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 . 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].
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.
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% . 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.
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▪].
Papers of particular interest, published within the annual period of review, have been highlighted as:
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.
2. Gonzalez U, Pinart M, Rengifo-Pardo M, et al. Interventions for American cutaneous and mucocutaneous leishmaniasis. Cochrane Database Syst Rev 2009; 2:CD004834.
3. Gonzalez U, Pinart M, Reveiz L, Alvar J. Interventions for Old World cutaneous leishmaniasis
. Cochrane Database Syst Rev 2008; 4:CD005067.
4. Eiras DP, Kirkman LA, Murray HW. Cutaneous leishmaniasis
: current treatment
practices in the USA for returning travelers. Curr Treat Options Infect Dis 2015; 7:52–62.
5. Monge-Maillo B, Lopez-Velez R. Therapeutic options for visceral leishmaniasis
. Drugs 2013; 73:1863–1888.
6. Berman J. Amphotericin B formulations and other drugs for visceral leishmaniasis
. Am J Trop Med Hyg 2015; 92:471–473.
7. WHO. Control of the leishmaniases: report of a meeting of the WHO Expert Committee on the control of leishmaniases; 22–26 March 2010; Geneva. Geneva, Switzerland: World Health Organization; 2010. WHO technical report series no. 949.
8. NVBDCP. National road map for kala-azar elimination. Directorate of National Vector Borne Disease Control Programme, Directorate General of Health Services, Minister of Health & Family Welfare, Government of India; 2014. http://nvbdcp.gov.in/Doc/Road-map-KA_2014.pdf
. [Accessed 27 March 2015]
9▪▪. Burza S, Sinha PK, Mahajan R, et al. Five-year field results and long-term effectiveness of 20 mg/kg liposomal amphotericin B (Ambisome) for visceral leishmaniasis
in Bihar. India PLoS Negl Trop Dis 2014; 8:e2603.
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.
10▪. Burza S, Sinha PK, Mahajan R, et al. Risk factors for visceral leishmaniasis
relapse in immunocompetent patients following treatment
with 20 mg/kg liposomal amphotericin B (Ambisome) in Bihar, India. PLoS Negl Trop Dis 2014; 8:e2536.
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.
12▪▪. Khalil EA, Weldegebreal T, Younis BM, et al. Safety and efficacy of single dose versus multiple doses of AmBisome® for treatment
of visceral leishmaniasis
in Eastern Africa: a randomised trial. PLoS Negl Trop Dis 2014; 8:e2613.
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.
14▪. Salih NA, van Griensven J, Chappuis F, et al. Liposomal amphotericin B for complicated visceral leishmaniasis
(kala-azar) in eastern Sudan: how effective is treatment
for this neglected disease? Trop Med Int Health 2014; 19:146–152.
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.
16▪. Perry MR, Prajapati VK, Menten J, et al. Arsenic exposure and outcomes of antimonial treatment
in visceral leishmaniasis
patients in Bihar, India: a retrospective cohort study. PLoS Negl Trop Dis 2015; 9:e0003518.
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.
21. University of Brasilia; Ministry of Health, Brazil; Drugs for Neglected Diseases; Conselho Nacional de Desenvolvimento Científico e Tecnológico. Efficacy and safety study of drugs for treatment
of visceral leishmaniasis
in Brazil. ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US). 2000. http://clinicaltrials.gov/show/NCT01310738
. [Accessed 23 March 2015]
22. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment
of opportunistic infections in HIV-infected adults and adolescents. Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America; 2014. T15–T25. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf
. [Accessed 15 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
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.