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Leishmaniasis is caused by obligate intracellular protozoa that survive and replicate in intracellular vacuoles within macrophages. The Leishmania genus has traditionally been differentiated into multiple species that cause cutaneous, mucosal, or visceral disease (1273Desjeux P. Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 2004;27(5): 305-18., 1274Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Edinburgh, Scotland: Churchill Livingstone Elsevier;2006:1095-1113.).

Leishmaniasis occurs in 88 countries worldwide with an estimated incidence of 2 million new cases annually (1275World Health Organization. Leishmaniasis and HIV co-infection. Available at: http://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinfection/en/index.html. Last accessed December 22, 2008.).

Leishmaniasis among persons with HIV/AIDS has been reported primarily from Spain, Italy, France, Brazil, and Ethiopia, but most coinfections in the developing world are never reported (1275World Health Organization. Leishmaniasis and HIV co-infection. Available at: http://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinfection/en/index.html. Last accessed December 22, 2008.). The incidence has decreased substantially in developed countries with the introduction of ART (1276Rosenthal E, Marty E, del Guidice P, et al. HIV and Leishmania coinfection: a review of 91 cases with focus on atypical locations of Leishmania. Clin Infect Dis 2000;31(4):1093-5., 1277Tortajada C, Perez-Cuevas B, Asuncion M, et al. Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral leishmaniasis in HIV-infected patients. J Acquir Immune Defic Syndr 2002;30(3):364-6.); however, HIV-leishmaniasis coinfection poses a growing problem in Asia and Africa (1278Mathur P, Samantaray JC, Vajpayee M, et al. Visceral leishmaniasis/human immunodeficiency virus co-infection in India: the focus of two epidemics. J Med Microbiol 2006;55(Pt 7:919-22., 1279Wolday D, Berhe N, Akuffo H, Desjeux P, Britton S. Emerging Leishmania/HIV co-infection in Africa. Med Microbiol Immunol 2001;190(1-2):65-7.).

Most infections in immunocompetent hosts are asymptomatic; in some disease-endemic areas, approximately 30% of the population has evidence of latent infection in the form of a positive leishmanin skin test (1280Marty P, Le Fichoux Y, Giordana D, Brugnetti A. Leishmanin reaction in the human population of a highly endemic focus of canine leishmaniasis in Alpes-Maritimes, France. Trans R Soc Trop Med Hyg 1992;86(3):249-50., 1281Moral L, Rubio EM, Moya M. A leishmanin skin test survey in the human population of l'Alacanti region (Spain): implications for the epidemiology of Leishmania infantum infection in southern Europe. Trans R Soc Trop Med Hyg 2002; 96(2):129-32., 1282Werneck GL, Rodrigues L, Santos MV, Arujo IB, Moura L. The burden of Leishmania chagasi infection during an urban outbreak of visceral leishmaniasis in Brazil. Acta Trop 2002;83(1):13-8.). After primary infection, Leishmania remain viable in healthy persons for long periods, leading to a susceptible population if immunosuppression occurs. In HIV-infected persons without severe immunosuppression, disease manifestations are similar to those in immunocompetent persons. Among those with advanced immunosuppression and low CD4⁺ counts (<200 cells/µL), manifestations of leishmaniasis might be both atypical and more severe, and relapse after treatment is common (1283Lopez-Velez R, Perez-Molina JA, Guerrero A. Clinicoepidemiologic characteristics, prognostic factors, and survival analysis of patients coinfected with human immunodeficiency virus and Leishmania in an area of Madrid, Spain. Am J Trop Med Hyg 1998;58(4):436-43.).

Leishmaniasis is usually spread by sand flies of the genus Phlebotomus or Lutzomyia (1274Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Edinburgh, Scotland: Churchill Livingstone Elsevier;2006:1095-1113.). However, in Southern Europe, HIV and Leishmania coinfections have been reported in association with injection-drug use, suggesting that Leishmania also might be acquired by needle sharing (1284Alvar J, Jimenez M. Could infected drug-users be potential Leishmania infantum reservoirs? AIDS 1994;8(6):854.). Leishmania parasites were demonstrated in 34%-52% of used syringes discarded by IDUs in Madrid, and based on molecular characteristics, investigators have described a new, epidemiologically significant leishmaniasis transmission cycle, relying on mechanical transfer of amastigotes via syringe (1285Chicharro C, Morales J, Serra T, Ares M, Salas A. Molecular epidemiology of Leishmania infantum on the island of Majorca: a comparison of phenotypic and genotypic tools. Trans R Soc Trop Med Hyg 2002;96 Suppl 1:S93-9., 1286Cruz I, Morales M, Noguer I, Rodriguez A, Alvar J. Leishmania in discarded syringes from intravenous drug users. Lancet 2002;359(9312):1124-5.).

Leishmaniasis can occur in four major syndromes: localized cutaneous, diffuse cutaneous, mucosal, and visceral disease. The most common clinical presentation of leishmaniasis in persons with AIDS is a disseminated visceral disease syndrome, but the distribution varies geographically, reflecting differences in the predominant parasite species. In Europe, visceral disease has been reported in 95% of cases (87% typical visceral, 8% atypical visceral) (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319.). In contrast, in Brazil, mucocutaneous (43%) and cutaneous (20%) are common (1288Rabello A, Orsini M, Disch J. Leishmania/HIV co-infection in Brazil: an appraisal. Ann Trop Med Parasitol 2003;97 Suppl 1: 17-28.).

Among persons with visceral disease, the most common clinical and laboratory findings are fever (65%-100%), systemic malaise (70%-90%), splenomegaly (usually moderate) (60%-90%), hepatomegaly without splenomegaly (34%-85%), hepatosplenomegaly (68%-73%), lymphadenopathy (12%-57%), and pancytopenia (50%-80%)(1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319., 1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73.). Anemia is usually marked with <10g hemoglobin/dL (49%-100%), leukopenia moderate with <2,400 leukocytes/µL (56%-95%), and thrombocytopenia is usually present (52%-93%). Splenomegaly is somewhat less common in HIV-coinfected patients than in immunocompetent patients with visceral leishmaniasis (1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73.). Among those with more profound immunosuppression, atypical manifestations have been described, including involvement of the upper and lower gastrointestinal tract, lung, pleural and peritoneal cavities, and skin (1276Rosenthal E, Marty E, del Guidice P, et al. HIV and Leishmania coinfection: a review of 91 cases with focus on atypical locations of Leishmania. Clin Infect Dis 2000;31(4):1093-5., 1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319., 1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73., 1290Mota SM, Matsumo CM, Schmitz FML, Machado MP. Cutaneous leishmaniasis coinfection in AIDS patients: case report and literature review. Braz J Infect Dis 1997;1(3):142-4.). Esophageal involvement can lead to dysphagia and odynophagia, and must be distinguished from other causes of esophagitis in HIV-infected patients, such as candidiasis (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319.). Nonulcerative cutaneous lesions that mimic KS, nodular diffuse leishmaniasis, and post-kala-azar dermal leishmaniasis have been described (1291Gonzalez-Beato MJ, Moyano B, Sanchez C, et al. Kaposi's sarcoma-like lesions and other nodules as cutaneous involvement in AIDS-related visceral leishmaniasis. Br J Dermatol 2000;143(6):1316-8.). However, the presence of Leishmania amastigotes in skin might occur in the absence of lesions or in combination with other pathology, such as KS, and might not indicate that the parasite is the cause of the lesions (1292Albrecht H, Stellbrink J, Gross G, et al. Treatment of atypical leishmaniasis with interferon gamma resulting in progression of Kaposi's sarcoma in an AIDS patient. Clin Investig 1994;72(12):1041-7., 1293Bosch RJ, Rodrigo AB, Sanchez P, de Galvez MV, Herrera E. Presence of Leishmania organisms in specific and non-specific skin lesions in HIV-infected individuals with visceral leishmaniasis. Int J Dermatol 2002;41(10):670-5.). Disfiguring mucosal lesions associated with anergy to Leishmania antigens have been observed among European persons with AIDS, in contrast to mucocutaneous disease in immunocompetent persons that is associated with strong leishmanin skin-test responses (1290Mota SM, Matsumo CM, Schmitz FML, Machado MP. Cutaneous leishmaniasis coinfection in AIDS patients: case report and literature review. Braz J Infect Dis 1997;1(3):142-4., 1294Canovas DL, Carbonell J, Torres J, Altez J, Buades J. Laryngeal leishmaniasis as initial opportunistic disease in HIV infection. J Laryngol Otol 1994;108(12):1089-92., 1295Miralles ES, Nunez M, Hibray Y Harto A, Moreno R, Ledo A. Mucocutaneous leishmaniasis and HIV. Dermatology 1994;(189(3): 275-7.).

Demonstration of characteristic amastigote forms of Leishmania by histopathology, cultures, and smears in tissue specimens (e.g., scrapings, aspirates, biopsies) is the standard for diagnosis of cutaneous leishmaniasis among HIV-coinfected patients (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319.). The diagnosis of visceral leishmaniasis can also be made by the demonstration of amastigote forms in blood smears (approximately 50% sensitivity in expert hands), buffy-coat smear preparations, cultures from the peripheral blood, and smears or cultures from bone marrow or splenic aspirates. Other methods useful for demonstrating Leishmania in the blood or tissue of coinfected patients include detection of Leishmania nucleic acid by PCR amplification (>95% sensitivity) (1296Cruz I, Canavate C, Rubio J, Morales M, Chicharro C. A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum infection in patients co-infected with human immunodeficiency virus. Trans R Soc Trop Med Hyg 2002;96 Suppl 1:S185-9.).

Antibodies against Leishmania antigens are of high sensitive for the diagnostic value among immunocompetent patients with visceral disease (1297Sundar S, Rai M. Laboratory diagnosis of visceral leishmaniasis. Clin Diagn Lab Immunol 2002;9(5):951-8.). However, the sensitivity of serologic tests is substantially lower in HIV-coinfected patients (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319., 1298Medrano FJ, Canavate C, Leal J, Rey C, Lissen E, Alvar J. The role of serology in the diagnosis and prognosis of visceral leishmaniasis in patients coinfected with human immunodeficiency virus type-1. Am J Trop Med Hyg 1998;59(1): 155-62.). The use of recombinant antigen (e.g., rK39) in ELISA assays might increase sensitivity, but a proportion of coinfected patients will remain seronegative (1299Houghton RL, Petrescu M, Benson DR, et al. A cloned antigen (recombinant K39) of Leishmania chagasi diagnostic for visceral leishmaniasis in human immunodeficiency virus type 1 patients and a prognostic indicator for monitoring patients undergoing drug therapy. J Infect Dis 1998;177(5):1339-44.). Immunoblotting with Leishmania infantum soluble antigen has been successful in detecting specific antileishmanial antibodies in up to 70% of European patients (1298Medrano FJ, Canavate C, Leal J, Rey C, Lissen E, Alvar J. The role of serology in the diagnosis and prognosis of visceral leishmaniasis in patients coinfected with human immunodeficiency virus type-1. Am J Trop Med Hyg 1998;59(1): 155-62.). Leishmania skin tests are nearly always negative in active visceral leishmaniasis, with or without HIV coinfection (1274Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Edinburgh, Scotland: Churchill Livingstone Elsevier;2006:1095-1113.).

Primary prevention of leishmanial infection relies on reservoir host control in areas with zoonotic transmission; vector control activities, such as indoor residual spraying and/or insecticide-treated nets; and measures to decrease transmission of infectious agents in IDUs, such as NEPs. For North American residents, these measures are only relevant during travel.

Not applicable

Liposomal amphotericin B is the only agent approved by the FDA for the treatment of visceral leishmaniasis (1300Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43(7):917-24., 1301Meyerhoff A. U.S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999;28(1):42-51.). Pentavalent antimony is the most widely used treatment for leishmaniasis in many parts of the world and remains the first-line treatment for cutaneous leishmaniasis caused by most species in otherwise healthy patients (1274Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Edinburgh, Scotland: Churchill Livingstone Elsevier;2006:1095-1113., 1302Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46(3):296-306.).

For HIV-visceral leishmaniasis-coinfected patients, the efficacy of conventional and lipid-associated formulations of amphotericin B appears to be similar to that of pentavalent antimony (1303Davidson RN, Martino L, Gradoni L, Giacchino R, Russo R. Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med 1994;87(2):75-81., 1304Laguna F, Lopez-Velez R, Pulido F, et al. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study Group. Aids 1999;13(9):1063-9., 1305Laguna F, Videla S, Jimenez-Mejias ME, et al. Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study. J Antimicrob Chemother 2003;52(3): 464-8., 1306Russo R, Nigro LC, Minniti S, et al. Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin B (AmBisome). J Infect 1996;32(2):133-7.). However, liposomal and lipid complex preparations are substantially better tolerated than conventional amphotericin B or pentavalent antimony (1307Lazanas MC, Tsekes S, Papandreu S, Harhalakis N, Nikiforakis F. Liposomal amphotericin B for leishmaniasis treatment of AIDS patients unresponsive to antimonium compounds. Aids 1993; 7(7):1018-9., 1308Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis 2004; 38(3):377-83., 1309Torre-Cisneros J, Vaillaneuva J, Kindelan J, Jurado R, Sanchez-Guijo P. Successful treatment of antimony-resistant visceral leishmaniasis with liposomal amphotericin B in patients infected with human immunodeficiency virus. Clin Infect Dis 1993;17(4):625-7.). The equivalent efficacy and better toxicity profile have led most clinicians to regard liposomal amphotericin B as the drug of choice for visceral leishmaniasis in HIV-coinfected patients (AII) (1300Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43(7):917-24.). The optimal amphotericin B dosage has not been determined (1300Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43(7):917-24., 1310Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol 2006;61:223-74.). Regimens with efficacy include conventional amphotericin B 0.5-1.0 mg/kg body weight/day IV to achieve a total dose of 1.5-2.0 grams (BII), or liposomal or lipid complex preparations of 2-4 mg/kg body weight administered on consecutive days or in an interrupted schedule (e.g., 4 mg/kg on Days 1-5, 10, 17, 24, 31, and 38) to achieve a total cumulative dose of 20-60 mg/kg body weight (BII) (1300Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43(7):917-24., 1301Meyerhoff A. U.S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999;28(1):42-51., 1303Davidson RN, Martino L, Gradoni L, Giacchino R, Russo R. Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med 1994;87(2):75-81., 1305Laguna F, Videla S, Jimenez-Mejias ME, et al. Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study. J Antimicrob Chemother 2003;52(3): 464-8., 1307Lazanas MC, Tsekes S, Papandreu S, Harhalakis N, Nikiforakis F. Liposomal amphotericin B for leishmaniasis treatment of AIDS patients unresponsive to antimonium compounds. Aids 1993; 7(7):1018-9., 1311Laguna F, Torre-Cisner J, Moreno, V, Villaneuva J, Valencia E. Efficacy of intermittent liposomal amphotericin B in the treatment of visceral leishmaniasis in patients infected with human immunodeficiency virus. Clin Infect Dis 1995;21(3):711-2.). A higher daily dosage is recommended for liposomal or lipid complex (ABLC) preparations than for conventional amphotericin B (BII) (1300Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43(7):917-24., 1301Meyerhoff A. U.S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999;28(1):42-51.).

Few systematic data are available on the efficacy of treatment for cutaneous, mucocutaneous, or diffuse cutaneous leishmaniasis in HIV-coinfected patients. On the basis of data in HIV-negative patients with cutaneous leishmaniasis and case reports in HIV-coinfected patients, first-line treatments include liposomal amphotericin B (BIII), as outlined above, and pentavalent antimony (sodium stibogluconate, which is available in the United States through CDC, and meglumine antimoniate), 20 mg/kg body weight/day, by IV or IM route for 3-4 weeks depending on the form of the disease and the clinical response (BIII) (1274Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Edinburgh, Scotland: Churchill Livingstone Elsevier;2006:1095-1113., 1302Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46(3):296-306.). Pentavalent antimony was recently demonstrated to increase viral transcription and HIV replication in cultures of human peripheral blood mononuclear cells, raising concerns about its use in coinfected patients (1312Barat C, Zhao C, Ouellette M, Tremblay MJ. HIV-1 replication is stimulated by sodium stibogluconate, the therapeutic mainstay in the treatment of leishmaniasis. J Infect Dis 2007; 195(2):236-45.). A first-line parenteral treatment should be used for mucocutaneous and disseminated cutaneous disease and for localized cutaneous disease caused by L. braziliensis, the species most likely to cause mucocutaneous disease. Potential second-line alternatives for cutaneous leishmaniasis include miltefosine, topical paromomycin, intralesional pentavalent antimony, and local heat therapy; however, the effectiveness of these modalities is dependent on the infecting species of Leishmania (1310Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol 2006;61:223-74., 1313Reithinger R, Mohsen J, Wahid M, et al. Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis 2005;40(8):1148-55., 1314Soto J, Arana BA, Toledo J, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 2004;38(9):1266-72.).

Second-line treatment options for visceral leishmaniasis in HIV-coinfected patients include miltefosine and paromomycin. Miltefosine is an oral antileishmanial agent currently available in Germany, India, and several Latin American countries; cure rates of visceral leishmaniasis in HIV-negative patients are reported to be approximately 95% (1315Sundar S, Jha TK, Thakur CP, Bhattacharya SM, Rai M. Oral miltefosine for the treatment of Indian visceral leishmaniasis. Trans R Soc Trop Med Hyg 2006.). The adult dose is 100 mg daily for 4 weeks. Although data to support its use among HIV-coinfected persons are limited, it is available for the treatment of visceral leishmaniasis in Europe under a compassionate use protocol (CIII) (1316Sindermann H, Engel KR, Fischer C, Bommer W. Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection. Clin Infect Dis 2004; 39(10):1520-3.). Gastrointestinal side effects are the most common adverse effects but rarely limit treatment. Data from an Ethiopian population with a high prevalence of HIV-coinfection suggest that use of miltefosine was associated with a somewhat lower visceral leishmaniasis cure rate, but substantially lower mortality than pentavalent antimony (1317Ritmeijer K, Dejenie A, Assefa Y, et al. A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. Clin Infect Dis 2006;43(3):357-64.). Miltefosine is teratogenic in experimental models, and its use in women of reproductive age requires a negative pregnancy test and effective contraception during and for at least 2 months after therapy. Paromomycin, a parenteral aminoglycoside, has been shown to be effective and safe in HIV-negative visceral leishmaniasis patients in India and is now in use in several countries (BI) (1310Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol 2006;61:223-74.).

Pentamidine isethionate has been used as a second-line alternative but is no longer recommended, because of toxicity that sometimes includes irreversible insulin-dependent diabetes mellitus (DIII).

ART should be initiated or optimized following standard practice for HIV-infected patients (AII). Appropriate use of ART has substantially improved the survival of coinfected patients in Europe and decreases the likelihood of relapse after antileishmanial therapy (1277Tortajada C, Perez-Cuevas B, Asuncion M, et al. Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral leishmaniasis in HIV-infected patients. J Acquir Immune Defic Syndr 2002;30(3):364-6., 1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73., 1318de la Rosa R, Pineda J, Delgado J, et al. Influence of highly active antiretroviral therapy on the outcome of subclinical visceral leishmaniasis in human immunodeficiency virus-infected patients. Clin Infect Dis 2001;32(4):633-5.). Immunotherapy, including interferon-gamma and recombinant human granulocyte macrophage colony stimulating factor, has been used experimentally as an adjunct to antileishmanial treatment for refractory cases (1319Badaro R, Johnson, WD Jr. The role of interferon-gamma in the treatment of visceral and diffuse cutaneous leishmaniasis. J Infect Dis 1993;167 Suppl 1:S13-7., 1320Badaro R, Nascimento C, Carvalho JS, et al. Granulocyte-macrophage colony-stimulating factor in combination with pentavalent antimony for the treatment of visceral leishmaniasis. Eur J Clin Microbiol Infect Dis 1994;13 Suppl 2:S23-8.). However, a clinical trial of pentavalent antimony plus interferon-gamma for visceral leishmaniasis in HIV-coinfected patients was suspended when an interim analysis indicated that there was no advantage over pentavalent antimony alone (1305Laguna F, Videla S, Jimenez-Mejias ME, et al. Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study. J Antimicrob Chemother 2003;52(3): 464-8.). In addition, the use of interferon-gamma was reported to be associated with acceleration of KS in two patients with visceral leishmaniasis and HIV coinfection (1292Albrecht H, Stellbrink J, Gross G, et al. Treatment of atypical leishmaniasis with interferon gamma resulting in progression of Kaposi's sarcoma in an AIDS patient. Clin Investig 1994;72(12):1041-7.).

Patients receiving pentavalent antimonials should be monitored closely for adverse reactions, which are frequent and vary from mild phlebitis to death (1302Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46(3):296-306.). Overall, at a dose of 20 mg/kg body weight/day, >60% of patients have one or more of the following reactions: thrombophlebitis, anorexia, myalgia, arthralgia, abdominal pain, elevation of liver transaminases, amylase or lipase, and in some patients, clinical pancreatitis. Occasional electrocardiographic changes might be observed (e.g., prolonged QT intervals and T-wave inversion). Rarely, arrhythmias and sudden death have occurred (1304, 1305). Severe adverse reactions to pentavalent antimony, including acute pancreatitis and leukopenia, appear to be more frequent in coinfected patients than in those without HIV (1321Delgado J, Macias J, Pineda JA, et al. High frequency of serious side effects from meglumine antimoniate given without an upper limit dose for the treatment of visceral leishmaniasis in human immunodeficiency virus type-1-infected patients. Am J Trop Med Hyg 1999;61(5):766-9.).

Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity, electrolyte disturbances, and infusion-related adverse reactions, which might be ameliorated by pretreatment with acetaminophen, diphenhydramine, or limited doses of corticosteroids (CIII). Previous fluid expansion with colloidal fluids can help reduce the risk of nephrotoxicity during treatment (CIII). The frequency of nephrotoxicity is lower for liposomal or lipid-associated preparations than for conventional amphotericin B (1308Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis 2004; 38(3):377-83.). Conventional amphotericin B treatment might be associated with an increased risk of anemia (1304Laguna F, Lopez-Velez R, Pulido F, et al. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study Group. Aids 1999;13(9):1063-9.).

Cases of newly symptomatic visceral and cutaneous leishmaniasis have been reported in association with the immune reconstitution syndrome following initiation of ART (1322Berry A, Abraham B, Dereure J, Pinzani V, Bastien P. Two case reports of symptomatic visceral leishmaniasis in AIDS patients concomitant with immune reconstitution due to antiretroviral therapy. Scand J Infect Dis 2004;36(3):225-7., 1323Posada-Vergara MP, Lindoso JAL, Tolezano JE, Pereira-Chioccola VL, Silva MV, Goto H. Tegumentary leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome in 2 patients with AIDS. J Infect Dis 2005;192(10):1819-22.). However, existing experience regarding IRIS-associated leishmaniasis is insufficient to provide data for specific IRIS management guidelines. Leishmaniasis that manifests after initiation of ART requires specific therapy consistent with guidelines for initial treatment or management of relapse.

For patients who fail to respond to initial therapy or experience a relapse after initial treatment, a repeat course of the initial regimen, or one of the recommended alternatives for initial therapy as outlined above, should be used (AIII). The response rate for retreatment appears to be similar to that for initial therapy, although certain patients might evolve to a chronic disease state with serial relapses despite aggressive acute and maintenance therapies.

Clinical cure is dependent on concurrent T-cell-mediated parasite killing (1324Murray HW, Ocani J, Granger AM, Schreiber RD. Requirement for T cells and effect of lymphokines in successful chemotherapy for an intracellular infection. Experimental visceral leishmaniasis. J Clin Invest 1989;83(4):1253-7.). Relapses, particularly of visceral leishmaniasis and disseminated cutaneous leishmaniasis, commonly follow cessation of therapy among immunosuppressed patients with AIDS. Among patients with visceral leishmaniasis who are not receiving or responding to ART, the risk of relapse at 6 and 12 months, in the absence of secondary prophylaxis (chronic maintenance therapy), is 60% and 90%, respectively (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319., 1325Ribera E, Ocana I, de Otero J, Cortes E, Gasser I, Pahlissa A. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996;100(5):496-501.). Therefore, secondary prophylaxis with an effective antileishmanial drug, administered at least every 2-4 weeks, is recommended, particularly for patients with visceral leishmaniasis and CD4⁺ counts <200 cells/µL (AII) (1287Alvar, J, Canavate C, Gutierrez-Solar B, Jimenez M. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997;10(2):298-319., 1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73., 1325Ribera E, Ocana I, de Otero J, Cortes E, Gasser I, Pahlissa A. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996;100(5):496-501., 1326Lopez-Velez R, Videla S, Marquez M, et al. Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. J Antimicrob Chemother 2004;53(3):540-3.). However, existing data are insufficient to recommend a specific regimen. The only published, randomized trial, which evaluated several patients, compared ABLC (3 mg/kg every 21 days) with no prophylaxis; this trial reported relapse rates of 50% versus 78%, respectively, after 1 year of follow-up (1326Lopez-Velez R, Videla S, Marquez M, et al. Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. J Antimicrob Chemother 2004;53(3):540-3.). In retrospective studies, monthly pentavalent antimony or lipid formulations of amphotericin every 2-4 weeks was also associated with decreased relapse rates (1289Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine 2001;80(1):54-73., 1325Ribera E, Ocana I, de Otero J, Cortes E, Gasser I, Pahlissa A. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996;100(5):496-501.). Daily allopurinol, in a dose of 300 mg three times daily, used for maintenance therapy is less effective than monthly pentavalent antimony and is not recommended (DIII) (1325Ribera E, Ocana I, de Otero J, Cortes E, Gasser I, Pahlissa A. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996;100(5):496-501.). Although no published data on efficacy are available, maintenance therapy might be offered in immunocompromised patients with cutaneous leishmaniasis with multiple relapses after adequate treatment.

For some investigators, clinical experience to date suggests that discontinuation of secondary antileishmanial prophylaxis can be considered in patients whose CD4⁺ count rises above 200-350 cells/µL in response to ART, but that prophylaxis should be continued in those with counts below 200 cells/µL (1327Berenguer J, Cosin J, Miralles P, Padilla B. Discontinuation of secondary anti-leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy. Aids 2000;14(18):2946-8.). Others, however, observe that ART might not be sufficient to control the disease, despite increases in CD4⁺ counts and undetectable viral loads, suggesting that secondary prophylaxis should be maintained indefinitely (1328Casado JL, Lopez-Velez R, Pintado V, Quereda C, Antela A, Moreno, S. Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy. Eur J Clin Microbiol Infect Dis 2001;20(3):202-5., 1329Mira JA, Corzo JE, Rivero A, et al. Frequency of visceral leishmaniasis relapses in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. Am J Trop Med Hyg 2004;70(3):298-301.). Although data are insufficient to provide a recommendation, discontinuation of secondary prophylaxis after successful treatment of leishmaniasis might be considered after a sustained (i.e., >3-6 months) increase in the CD4⁺ count to levels >350 cells/µL after initiation of ART (CIII) (1327Berenguer J, Cosin J, Miralles P, Padilla B. Discontinuation of secondary anti-leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy. Aids 2000;14(18):2946-8.).

Diagnostic considerations are the same among pregnant women as in nonpregnant women. Labeling for pentavalent antimony compounds (sodium stibogluconate, available in the United States through CDC, and meglumine antimoniate) states that these drugs are contraindicated for use among pregnant women, although various antimonial compounds were not teratogenic among chickens, rats, or sheep (1330James LF, Lazar VA, Binns W. Effects of sublethal doses of certain minerals on pregnant ewes and fetal development. Am J Vet Res 1966;27(116):132-5., 1331Ridgway LP, Karnofsky DA. The effects of metals on the chick embryo: toxicity and production of abnormalities in development. Ann N Y Acad Sci 1952;55:203-15., 1332Rossi F, Acampora R, Vacca C, et al. Prenatal and postnatal antimony exposure in rats: effect on vasomotor reactivity development of pups. Teratog Carcinog Mutagen 1987;7(5):491-6.). Good clinical and pregnancy outcomes have been reported for three pregnant women treated with meglumine antimoniate (1333Gradoni L, Gaeta GB, Pellizzer G, Maisto A, Scalone A. Mediterranean visceral leishmaniasis in pregnancy. Scand J Infect Dis 1994;26(5):627-9., 1334Utili R, Rambaldi A, Tripodi MF, Andreana A. Visceral leishmaniasis during pregnancy treated with meglumine antimoniate. Infection 1995;23(3):182-3.) and five women treated with liposomal amphotericin B (1335Pagliano P, Corannante N, Rossi, et al. Visceral leishmaniasis in pregnancy: a case series and a systematic review of the literature. J Antimicrob Chemother 2005;55(2):229-33.). Because of concerns about toxicity and lack of experience with use of pentavalent antimony compounds in human pregnancy, liposomal amphotericin B is the first choice for therapy of visceral leishmaniasis in pregnancy (AIII) (1335Pagliano P, Corannante N, Rossi, et al. Visceral leishmaniasis in pregnancy: a case series and a systematic review of the literature. J Antimicrob Chemother 2005;55(2):229-33.). Pentavalent antimony should be the second choice (AIII). Miltefosine is teratogenic and is contraindicated in pregnancy (1310Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol 2006;61:223-74.). Perinatal transmission of Leishmania spp. occurs rarely; eight documented cases have been reported. No data on the risk of transmission of Leishmania spp. among HIV-infected pregnant women are available.