months [10▪]; in the actively followed subset, cumulative probability of relapse was 2.3% at 12 months [9▪▪]. Post kala-azar dermal leishmaniasis, considered a marker of ineffective therapy, was diagnosed in 0.3% of those undergoing initial treatment for visceral leishmaniasis [11]. Additionally, the MSF programme utilized the existing rural primary healthcare centers to treat 1397 (16.0%) patients, achieving equivalent results to the larger cohort while demonstrating a cost-effective cold chain and a shorter time to therapy from symptom onset [9▪▪].

Unfortunately, evidence supporting the use of L-AmB for visceral leishmaniasis in East Africa is not as robust [5–7]. Underscoring this, a trial of L-AmB in Ethiopia and Sudan was stopped early because of poor efficacy in the reference arm of multiple dose L-AmB treatment with a dose greater than what is effective in India (initial clinical cure 85.5%, parasitological cure 54.1%); efficacy was even lower in the single-dose arms [12▪▪]. However, patients from this study treated in southern Ethiopia (rather than northern Ethiopia or Sudan) had 100% parasitological cure with both the multiple and 10 mg/kg single L-AmB dose arms [12▪▪], suggesting that potential regional differences in treatment efficacy exist within Africa, a concept supported by others [5,13▪]. In a highly endemic region of eastern Sudan, MSF showed a more than 90% initial clinical cure with L-AmB totaling 30–50 mg/kg in 379 hospitalized complicated visceral leishmaniasis cases – defined as age 2 or less or at least 45 years, advanced disease, pregnancy, pentaviral antimonial drug (SbV) contraindication, HIV coinfection (only nine patients), or prior relapse [14▪]. Less than 10% relapsed and the death rate was 5.5% compared with 30% in similar studies using SbV [14▪], suggesting that L-AmB may be superior in this setting.

Trial results and clinical experience support using L-AmB as first-line therapy for Leishmania infantum visceral leishmaniasis, although most data are from prior Mediterranean region studies [5,7]. A multicenter Italian study of 119 immunocompetent patients demonstrated good efficacy and safety in clinical practice [15]. Published efficacy data for L-AmB in visceral leishmaniasis treatment in Brazil are limited [5].

Used for visceral leishmaniasis treatment since the 1940s, SbV continues to show ample efficacy; apart from India where high levels of resistance are present [5,7]. One hypothesis is that in India, SbV resistance may be a result of chronic exposure to the arsenic present in regional ground water [16▪,17]. A small, retrospective study showed a nonsignificant trend toward higher arsenic levels in the wells of those who failed treatment along with a significant increase in visceral leishmaniasis specific mortality in those with higher arsenic exposure [16▪]. In contrast, effective SbV treatment in East Africa was demonstrated with low rates of relapse, post kala-azar dermal leishmaniasis, or death in over 4000 patients treated with sodium stibogluconate [18▪].

Miltefosine (MILT), an oral option for visceral leishmaniasis treatment, although not recommended as first-line visceral leishmaniasis therapy by the WHO [7], has been used extensively in India as part of the national eradication programme [8]. Regrettably, use in India has met with increasing disappointment: a recent study showed only 86.6% cure with 12.8% relapse at 12 months in the per protocol analysis of over 1000 patients from India and Nepal [19▪]. Pharmacokinetic data show failure with MILT treatment correlates with low plasma drug concentrations over time and that children often had low concentrations with typical dosing regimens [20▪▪]; the latter corresponding to relatively more clinical failures seen in children younger than 15 years [19▪]. Despite the drawbacks of monotherapy, MILT has an expanding role in combination therapy [5,7].

Ongoing clinical research in visceral leishmaniasis treatment includes trials on combination therapy and potential new therapeutics. Although recent experience supports combination therapy [5], this has yet to be adopted by guideline recommendations apart from SbV and paromomycin in East Africa [7]. A Brazilian trial with 378 patients with visceral leishmaniasis followed for 6 months compared SbV (meglumine antimoniate), AmB, L-AmB, and SbV and L-AmB with the AmB arm being stopped early due to increased toxicity; the results should be presented in 2015, but have led to an expanded role for L-AmB in Brazil (personal communication; Fabiana Alves PA, written communication, DNDi, Geneva, Switzerland, March 2015; [21]). Combination regimens should become the mainstay of therapy as a result of a shortened duration of therapy, lower cost, and theoretically increased barrier to resistance.

A summary of selected guidelines for the treatment of visceral leishmaniasis in the immunocompetent and immunosuppressed host is found in Table 1. Because of a stronger evidence base, these visceral leishmaniasis guidelines are fairly similar in their recommendations in contrast to cutaneous leishmaniasis treatment guidelines (Tables 2 and Tables 3).

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

Table 3

Table 3

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Treatment of visceral leishmaniasis in the immunosuppressed host

Conditions affecting cell-mediated immune responses complicate visceral leishmaniasis management, posing diagnostic challenges and significantly decreasing treatment responses [29▪]. The most common immunocompromising condition is HIV, and coinfection leads to increased treatment failure, relapse, drug toxicity, and mortality [29▪]. Visceral leishmaniasis–HIV coinfection is becoming an increasingly recognized problem globally, with HIV seen in up to 5.5% of visceral leishmaniasis patients in India [30▪] and estimated to occur in 8.5% in Brazil [31].

The role and timing of antiretroviral therapy (ART) and/or secondary prophylaxis for visceral leishmaniasis remains poorly explored in East African and Indian populations with HIV, but extrapolating from European data both should be implemented whenever feasible [5,29▪]. In India, L-AmB monotherapy (without secondary prophylaxis) was not as effective in coinfected patients, with high rates of relapse and mortality in more than 20% [32▪]. However, with initiation of ART immediately following treatment for visceral leishmaniasis, one study showed a 64–66% reduction in mortality compared with those not on ART [32▪]. In Brazil, poor efficacy was reported regardless of treatment used, but one study using predominantly SbV had a much higher mortality than another wherein AmB formulations were utilized (19.4% compared with 8.7%) [33,34▪]. In a recent multiregional systematic review of a total of 920 visceral leishmaniasis–HIV, SbV was associated with three times higher mortality than AmB formulations (18.4 vs. 6.1%); additionally, lipid formulations showed better clinical improvement with less adverse events [35]. Limited data suggest that combination L-AmB and MILT may be an effective visceral leishmaniasis treatment option [13▪]. Currently, the AfriCoLeish Consortium is conducting trials in Ethiopian patients with visceral leishmaniasis–HIV evaluating combination L-AmB and MILT as well as monthly pentamidine prophylaxis [36,37].

Table 1 also summarizes selected guidelines for the treatment of visceral leishmaniasis–HIV coinfection. There are significantly less data supporting these recommendations relative to those for immunocompetent patients. Additionally, the WHO recommendation of L-AmB 40 mg/kg has not been studied in East Africa [7,13▪].

Other immunocompromising conditions, such as organ transplantation, have been less well studied. Data predominantly from case studies and series suggested that treatment response and relapse rates were somewhere between visceral leishmaniasis–HIV coinfected and immunocompetent patients [29▪]. A retrospective case–control study of more than 25 000 solid organ transplant recipients from Brazil and Spain demonstrated 91.7% cure in 36 patients with visceral leishmaniasis, with most using L-AmB (61.1%) or SbV (25.0%) [38▪▪]. Relapse was common, but seen less frequently in patients receiving secondary prophylaxis compared those with no prophylaxis (rate: 8.3 vs. 34.8%, P = 0.19) [38▪▪]. L-AmB is the best option in the organ transplant (especially renal) population because of better safety and fewer drug interactions, but further studies are needed on the role of secondary prophylaxis. Immunosuppressing medications (e.g., tumor necrosis factor-α inhibitors) may have similar decrements in efficacy with visceral leishmaniasis treatment, but limited data are available addressing specific management.

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CUTANEOUS LEISHMANIASIS

New treatment guidelines

In the past 18 months, several European guidelines for the management of cutaneous leishmaniasis have suggested a new species-directed approach [26▪▪,27▪]; an approach made possible by more available molecular techniques for species determination [39]. Globally, geographic region experience has generally informed initial therapy, such as Old World and New World approaches to treatment. The WHO guidelines 2010 [7] were primarily targeted to endemic countries and provide syndromic treatment options for Old World cutaneous leishmaniasis (OWCL, L. major and L. tropica) and New World cutaneous leishmaniasis (NWCL), specifying preferences for management of a few selected Leishmania species (Tables 2 and 3).

The European leishmaniasis treatment guideline, LeishMan guidelines [26▪▪], employed the Oxford evidence grading system and provided ranked treatment options for Leishmania major, Leishmania tropica, Leishmania(V). panamensis, Leishmania(V). guyanensis, Leishmania(V). braziliensis, and Leishmania mexicana, etc. In their recommendations, they account for the severity measures of infection (e.g., risk of mucosal spread, size, number, location of lesions) and recommended observation or topical therapy for simple cutaneous leishmaniasis and oral or parenteral systemic treatment for complex cutaneous leishmaniasis. Tables 2 and 3 compare published European and WHO cutaneous leishmaniasis treatment guidelines.

Another species-directed treatment guideline for cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis [27▪] varied this approach using an expert panel to rank treatment options that were provided based on pooled efficacy and practical considerations. This analysis permitted up to 50% lost to follow-up cutaneous leishmaniasis studies to be included and the authors stated that 37% of the analyses were based on observational studies only. Treatment was divided into clinical categories, 13 OWCL and 12 NWCL categories. In less than 50% the TOC recommendation was supported by medical literature, 13 categories were primarily expert opinion, and five of 25 categories had no evidence base identified for treatment recommendations. This analysis excluded a significant portion of the armamentarium available to treat cutaneous leishmaniasis; no monotherapy with liquid nitrogen or intralesional SbV (SbV–IL) was considered, no azoles or topical paromomycin, and all lipid formulations of AmB were pooled, although differences in efficacy have been reported in cutaneous leishmaniasis. Although this approach highlights the limited evidence base that exists for the treatment of cutaneous leishmaniasis, these guidelines should be evaluated mainly as expert opinion blinded to the full spectrum of treatment options (Tables 2 and 3).

The French cutaneous leishmaniasis treatment recommendations include an algorithmic approach as follows (Fig. 1; [28]). This algorithm was applied through consultation from the French Leishmaniasis Reference Center in 135 parasitologically confirmed patients with cutaneous leishmaniasis [28]. Of these patients, 12 were immunocompromised (five HIV, one chronic lymphocytic leukemia, six immunosuppressive therapy). OWCL was the majority (79%) of the cases, and 19 of 28 NWCL were L. (V.) braziliensis or L. (V.) guyanensis. Notably, follow-up time was short (42–60 days). Their results suggested that the majority of OWCL can be treated locally with a good outcome (among those given solely wound care 92% healed, among those with topical paromomycin or SbV–IL 79% were healed). About 10% were considered ineligible for topical treatment, and systemic therapy was given. The authors conclude their recommendations by suggesting when third-generation topical paromomycin becomes readily available (e.g., WR 279 396) that it will replace watchful waiting with no specific therapy and local treatment with SbV–IL and cryotherapy.

FIGURE 1

FIGURE 1

The North American treatment guidelines are in final development; if approved they should be published in 2016. The general approach to cutaneous leishmaniasis treatment is an individualized one. These guidelines stratify guidance by the simple vs. complex differentiation of leishmanial skin lesions (complex definition includes species, geography, host factors, and clinical factors). Available treatments that have been studied in clinical trials, and more recently in observational series for new therapies, are discussed, along with information to allow a provider to weigh the individual risk–benefit of treatment options. Management is not species-directed as in the recent European guidelines, and given the limited evidence base of well done randomized clinical trials, algorithmic care plans were not provided (Aronson NE, personal communication).

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Wound care

The more nuanced approach to the cutaneous leishmaniasis treatment spectrum includes wound care. Wound management includes debridement, control of infection, and moisturizing. Three studies [40–42] evaluated the role of adjunctive dressings. In L. major infection, one studied an antimicrobial silver impregnated polyester dressing and SbV-IL compared with a plain polyester dressing and SbV-IL vs. SbV-IL only. At 10 weeks follow-up, neither dressing added to the efficacy of SbV-IL, which was unexpectedly low at 40% [40]. In Afghanistan (both L. major and L. tropica), the antimicrobial solution 0.045% DAC N-055 (alkaline sodium chlorite) was studied in conjunction with moisturized wound dressings after electrocautery debridement. These studies [41,42] suggested that 70–90% persons with cutaneous leishmaniasis treated with electrocautery, followed with DAC N-055 solution and dressings, were healed vs. 63% treated with SbV-IL by day 75. In the study using polyacrylic hydrogel dressings after electrocautery, there was no difference gained by adding DAC N-55 to the dressing [42].

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New topical treatments

A proof-of-concept study of 31 patients, 17 self-administering daylight-activated photodynamic therapy in cutaneous leishmaniasis (L. major and L. tropica), showed healing in 70% [43]. After curettage of the crust over lesions, a thick layer of the photosensitizer aminolevulinate (Metvix, Galderma, France) was applied to the lesions weekly, covered with a dressing and foil for 30 min, then the dressing removed, and the patient was asked to expose the area to daylight for 2.5 h. In those patients with multiple lesions, a control lesion was not initially treated and none of these healed spontaneously during the 8–10 weeks treatment session.

Another novel topical treatment reported was the use of intralesional AmB as a second-line treatment of antimonial resistant OWCL [44]. Ninety-three patients received AmB 2 mg/ml injected into lesions weekly for up to 12 weeks. Adverse events were ‘low and insignificant’ ([44], page 635). By 12 weeks, 61% of patients with cutaneous leishmaniasis had healed completely (>90% reduction in size and induration) and 22% more had a partial remission (60–90% reduction). Although pentavalent antimonials are frequently injected intralesionally, this study describes a similar method using AmB – which one might think would be very sclerotic/reactogenic based on the phlebitis that it may cause.

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What is new with liposomal amphotericin B in the treatment of cutaneous leishmaniasis?

Additional experience with L-AmB for the treatment of cutaneous leishmaniasis and mucosal leishmaniasis continues to support off-label use for these infections, although we advocate for a convincing clinical trial to develop more definitive recommendations. A retrospective case series reported on 24 children with cutaneous leishmaniasis caused by L. tropica who were treated with L-AmB 3–5 mg/kg/day for 5 days and then received an additional dose on day 10 [45]. Seventy-five percent experienced a complete response at 3 months; the four children who failed L-AmB responded to systemic SbV.

The largest published case series of mucosal leishmaniasis treated with L-AmB reported the responses of 16 patients; 88% were healed after receiving a mean daily dose of L-AmB of 2.5 mg/kg/day. Two patients stopped L-AmB due to toxicity and were nonresponders [46▪]. The author concluded that a total dose of 30–35 mg/kg L-AmB yielded 100% effective treatment of mucosal leishmaniasis in this Brazilian cohort that had nasal>pharyngeal>oral cavity>larynx involvement [46▪].

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Miltefosine

In 2014, the Food and Drug Administration approved oral MILT for the treatment of cutaneous leishmaniasis due to L. (V.) braziliensis, L. (V.) guyanensis, and L. (V.) panamensis[47▪]. This drug and the relevant clinical trial evidence base were recently reviewed [48]. This exciting first Food and Drug Administration approved drug indicated for cutaneous leishmaniasis treatment should be considered in light of two concerning developments: clinical resistance given the prolonged drug half-life [19▪,49▪] and data [20▪▪] suggesting that the response rate is lower in persons receiving less than 2.5 mg/kg/day (this means that anyone weighing >60 kg [132 lbs] could be underdosed).

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CONCLUSION

Recent studies have highlighted the complexity of leishmaniasis treatment. Updates in visceral leishmaniasis management are informed by the long-term follow-up on treatment efficacy of L-AmB and MILT in India, to data observing the relative ineffectiveness of L-AmB in East Africa where SbV remains the mainstay of therapy. Advances in our understanding of MILT monotherapy failure pinpoint the need for more studies looking at combination therapy and the need for novel drug development. Two promising nitroimidazoles are being evaluated, fexinidazole in phase II trials in Sudan and (R)-PA-824, an enantiomer of a new tuberculosis drug [50▪]. Current treatment continues to be disappointing in immunocompromised patients, especially in HIV–visceral leishmaniasis coinfection, and there are new data suggesting an expanded role of secondary prophylaxis in organ transplant patients. Clinical practice guidelines for the treatment of cutaneous leishmaniasis are not standardized; a sea change in approach has occurred with broader options considered than previously. The North American clinical practice guidelines for cutaneous leishmaniasis, expected in 2016, will focus on an individualized treatment approach. Finally, more research is needed in visceral leishmaniasis regarding combination therapies, especially in HIV coinfected patients, and clinical trials are sorely needed in cutaneous leishmaniasis and mucosal leishmaniasis to not only clarify best approaches to treatment in an often self-healing infection, but also to evaluate various options (such as L-AmB) head-to-head. Unfortunately, there is little financial incentive for the development of effective leishmaniasis treatments and support from governmental and nonprofit organizations such as the Drugs for Neglected Diseases Initiative is crucial for ongoing progress.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

N.E.A. receives royalties for writing leishmaniasis chapters for UpToDate. She is also the Chair, IDSA-ASTMH leishmaniasis clinical practice guidelines writing committee.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Gonzalez U, Pinart M, Reveiz L, et al.. Designing and reporting clinical trials on treatments for cutaneous leishmaniasis. Clin Infect Dis 2010; 51:409–419.
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A retrospective cohort study of 8749 patients with visceral leishmaniasis treated with L-AmB in Bihar, India. It is the largest cohort (in this context) published to date and demonstrated the excellent efficacy of L-AmB with low rates of relapse. With 1397 of the patients treated in community health centers, it serves as a model for use of L-AmB in resource-limited settings.

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This is an analysis of a large cohort of patients treated with L-AmB regarding risks of relapse showing that, although uncommon, relapse often occurs 6–12 months after treatment, suggesting this may be the key follow-up period.

11. Burza S, Sinha PK, Mahajan R, et al. Post kala-azar dermal leishmaniasis following treatment with 20 mg/kg liposomal amphotericin B (Ambisome) for primary visceral leishmaniasis in Bihar, India. PLoS Negl Trop Dis 2014; 8:e2611.
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This is a multicenter, prospective, open-label, randomized trial attempting to find a single-dose L-AmB regimen appropriate for East Africa; unfortunately, the multiple dose L-AmB control arm only demonstrated 85% efficacy leading to early termination of the study. Interestingly, although underpowered to make conclusions, the study sites in southern Ethiopia showed 100% cure at 6 months of both the multiple dose and 10 mg/kg single dose arms, suggesting possible regional differences within Eastern Africa.

13▪. Diro E, Lynen L, Ritmeijer K, et al. Visceral leishmaniasis and HIV coinfection in East Africa. PLoS Negl Trop Dis 2014; 8:e2869.

This is a review discussing the growing challenge of visceral leishmaniasis and HIV coinfection in East Africa. They highlight the high death rates associated with treatment using pentavalent antimonials, the lack of data to support the WHO's recommended L-AmB treatment regimen, and field evidence supporting the use of L-AmB combined with MILT. They also note a regional difference in East Africa with northern Ethiopia and Sudan having lower cure rates than other areas.

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This is a retrospective cohort study in East Africa showing 92–94% initial clinical cure in 379 complicated or relapsing visceral leishmaniasis cases treated with L-AmB, but also a 7–10% observed relapse rate and nearly 40% of patients lost to follow-up.

15. Di Masi F, Ursini T, Iannece MD, et al. Five-year retrospective Italian multicenter study of visceral leishmaniasis treatment. Antimicrob Agents Chemother 2014; 58:414–418.
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This is a retrospective cohort study evaluating whether water arsenic exposure correlates to treatment failure with pentavalent antimonials. This was the first clinical study evaluating this question and showed a 1.78 odds of treatment failure if exposed to higher arsenic levels, but this failed to attain statistical significance (confidence interval: 0.7–4.6, P = 0.23).

17. Perry MR, Wyllie S, Raab A, et al. Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis. Proc Natl Acad Sci U S A 2013; 110:19932–19937.
18▪. Mueller YK, Kolaczinski JH, Koech T, et al. Clinical epidemiology, diagnosis and treatment of visceral leishmaniasis in the Pokot endemic area of Uganda and Kenya. Am J Trop Med Hyg 2014; 90:33–39.

This is a retrospective analysis of nearly 5000 patients with visceral leishmaniasis in East Africa utilizing primarily pentavalent antimonials demonstrating their continued efficacy with relatively low rates of relapse or death.

19▪. Ostyn B, Hasker E, Dorlo TP, et al. Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia. PLoS One 2014; 9:e100220.

This is a prospective observational study looking at patients treated with oral MILT showing a more than 9% relapse and identifying age less than 15 in particular to be associated with relapse, postulating that a factor such as pharmacokinetics could be responsible rather and not likely parasite resistance.

20▪▪. Dorlo TP, Rijal S, Ostyn B, et al. Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. J Infect Dis 2014; 210:146–153.

This is a pharmacokinetics–pharmacodynamics study showing that failure with MILT is associated with shorter duration of time spent 10 times above the half maximal effective concentration and that, with standard dosing regimens, children are less exposed to MILT than adults, likely explaining the higher rate of relapse and treatment failure in children seen in other studies.

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        25. Grupo Técnico das Leishmanioses [Technical Group of Leishmanioses]. MS amplia indicação de medicamento para o tratamento da leishmaniose visceral [MS expands indications of drugs for treatment of visceral leishmaniasis]. Departamento de Vigilância Epidemiológica, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasil; 2014. http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/726-secretaria-svs/vigilancia-de-a-a-z/leishmaniose-visceral-lv/13058-ms-amplia-indicacao-de-medicamento-para-o-tratamento-da-leishmaniose-visceral. [Accessed 24 March 2015]
          26▪▪. Blum J, Buffet P, Visser L, et al. LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers. J Travel Med 2014; 21:116–129.

          This comprehensive European clinical guideline for cutaneous leishmaniasis and mucosal leishmaniasis treatment in travelers proposes a species-directed approach and uses a formal grading system to evaluate the evidence base. The limitations of the underlying studies confound this simplified regimen, but until further studies are completed this is a good start for a clinician to use as a reference.

          27▪. Hodiamont C, Kager P, Bart A, et al. Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide. PLoS Negl Trop Dis 2014; 8:e2832.

          A Dutch guideline using species-directed treatment recommendations for travelers. Final ranking was done by expert opinion and several categories have little or no evidence base to be considered TOC. This study may be useful to point out research gaps.

          28. Morizot G, Kendjo E, Mouri O, et al. Travelers with cutaneous leishmaniasis cured without systemic therapy. Clin Infect Dis 2013; 57:370–380.
          29▪. van Griensven J, Carrillo E, Lopez-Velez R, et al. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014; 20:286–299.

          This is a review of leishmaniasis in immunosuppressed patients, particularly of interest is discussion of the treatment of visceral leishmaniasis in HIV coinfected patients, supporting the use of L-AmB despite limited data and role of secondary prophylaxis. Authors deal minimally with treatment and prophylaxis in non-HIV immunosuppressed patients, again recommending L-AmB as first-line and discussing the lack of a clear role of prophylaxis in this group.

          30▪. Burza S, Mahajan R, Sanz MG, et al. HIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination. Clin Infect Dis 2014; 59:552–555.

          This study screening 2077 patients with visceral leishmaniasis from Bihar, India, for HIV found a prevalence of 5.6% for coinfection, supporting the need for increased screening and not just of those who have visceral leishmaniasis relapse.

          31. Lindoso JA, Cota GF, da Cruz AM, et al. Visceral leishmaniasis and HIV coinfection in Latin America. PLoS Negl Trop Dis 2014; 8:e3136.
          32▪. Burza S, Mahajan R, Sinha PK, et al. Visceral leishmaniasis and HIV co-infection in Bihar, India: long-term effectiveness and treatment outcomes with liposomal amphotericin B (AmBisome). PLoS Negl Trop Dis 2014; 8:e3053.

          This is a subgroup analysis of the retrospective study of a larger cohort of patients with visceral leishmaniasis treated with L-AmB by the same authors focusing on HIV coinfection; whereas initial effectiveness was excellent at 96%, not unexpectedly relapse was nearly 20% at 1 year and 23% of coinfected patients died at a median of 11 months. They also found that starting ART immediately after initiating treatment for visceral leishmaniasis was associated with a more than 60% reduction in mortality.

          33. Albuquerque LC, Mendonça IR, Cardoso PN, et al. HIV/AIDS-related visceral leishmaniasis: a clinical and epidemiological description of visceral leishmaniasis in northern Brazil. Rev Soc Bras Med Trop 2014; 47:38–46.
          34▪. Cota GF, de Sousa MR, de Mendonça AL, et al. Leishmania-HIV co-infection: clinical presentation and outcomes in an urban area in Brazil. PLoS Negl Trop Dis 2014; 8:e2816.

          This is a small prospective cohort study of visceral leishmaniasis and HIV-coinfected patients in Brazil compared with noncoinfected patients all treated with mostly AmB formulations showing similar initial response rates, but a 37% relapse rate in the coinfected group compared with only 3% in the immunocompetent patients.

          35. Cota GF, de Sousa MR, Fereguetti TO, Rabello A. Efficacy of antileishmania therapy in visceral leishmaniasis among HIV infected patients: a systematic review with indirect comparison. PLoS Negl Trop Dis 2013; 7:e2195.
          36. Institute of Tropical Medicine, Belgium; Addis Ababa University; University of Gondar; et al. Prophylaxis of visceral leishmaniasis relapses in HIV co-infected patients with pentamidine: a cohort study. ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US). 2000. NLM Identifier: NCT01360762. http://clinicaltrials.gov/show/NCT01360762. [Accessed 23 March 2015]
          37. Drugs for Neglected Diseases; Médicins Sans Frontières; London School of Hygiene and Tropical Medicine; et al. Efficacy trial of AmBisome given alone and AmBisome given in combination with miltefosine for the treatment of VL HIV positive Ethiopian patients. ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US). 2000. NLM Identifier: NCT02011958. http://clinicaltrials.gov/show/NCT02011958. [Accessed 23 March 2015]
          38▪▪. Clemente W, Vidal E, Girao E, et al. Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case-control study. Clin Microbiol Infect 2015; 21:89–95.

          This is a large retrospective case–control study identifying 36 visceral leishmaniasis cases out of over 25 000 solid organ transplant recipients demonstrating an initial cure rate of 94% with mostly AmB formulations used for therapy. Interestingly, patients who used some sort of prophylaxis had only 8% relapse rate compared with 35% in those with none; although the number of cases is too low to draw any firm conclusions, this study suggests a role for secondary prophylaxis in non-HIV-related immunosuppression that needs to be further studied prospectively.

          39. Van der Auwera G, Dujardin J. Species typing in dermal leishmaniasis. Clin Microbiol Rev 2015; 28:265–294.
          40. Khatami A, Talaee R, Rahshenas M, et al. Dressings combined with injection of meglumine antimoniate in the treatment of cutaneous leishmaniasis: a randomized controlled clinical trial. PLoS One 2013; 8:e66123.
          41. Stahl H-C, Faridullah Ahmadi, Schleicher U, et al. A randomized controlled phase IIb wound healing trial of cutaneous leishmaniasis ulcers with 0.045% pharmaceutical chlorite (DAC N-055) with and without bipolar high frequency electro-cauterization versus intralesional antimony in Afghanistan. BMC Infect Dis 2014; 14:619.
          42. Jebran A, Schleicher U, Steiner R, et al. Rapid healing of cutaneous leishmaniasis by high-frequency electrocauterization and hydrogel wound care with or without DAC N-055:a randomized controlled phase IIa trial in Kabul. PLoS Negl Trop Dis 2014; 8:e2694.
          43. Enk C, Nasereddin R, Alper M, et al. Cutaneous leishmaniasis responds to daylight-activated photodynamic therapy: proof of concept for a novel self-administered therapeutic modality. Br J Dermatol 2015; 172:1364–1370.
          44. Goyonlo V, Vosoughi E, Kiafar B, et al. Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis. Indian J Dermatol 2014; 59:631.
          45. Solomon M, Schwartz E, Pavlotsky F, et al. Leishmania tropica in children: a retrospective study. J Am Acad Dermatol 2014; 71:271–277.
          46▪. Rocio C, Amato V, Camargo R, et al. Liposomal formulation of amphotericin B for the treatment of mucosal leishmaniasis in HIV-negative patients. Trans R Soc Trop Med Hyg 2014; 108:176–178.

          A retrospective review of 16 patients with mucosal leishmaniasis treated with L-AmB, this is the largest series published to date and gives a reasonable sense of what dose and duration to use. In addition, this obliquely supports the use of L-AmB in L.(V). braziliensis cutaneous leishmaniasis because it suggests that adequate concentrations will accumulate in the nasopharynx in the event of metastatic infection.

          47▪. FDA, Center for Drug Evaluation and Research. Application Number:204684Orig1s000 Application Review. 2014. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204684Orig1s000SumR.pdf. [Accessed 2 May 2015]

          This review documents the data, analysis, and discussion that led the Food and Drug Administration to approve MILT for the treatment of cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis in the United States.

          48. Monge-Maillo B, Lopez-Velez R. Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clin Infect Dis 2015; 60:1398–1404.
          49▪. Obonaga R, Fernandez O, Valderrama L, et al. Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species. Antimicrob Agents Chemother 2014; 58:144–152.

          Parasite isolates from patients with cutaneous leishmaniasis who failed therapy, obtained before and after MILT treatment, found two of six had resistance, one a high-effective concentration more than 32, and one developed a decreased expression of MILT transporter LbMT. These findings raise concern that MILT monotherapy may select for drug-resistant cutaneous leishmaniasis parasites.

          50▪. Sundar S, Chakravarty J. Investigational drugs for visceral leishmaniasis. Expert Opin Investig Drugs 2015; 24:43–59.
          Keywords:

          cutaneous leishmaniasis; Leishmania; practice guidelines; treatment; visceral leishmaniasis

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