ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Visceral leishmaniasis: Treatment

Visceral leishmaniasis: Treatment
Literature review current through: Jan 2024.
This topic last updated: Nov 15, 2022.

INTRODUCTION — Visceral leishmaniasis (VL; also known as kala-azar) is caused by parasites of the Leishmania donovani complex [1]. These parasites may be divided taxonomically and geographically into two groups: L. donovani (South Asia and East Africa) and Leishmania infantum (Mediterranean basin, western Asia from the Middle East to Pakistan, and the Americas) (table 1) [2,3]. Leishmania chagasi is synonymous with L. infantum [3].

Issues related to treatment of VL will be reviewed here. Issues related to epidemiology, clinical manifestations, and prevention of VL are discussed separately, as are issues related to cutaneous leishmaniasis. (See "Visceral leishmaniasis: Epidemiology and control" and "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Cutaneous leishmaniasis: Epidemiology and control" and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis" and "Cutaneous leishmaniasis: Treatment".)

GENERAL PRINCIPLES — In the absence of treatment, the case fatality rate of fully manifest clinical VL (kala-azar) without treatment is greater than 90 percent [4,5]. Mortality is often due to hemorrhagic or infectious complications.

Treatment consists of antileishmanial therapy; the main constraints on the choice of antileishmanial drug are cost and availability. Drug resistance must also be considered, especially for VL originating in South Asia. Supportive therapy to address nutritional status, concomitant anemia, hemorrhagic complications, and secondary infections is also essential to optimize treatment outcomes [2,6]. (See 'Clinical approach' below.)

Patients with VL should be evaluated for human immunodeficiency virus (HIV) coinfection; if found, HIV should be treated aggressively. In the absence of effective immune reconstitution, treatment response is poor in patients with HIV-VL coinfection [7-9]. (See 'HIV coinfection' below.)

CLINICAL APPROACH

Overview — Agents with efficacy against VL include amphotericin B, pentavalent antimonial drugs, paromomycin (a parenteral aminoglycoside), and miltefosine (the first oral drug for treatment of VL) (table 2):

Liposomal amphotericin B is the drug with the highest therapeutic efficacy and the most favorable safety profile; monotherapy (total dose 20 to 21 mg/kg; see below for dosing schedules) with this agent is the preferred treatment in Europe, North America, and South America [1,10-12] (see 'Liposomal' below). Conventional amphotericin B deoxycholate has high antileishmanial efficacy but is associated with high risk of renal toxicity and other side effects. Other lipid-associated amphotericin B formulations have toxicity profiles intermediate between liposomal and conventional amphotericin B, but efficacy data are limited [12].

The pentavalent antimonial drugs, sodium stibogluconate (SSG) and meglumine antimoniate, are still widely used; however, monotherapy with antimonial agents is no longer a first-line treatment for VL when other less toxic drugs are available [10,13,14].

Two new drugs have been added to the armamentarium since 1999: paromomycin and miltefosine [10,13]. Miltefosine was approved for use in adults by the US Food and Drug Administration (FDA) in March 2014, although cost of drug limits availability [15]. Parenteral formulation of paromomycin is not FDA approved and not available in the United States.

Pentamidine isethionate was previously a second-line treatment but is rarely used as primary therapy due to suboptimal efficacy and toxicity (with particular risk of irreversible insulin-dependent diabetes mellitus) [16]. However, a clinical trial in Ethiopia has demonstrated its efficacy as secondary prophylaxis for patients with HIV-VL coinfection [17,18]. (See 'Secondary prophylaxis' below.)

Species identification usually is not critical to treatment decisions for VL (in contrast with cutaneous leishmaniasis). However, sensitivity to specific drugs varies by region and first-line treatment recommendations in major VL-endemic areas have diverged [19,20]:

South Asia – For patients with VL in South Asia, we suggest liposomal amphotericin B as first-line treatment. In India and Nepal, high-level resistance to antimonial drugs is common; in these regions, miltefosine and conventional or lipid-associated amphotericin B deoxycholate have replaced antimonial drugs as first-line treatments over the past 15 years [10,13,21,22]. In South Asia, L. donovani responds to lower doses of liposomal amphotericin B and paromomycin than L. infantum or East African L. donovani [11,23].

In a phase IV implementation trial in India, three regimens were compared: single-dose liposomal amphotericin 10 mg/kg single dose (SDA; n = 891), miltefosine plus paromomycin 11 mg/kg for 10 days (Milt-PM; n = 512), and liposomal amphotericin 5 mg/kg single dose plus miltefosine for 7 days (AmB-Milt; n = 358) [24]. Rates of VL relapse and post kala-azar dermal leishmaniasis (PKDL) were low following all three regimens. In 36-month follow-up data for 1750 patients who completed treatment, 79 had VL relapse and 104 had PKDL. Relapse incidence density was 1.58, 2.08, and 0.40 per 1000 person-months for SDA, AmB-Milt, and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45, and 2.65 per 1000 person-months for SDA, AmB-Milt, and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse.

East Africa – For treatment of patients with VL in East Africa, we suggest SSG 20 mg/kg/day with paromomycin 15 mg/kg/day for 17 days as first-line treatment [20,25] (table 2). Alternative options include combination therapy with miltefosine 2.5 mg/kg/day and paromomycin 20 mg/kg/day for 14 days or liposomal amphotericin B monotherapy (30 mg/kg total dose). A higher total dose of liposomal amphotericin (30 mg/kg) is required for acceptable efficacy in East Africa than in the Indian subcontinent. The efficacies of miltefosine and paromomycin monotherapy are unacceptably low [26-29].

In a phase II trial in East Africa, three alternative regimens were compared in about 50 patients per arm: 10 mg/kg single-dose liposomal amphotericin plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single-dose liposomal amphotericin plus 10 days of miltefosine (2.5 mg/kg/day), and miltefosine alone (2.5 mg/kg/day for 28 days) [29]. At day 210 post-treatment, definitive cure was 87 percent (95% CI 77-97) for liposomal amphotericin plus SSG, 77 percent (95% CI 64-90) for liposomal amphotericin plus miltefosine, and 72 percent (95% CI 60-85) for miltefosine alone. Lower efficacy of all three treatment regimens was observed in younger patients. In a phase III trial of 439 patients in East Africa, those randomized to receive miltefosine (2.5 mg/kg/day) plus paromomycin (20 mg/kg/day) for 14 days had a similar cure rate at six months compared with those who received SSG (20 mg/kg/day) plus paromomycin (15 mg/kg/day) for 17 days (91.2 versus 91.8 percent, 0.6 percent difference, 97.5% CI -6.2 to 7.4) [30].

Europe/Americas – For treatment of patients with VL in Europe and the Americas, we suggest liposomal amphotericin B (3 mg/kg/day for seven days) as first-line therapy [31]. If liposomal amphotericin B is not available, other lipid formulations or amphotericin B deoxycholate should be used. If adverse effects or comorbidities prevent the use of amphotericin B, then pentavalent antimonials may be used instead. The Pan American Health Organization (PAHO) advises against the use of miltefosine for treatment of VL in these regions due to poor efficacy.

Data from the Americas demonstrate the best efficacy and tolerability with liposomal amphotericin B rather than pentavalent antimonials. As an example, a trial in Brazil randomized 332 patients to liposomal amphotericin B monotherapy, amphotericin B deoxycholate monotherapy, meglumine antimoniate monotherapy, or combination therapy with liposomal amphotericin B and meglumine antimoniate [32]. Cure rates were similar among all regimens (above 78 percent) but patients who received liposomal amphotericin B had the lowest percentage of adverse effects.

Miltefosine has shown poor efficacy against L. infantum, the prevalent Leishmania spp. causing VL in the Americas. In an open-label trial of 42 patients in Brazil randomized to 28 versus 42 days of miltefosine, definitive cure was achieved in only 43 and 68 percent of the patients, respectively [33].

Special circumstances

HIV coinfection — VL and HIV both target the cellular immune response and exert synergistically detrimental effects [7,34-36]. Patients with HIV-VL coinfection may have severe and/or atypical clinical presentations and may respond poorly to treatment in the absence of immune reconstitution [7-9]. The highest cumulative number of HIV-VL coinfections have been reported from Spain, but this is presumed to reflect better reporting from this region compared with Africa or Asia [7,37]. The disease burden is greatest in the Horn of Africa and is increasing in South Asia [7,37]. In treatment facilities on the Ethiopia-Sudan border, up to 20 percent of VL patients are coinfected with HIV [38,39]. In one treatment facility in Bihar, India, the prevalence of HIV coinfection in VL patients rose from 0.9 to 2.2 to 7 percent between 2000, 2006, and 2014 [37,40].

Antiparasitic therapy — Treatment regimens for patients with HIV-VL coinfection differ by geographic region:

East Africa − For patients with VL in East Africa, we suggest liposomal amphotericin B (5 mg/kg intravenously administered on days 1, 3, 5, 7, 9, and 11) with miltefosine (100 mg orally daily for 28 days) [41]. If miltefosine is not available, monotherapy with liposomal amphotericin B (5 mg/kg intravenously on days 1-5, 10, 17, and 24) is an appropriate alternative.

South Asia – For patients infected with VL in South Asia, we suggest liposomal amphotericin B (5 mg/kg intravenously administered on days 1, 3, 5, 7, 9, and 11) with miltefosine (100 mg orally daily for 14 days) [41]. If miltefosine is not available, monotherapy with liposomal amphotericin B (5 mg/kg intravenously on days 1-4, 8, 10, 17, and 24) is an appropriate alternative.

Europe/Americas – For patients with VL and HIV in the Mediterranean or the Americas, we suggest liposomal amphotericin B (40 mg/kg administered in eight equal doses over 24 days) monotherapy [31,42]. If liposomal amphotericin B is not available, amphotericin B deoxycholate at 1 mg/kg intravenously daily for 28 days can be used. PAHO also advises against the use of pentavalent antimonials in the treatment of VL in this patient population [31].

Treatment should be administered in a hospital setting when possible to monitor clinical response and for any adverse effects that may arise. Details on amphotericin B and miltefosine administration, adverse effects, and precautions (eg, for females of childbearing age) are discussed elsewhere. (See 'Amphotericin B' below and 'Miltefosine' below.)

Data suggest that a lower total dose of amphotericin B plus miltefosine combination therapy is well tolerated and as effective as amphotericin B monotherapy against VL in patients with HIV. In a small, randomized, open-label trial of 58 adults with HIV-VL coinfection in Ethiopia, combination therapy with liposomal amphotericin B (30 mg/kg administered in six equal doses over 11 days) with miltefosine (100 mg/day for 28 days) had higher parasitologic cure at 29 days compared with liposomal amphotericin B monotherapy (40 mg/kg administered in eight equal doses over 24 days;67 versus 50 percent) [43]. Similarly, in a small, randomized, open-label, phase-3 study of 122 adults with HIV-VL coinfection in India, combination therapy with liposomal amphotericin B (30 mg/kg administered in six equal doses over 11 days) plus miltefosine (50 mg twice daily for 14 days) had a similar 210-day relapse-free survival compared with liposomal amphotericin B monotherapy (40 mg/kg administered in eight equal doses over 24 days; 97 versus 90 percent) [44]. Retrospective studies have shown similar results in both geographic regions [45,46]. As an example, in a retrospective study of 102 patients in India with HIV-VL coinfection, a combination regimen of liposomal amphotericin (30 mg/kg total dose; 5 mg/kg every other day for 14 days) and miltefosine (50 mg twice daily if ≥25 kg; 50 mg once daily if 12 to 24 kg) was associated with 12-month mortality and relapse rates of 11 and 6 percent [45]. In comparison, in a study evaluating amphotericin B monotherapy, 12-month mortality and relapse rates were 9 and 16 percent, respectively [47]. (See 'Combination therapy' below.)

For patients in the Americas and Europe, data are limited to small studies conducted in Spain and Brazil that demonstrate equal efficacy of amphotericin B and pentavalent antimonials but better tolerability with amphotericin B [8,48]. As an example, in an open-label, randomized trial in 89 coinfected patients in Spain, initial cure rates were similar between those assigned to meglumine antimoniate versus amphotericin B (66 versus 62 percent) [48]. However, patients treated with meglumine antimoniate had higher incidence of cardiotoxicity (14 versus 0 percent) and chemical pancreatitis (36 versus 5 percent).

Patients with HIV require higher total doses of amphotericin B (30 to 40 mg/kg total dose) than VL patients without HIV (20 to 21 mg/kg total dose). Because of greater tolerability, higher daily dosing is recommended for liposomal or lipid complex preparations than conventional amphotericin B [11,49]. Molecular data suggest that parasite clearance is more rapid and complete for liposomal amphotericin B than for lipid emulsion preparations [50]. Dosing regimens are summarized in the table (table 2) [11,49,51-54]. (See 'Liposomal' below.)

Monotherapy with miltefosine or paromomycin is not recommended due to suboptimal efficacy. In a series of 39 patients with HIV-VL coinfection who received miltefosine monotherapy, only 25 (64 percent) achieved an initial clinical response [55]. (See 'Miltefosine' below and 'Paromomycin' below.)

Antiretroviral therapy — Antiretroviral therapy (ART) should be initiated or optimized as soon as the patient is sufficiently able to tolerate it (eg, either during or soon after the initial course of therapy for VL) [1]. VL that becomes clinically manifest or worsens after initiation of ART should be treated with antileishmanial (and, if indicated, corticosteroid) therapy [1].

ART has significantly improved the survival of coinfected patients. As an example, in one study of 102 patients coinfected with HIV and VL, those not on ART prior to VL treatment were significantly more likely to die than those already on ART (adjusted hazard ratio 8.0, 95% CI 2.0-32.5; p<0.01) [45].

ART can also decrease the likelihood of relapse after antileishmanial therapy [38,56-58]. In one study including 356 Ethiopian patients, ART decreased VL relapse rates by approximately 50 percent [38]. In another study including 146 patients with HIV-VL coinfection in Ethiopia, the cumulative incidence of relapse at 12 and 24 months was 26 and 35 percent, respectively [59]. ART was associated with significant protection (adjusted hazard ratio [aHR] 0.39, 95% CI 0.17-0.86 for ART started during VL treatment; aHR 0.22, 95% CI 0.10-0.52 for ART started prior to VL treatment), and high splenic parasite load was associated with elevated risk. A subsequent paper suggested that higher peripheral blood parasite load one to two months post-treatment is an indicator of greater relapse risk [60]. Among European patients with HIV-VL coinfection not taking ART, the 12-month risk of VL relapse after initial antileishmanial treatment was 90 percent [61,62].

ART should be managed as discussed in detail separately [9]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Secondary prophylaxis — We administer secondary prophylaxis to all patients with HIV-VL coinfection to decrease the risk for post-treatment relapse of VL, particularly in patients with CD4 counts <200 cells/microL [41,42,56,61-63]. We continue secondary prophylaxis until CD4 count is >350 cells/microL (or the HIV viral load is undetectable) for at least six months and there is no clinical evidence of VL relapse [7,41]. However, VL relapses have been reported even with CD4 counts >350 cells/microL [38,64,65].

Regimens for secondary prophylaxis differ by geographic region:

East Africa – For patients in East Africa, we suggest pentamidine isethionate (4 mg/kg [300 mg for adults] intravenously every three to four weeks) [41].

Limited data are available to guide regimen selection for secondary prophylaxis. Prospective cohort studies from Ethiopia guide secondary prophylaxis regimen selection in East Africa. In a study of 74 patients with HIV-VL coinfection in Ethiopia on ART who received monthly infusions of pentamidine-isethionate (4 mg/kg), the probability of 12-month relapse-free survival was 71 percent while on prophylaxis, comparing favorably with historical controls [17]. In a subsequent publication of data on this cohort, patients whose CD4 count was >200 cells/microL after 12 to 18 months of prophylaxis discontinued the drug and were followed for 12 months off prophylaxis [18]. At the end of follow-up, 53 percent were relapse free, 27 percent had relapsed, 7 percent had died, and 14 percent were lost to follow-up. The two-year risk of relapse was 37 percent (95% CI 23-55 percent) and was highest for those with a history of VL relapse and low baseline CD4 count. The two-year risk of relapse or death was 42 percent (95% CI 28-58 percent).

South Asia – For patients in South Asia, we suggest liposomal amphotericin B (3 to 5 mg/kg intravenously every three to four weeks) [41]. If liposomal amphotericin B is not available, amphotericin B deoxycholate at 1 mg/kg intravenously every three to four weeks can be used [17,18].

Data to guide secondary prophylaxis regimen selection in South Asia are sparse. In a retrospective analysis of 53 of adults with HIV-VL coinfection, secondary prophylaxis with monthly liposomal amphotericin B was associated with decreased relapse (0 versus 75 percent) and mortality (0 versus 46 percent) rates compared with no prophylaxis [66]. Other studies have been conducted in Spain. As an example, one randomized trial conducted from 1997 to 1999 demonstrated lower relapse rates at one year with intermittent administration of amphotericin B lipid complex (3 mg/kg every 21 days) compared with no prophylaxis (50 versus 78 percent, respectively) [63]. Decreased relapse rates have also been observed in retrospective studies of prophylaxis with monthly SSG (850 mg) or liposomal amphotericin B (200 to 350 mg) [56,62], although SSG is rarely used as secondary prophylaxis due to high rates of toxicity.

Europe/North America/South America − For patients in the Mediterranean or the Americas, we suggest liposomal amphotericin B (3 to 5 mg/kg intravenously every three to four weeks) [31]. If liposomal amphotericin B is not available, amphotericin B deoxycholate at 1 mg/kg intravenously every three to four weeks can be used.

Data on secondary prophylaxis in patients with HIV-VL coinfection in Europe and the Americas are scarce. Recommendations are extrapolated from studies conducted in Spain [63] and to a lesser extent in South Asia [66].

Other immunocompromised hosts — The treatment of choice for VL in patients with solid organ transplant, malignancy, or other forms of immunosuppression is liposomal amphotericin [1]. Whenever possible, doses of immunosuppressive drugs should be decreased in patients with VL during antileishmanial therapy.

Secondary prophylaxis is not required for initial management of immunosuppressed patients without HIV who have not manifested a relapse. In addition, patients with asymptomatic VL warrant close monitoring but do not require pre-emptive treatment or primary prophylaxis.

Pregnancy — VL infection in the setting of pregnancy has been associated with congenital infection and fetal death [67]. Liposomal amphotericin B is the drug of choice for treatment of VL in pregnancy [68,69]. Alternative choices include amphotericin B deoxycholate and pentavalent antimony. Good clinical and pregnancy outcomes have been reported for five pregnant women treated with liposomal amphotericin B and three cases treated with meglumine antimoniate [68-70].

Miltefosine is contraindicated in pregnancy [10].

Post kala-azar dermal leishmaniasis — Management of post kala-azar dermal leishmaniasis (PKDL) requires prolonged treatment; the optimal approach is uncertain, and clinical trial data are limited.

In South Asia, the first-line treatment for PKDL consists of miltefosine 2.5 mg/kg/day for 12 weeks. In one trial including 35 patients treated with 100 mg/day for 8 or 12 weeks, intention-to-treat cure rates were 76 and 78 percent, respectively; per-protocol cure rates were 81 and 93 percent, respectively [71]. However, data suggest some PKDL patients may require up to 16 weeks of miltefosine and that relapse rates among those treated for 12 weeks may be increasing in northern India due to selection for resistant parasites over the prolonged treatment course [72,73]. The traditional approach to PKDL in India consisted of SSG (20 mg/kg) for two to four months [74]. In an Indian trial performed in 1987 including 108 patients with PKDL, cure rates for those treated for four months with daily injections of 10 mg/kg, 15 mg/kg, or 20 mg/kg were 50, 67, and 92 percent, respectively [75].

In Africa, conventional treatment for PKDL consists of SSG 20 mg/kg/day for 30 to 60 days (substantially shorter than for PKDL in South Asia).

Amphotericin B deoxycholate may be superior to antimony treatment in terms of speed of response and cure [76]. This was evaluated in a study of 22 patients in India in 1997 treated with amphotericin B deoxycholate infusion (1 mg/kg/day for 20 days with intervening 20-day drug-free intervals) or SSG intramuscular injection (20 mg/kg day for 20 days with intervening 20-day drug-free intervals) [76]. Cure rates for the amphotericin arm and the SSG arm were 100 percent (11 of 11) and 64 percent (7 of 11), respectively. The decrease in the cure rate with SSG from 1987 to 1997 may also reflect the increasing SSG resistance in Bihar observed over that period of time [21].

Subsequent studies have focused on the use of liposomal amphotericin B and combination regimens for PKDL. However, the optimal regimen is still uncertain and probably will be found to differ by geographic region. A trial that included 12 Sudanese patients with PKDL suggested that prolonged treatment with liposomal amphotericin B (2.5 mg/kg for 20 days) may succeed in curing PKDL unresponsive to SSG [77]. SSG (30 mg/kg/day for a minimum of 17 days) plus paromomycin (15 mg sulphate/kg/day for 17 days) may have higher efficacy than SSG alone [78].

In a prospective cohort study including 280 patients with PKDL in Bangladesh, liposomal amphotericin (15 mg/kg; 3 mg/kg administered for 5 doses over 15 days) demonstrated cure in 78 percent of patients and major or complete improvement after 12 months of follow-up in 89 percent of patients with no severe adverse effects [79]. However, an observational study in India demonstrated sustained clearance of parasites by polymerase chain reaction in skin in those treated with miltefosine, but a resurgence of skin parasite load six months after treatment with liposomal amphotericin, especially in those with polymorphic PKDL [80]. Loss to follow-up was high: six-month follow-up was completed for 29 percent of 84 patients treated with miltefosine and 39 percent of 98 patients treated with liposomal amphotericin.

Combination therapy with liposomal amphotericin and miltefosine may be associated with lower relapse rate; further study is needed. In an observational study in India including 2 series of 16 PKDL cases, patients were treated with miltefosine (100 mg/day for patients ≥25 kg or 50 mg/day for patients <25 kg; duration 90 days) or miltefosine (duration 45 days) plus liposomal amphotericin (5 mg/kg for 3 doses on days 1, 8, and 15); relapse rates at 18 months were 25 versus 0 percent, respectively [81].

Assessing response to treatment — Response to treatment of VL is generally assessed clinically, based on resolution of fever, which typically occurs within one to two weeks, decrease in spleen size within a month of treatment initiation, and weight gain. Patients with clinical response need not undergo additional testing for parasitologic confirmation but should be followed clinically for at least 12 months and instructed to return if symptoms recur [1]. In immunocompetent patients, most relapses occur within 6 to 12 months of completion of treatment, although relapses were seen up to 18 months post-treatment in observational studies with extended follow-up [24,82]. Immunocompromised patients should be followed for a minimum of one year (ideally, lifelong or until effective immune reconstitution) to assess for symptoms of posttreatment relapse.

In patients whose clinical response is equivocal (eg, no decrease in spleen size, continued fever) or are suspected to have relapse, bone marrow or splenic aspirate should be performed to confirm the diagnosis of VL and/or to evaluate for alternative diagnoses.

Conventional serologic tests are not useful tests of cure, as they remain positive for months to years after treatment [83,84]. The urine KAtex assay detects parasite antigen in urine and becomes negative more rapidly than serologic assays but has poor sensitivity for diagnosis and is not widely available [85].

Anti-rK39 immunoglobulin (Ig)G1 (in either enzyme-linked immunosorbent assay [ELISA] or rapid test format) may be an effective test of cure. In one study including 37 patients who demonstrated clinical response to treatment, a negative anti-rK39 IgG1 ELISA result at six months was observed in 81 percent of cases; among patients with clinical signs of relapse, the assay was positive in more than 85 percent of cases [86].

Adjusting therapy — Immunocompetent patients with VL who do not respond to initial therapy with liposomal amphotericin should be treated with an alternative drug, with a higher dose or longer course of liposomal amphotericin, or with a combination regimen. Depending on drug availability and geographic origin, combinations may include liposomal amphotericin with either miltefosine or paromomycin or miltefosine plus paromomycin [1,20].

Immunocompetent patients with VL who do not respond to initial therapy with miltefosine or a pentavalent antimonial compound should be treated with liposomal amphotericin or an alternative drug if liposomal amphotericin is not available. Immunocompetent patients with VL who respond to initial therapy but subsequently relapse should be treated with an alternative or another potentially longer course of therapy with the initial drug. If liposomal amphotericin was the drug used for initial therapy, use of a higher total dose (eg, 30 to 40 mg/kg) may be warranted.

Immunocompromised patients with VL who do not respond to initial therapy can be managed by retreatment with liposomal amphotericin at the same or a higher total dose or with a combination such as liposomal amphotericin B plus miltefosine [39].

THERAPEUTIC AGENTS

Amphotericin B — Amphotericin B deoxycholate binds to parasite ergosterol precursors such as lanosterol, causing disruption of the parasite membrane [87]. Liposomal and lipid complex preparations are significantly better tolerated than amphotericin B deoxycholate or pentavalent antimony, although these agents have comparable efficacy [12,48,51-53,88,89]. In VL-endemic areas in Asia, Africa, and Latin America, the use of liposomal amphotericin B has been constrained by the high cost of the drug, but the drug is available under a donation program [11].

Liposomal — Liposomal amphotericin B consists of amphotericin B packaged with cholesterol and other phospholipids within a small unilamellar liposome [90]. The characteristics of this specialized formulation facilitate improved antimicrobial efficacy with reduced systemic toxicity. The liposomal drug formulation has improved stability in blood, macrophages, and tissues, permitting more effective tissue penetration with sustained tissue drug levels, especially in the liver and spleen. This formulation has increased affinity for ergosterol and its precursors with excellent antimicrobial efficacy [91]. In addition, the presence of cholesterol in the formulation minimizes interaction with mammalian cell membranes, thereby reducing toxicity [91].

Liposomal amphotericin B is approved by the US Food and Drug Administration (FDA) for treatment of VL in the United States [49]. Four European trials including a total of 348 patients treated with total cumulative doses >18 mg/kg demonstrated cure rates of 98 to 100 percent [51,92-94]. Two African studies including a total of 74 patients treated with total doses ranging from 10 to 24 mg/kg demonstrated cure rates of 88 to 100 percent [95,96]. Three Indian trials including a total of 144 patients treated with total doses of 14 to 20 mg/kg demonstrated cure rates of 96 to 100 percent [97-99]. An expert panel convened by the World Health Organization (WHO) in 2005 concluded that a total cumulative dose of 20 mg/kg is adequate to achieve high cure rates in immunocompetent VL patients in all regions of the world, regardless of the specific dosing schedule [11].

The wide variation in successful dosing schedules may reflect the fact that the drug accumulates in viscera and the active drug is then slowly released. Pharmacokinetic studies suggest that optimal tissue levels may be achieved if the initial dose is at least 5 mg/kg [90], although the FDA recommends 3 mg/kg on days 1 to 5, 14, and 21 for a total dose of 21 mg/kg [49]. In New Zealand, the recommended regimen is 1 to 1.5 mg/kg for 21 days or 3 mg/kg for 10 days. In Italy, the standard regimen consists of 3 mg/kg days 1 to 5 and 10 for a total dose of 18 mg/kg [100]. Many European pediatricians favor a regimen of 10 mg/kg/day on two consecutive days, obviating the need for longer hospitalization [101].

In VL-endemic areas in Asia, Africa, and Latin America, the use of liposomal amphotericin B has been constrained by the high cost of the drug [11]. Liposomal amphotericin B is available through the WHO at preferential pricing for nonprofit and public sectors in low- and selected moderate-income VL-endemic countries; nonetheless, the total cost of a treatment course is substantially higher than generic SSG or conventional amphotericin B deoxycholate. A large donation by the manufacturer has further increased access to liposomal amphotericin B in several highly endemic countries.

Because cost is the limiting factor for use of liposomal amphotericin B, many different regimens have been evaluated in India in an attempt to find the lowest total dose with acceptable efficacy. Among 203 patients in one study, a single dose of 7.5 mg/kg gave a 90 percent cure rate at six months [102]. Among 84 patients with VL in another study, total doses of 10 to 15 mg/kg in various schedules gave cure rates >95 percent, while a single dose of 3.75 mg/kg led to a cure rate of 89 percent in a limited number of patients [97]. A third trial including 304 patients compared a single dose of liposomal amphotericin B (10 mg/kg) with conventional amphotericin B deoxycholate (15 mg/kg total dose; 1 mg/kg every other day for 15 doses); efficacy was equivalent (96 percent) [103]. Single-dose therapy (10 mg/kg) has been approved as first-line treatment in Bangladesh and is under consideration in the Indian VL control program for treatment in the epidemic settings facing these countries [104,105]. However, the use of 10 mg/kg as a single infusion carries a risk of severe hypotension [105], and this total dose is clearly insufficient outside of South Asia. For settings other than those covered by leishmaniasis treatment programs in the South Asia, the FDA-approved regimen outlined above is preferred because of the better safety profile and high efficacy.

Liposomal amphotericin B causes substantially less toxicity than conventional amphotericin B deoxycholate because of differences in cell penetration, pharmacokinetic properties, and interactions with lipoproteins and host cells [87]. Infusion-related reactions are less common and less severe than with conventional amphotericin B or amphotericin B lipid complex [12]. Although transient rises in creatinine can occur, acute and chronic toxicity from liposomal amphotericin B is low even when 15 mg/kg is administered as a single dose [106].

Clinical resistance to liposomal amphotericin B appears to be rare, although resistant parasites have been generated in culture [87].

Conventional — Conventional amphotericin B deoxycholate should be administered as a slow intravenous (IV) infusion over four hours. Effective regimens include 0.75 to 1.0 mg/kg daily for 15 to 20 days or 0.75 to 1.0 mg/kg every other day for 30 to 40 days. Alternate day dosing and pretreatment saline loading may decrease risk of renal toxicity and other adverse effects [107].

Renal function should be monitored carefully; amphotericin B can cause renal abnormalities such as distal renal tubular acidosis, arginine vasopressin resistance (AVP-R; previously called nephrogenic diabetes insipidus), and renal potassium wasting. These are usually reversible with discontinuation of the drug, although dose-related acute renal insufficiency can be progressive and incompletely reversible.

Fever and rigors are also common, especially at the beginning of infusion; pretreatment antipyretics may decrease severity. Other adverse effects include malaise, anorexia, bone marrow suppression, myalgia, arthralgia, and rash.

Other preparations — The pharmacokinetics and in vitro and in vivo activity profiles differ with different lipid delivery vehicles, although the mechanism of action for all formulations of amphotericin B is the same [87].

Clinical trial data are limited for lipid associated amphotericin preparations other than liposomal amphotericin B, and optimum dosing schedules are not established. In India, efficacy has been demonstrated for amphotericin B lipid complex (short courses totaling 5 to 15 mg/kg) and amphotericin B lipid emulsion (15 mg/kg) [12,108].

Amphotericin B lipid complex has a side effect profile intermediate between liposomal amphotericin B and conventional amphotericin B deoxycholate [12,98].

Pentavalent antimonial compounds — Pentavalent antimonial drugs have been used for the treatment of VL since the 1940s. Sodium stibogluconate (SSG; brand name Pentostam; also generic versions from many manufacturers) and meglumine antimoniate (brand name Glucantime) remain the most widely used antileishmanial agents [109].

There are no trials comparing the efficacy and toxicity of SSG with meglumine antimoniate for VL; the two drugs are considered largely interchangeable and the choice between them is governed by availability and historical usage patterns [10]. There have been several double-blind controlled comparisons of Pentostam and generic SSG from one specific manufacturer demonstrating equivalent efficacy and toxicity profiles [110-112]. However, generic SSG from other manufacturers has not been tested, and the efficacy and toxicity of these preparations are considered unproven [10]. In India and Nepal, clusters of patients with severe toxicity and fatal outcomes have raised concern about the use of untested generic SSG [113,114].

The mechanism of action of pentavalent antimonial drugs is uncertain; in vivo conversion to trivalent antimony compounds may be involved in both antileishmanial activity and drug toxicity [115]. Other studies suggest that antileishmanial activity may occur via inhibition of parasite ADP phosphorylation, deoxyribonucleic acid (DNA) I topoisomerase, and/or trypanothione reductase [87,116].

Toxicity is usually related to the cumulative dose. The most serious adverse effects are cardiotoxicity and clinical pancreatitis, either of which can lead to death. Other side effects are frequent and include myalgia and arthralgia, nausea, vomiting, abdominal pain, headache, fatigue, rash, electrocardiographic (EKG) abnormalities, elevated liver function tests, elevated lipase and amylase levels, and decreased hemoglobin, white blood cell, and platelet counts [117].

Antimony can lead to nonspecific EKG changes, including flattening or inversion of the T waves [118]. Prolongation of the corrected QT interval (measured QT interval divided by the square root of the preceding RR interval) to >0.5 seconds or development of T wave inversion with concave ST segments are considered signs of serious cardiotoxicity and should prompt immediate cessation of treatment [117]. Pre-existing cardiac disease is thought to increase the risk of cardiotoxicity and is a contraindication to use of antimonial drugs.

The standard dosing regimen consists of 20 mg/kg/day of antimony for 28 to 30 days [117]. Administration is IV or intramuscular. Intramuscular injections are frequently used in regions with limited health infrastructure but are very painful as the volume is large and the compound is a tissue irritant [109]. Sterile abscesses can result from intramuscular injection and phlebitis is a common complication of IV administration.

Prior to and during therapy, clinical monitoring as well as EKG, complete blood count, creatinine, transaminase, lipase, and amylase levels should be performed weekly. Asymptomatic elevations of amylase and/or lipase levels occur in the majority of patients and do not require cessation of therapy [119]. However, clinical pancreatitis is an indication for suspending treatment, as are EKG findings as described above.

Accurate in vitro testing for antimonial resistance requires the use of amastigotes in a macrophage cellular system (not promastigote-based assays) [120]. High-level resistance to antimonial drugs is common in Bihar State, India, especially north of the river Ganges, and in southeastern Nepal [21,22,121]. In these regions, conventional amphotericin B deoxycholate has replaced SSG as the first-line treatment [10,13,21,22]. Outside of these regions, efficacy of antimonial drugs is generally >95 percent.

Pentavalent antimonial compounds are not licensed in the United States and are not available in the United States or Canada. Meglumine antimoniate may be obtained via investigator-initiated investigational new drug (IND) protocol. Instructions on how to initiate the process to obtain these therapeutic agents can be found on the American Society of Tropical Medicine and Hygiene website. Consultations about diagnostic testing, management, and drug requests should be addressed to the Division of Parasitic Diseases Public Inquiries line (404-718-4745; email [email protected]), CDC Drug Service (404-639-3670), or for emergencies outside of business hours, CDC Emergency Operations Center (770-488-7100).

Miltefosine — Miltefosine is the only oral agent for treatment of VL. It was approved by the FDA in March 2014 for treatment of VL caused by L. donovani in adults and adolescents who weigh at least 30 kg. The drug is available in 50 mg capsules. The treatment regimen approved by the FDA is based on patient weight: for patients 30 to 44 kg, the approved regimen consists of 50 mg twice daily for 28 consecutive days; for patients ≥45 kg, the approved regimen consists of 50 mg three times daily for 28 consecutive days [122]. The use of miltefosine to treat VL caused by L. infantum or VL in children who weigh less than 30 kg is considered off-label use.

The mechanism of action of miltefosine is not fully understood. The drug is a phosphocholine analogue thought to interfere with cell-signaling pathways, and there is some evidence that it targets parasite lipid biosynthetic enzymes [87].

Miltefosine is an effective drug for treatment of VL. Efficacy data are strongest for the Indian subcontinent [123]. In a study including 398 patients with VL in India, 299 received treatment with miltefosine (50 mg/day if <25 kg and 100 mg/day if >25 kg) and 99 received treatment with conventional amphotericin deoxycholate (1 mg/kg every other day; total 15 infusions); cure rates at six months were 94 and 97 percent, respectively [124]. Among Indian children, miltefosine was safe and approximately 90 percent effective at six months [125]. Among 1132 adult and pediatric VL patients in northern India, six-month cure rates were 82 percent by intention to treat analysis and 94 percent by per protocol analysis [126]. However, after a decade of use in the Indian subcontinent, substantially higher failure rates are being reported. Data from longer follow-up studies have suggested that failure rates may reach 10 percent at 6 months and 20 percent at 12 months [127,128]. Published efficacy data are lacking in East Africa, the Mediterranean, and South America [123].

The standard regimen is 2.5 mg/kg/day orally for 28 days. Miltefosine is teratogenic in experimental models; if miltefosine therapy is planned for women of reproductive age, a negative pregnancy test and effective contraception during and for at least four months after therapy are required [129].

Allometric dosing (based on sex, height, and weight) should be used for children <12 years (table 3). Pharmacokinetic data suggest that linear dosing regimens result in suboptimal blood levels in children and that allometric dosing is preferable [129,130]. One trial conducted in 30 East African children aged 4 to 12 years noted that allometric dosing resulted in more adequate blood levels and substantially higher six-month cure rates than linear dosing (90 versus 59 percent) [29,131].

Vomiting may occur in up to 65 percent of patients and diarrhea in 5 to 20 percent of patients, but these adverse effects rarely require suspension of treatment [128]. Transaminase elevations occur in 15 to 30 percent of patients, which may require suspension of therapy if severe [132]. If the patient cannot tolerate miltefosine due to side effects, an alternative drug should be used.

The long half-life of miltefosine and the potential for poor compliance with oral therapy administered without clinician supervision has raised concern regarding potential for emergence of resistance. Laboratory-confirmed resistance to miltefosine has not been reported, although clinical failure rates of 8 to 30 percent have been reported in miltefosine treatment programs (compared with 3 to 4 percent in phase III trials) [127,128,133]. Relapse of VL following miltefosine treatment has been described in 3 to 11 percent of patients treated in clinical trials with at least six months of follow-up; such patients usually respond well to amphotericin B rescue therapy [128,134].

Paromomycin — Paromomycin (aminosidine) is an aminoglycoside antibiotic with activity against Leishmania as well as bacteria and some enteric protozoa. It binds the 30S ribosomal subunit, causing impaired parasite protein synthesis [135]. Parenteral paromomycin was used as an antibiotic until the 1980s when the introduction of newer antibiotics led to cessation of its manufacture. Topical and oral forms of paromomycin have been used for treatment of cutaneous leishmaniasis and intestinal amebiasis, respectively, but availability of these forms in the United States is limited. The parenteral form has received FDA Orphan Drug Status, but is not FDA approved and not available in the United States. Injectable paromomycin is produced in India for the nonprofit sector [135].

Trials conducted in India have demonstrated good efficacy for doses ranging from 12 to 20 mg/kg/day (intramuscular or IV administration) for 21 to 28 days (88 to 95 percent) [136-138]. In India, the recommended dosing schedule for paromomycin monotherapy is 15 mg/kg/day (equivalent to 11 mg/kg/day paromomycin base) for 21 days [137]. However, paromomycin is not recommended as monotherapy; instead, it is used in combination with miltefosine in selected facilities in India [20,24].

Parasite susceptibility to paromomycin appears to be geographically variable. In East Africa, the efficacy of paromomycin monotherapy with the dosing range evaluated in India was <90 percent, thus higher daily doses of paromomycin are recommended in East Africa [139,140]. Paromomycin (15 mg/kg/day) in combination with pentavalent antimony (20 mg/kg/day) for 17 days is the first-line regimen in East Africa [20,25,109,140]. (See 'Combination therapy' below.)

Adverse effects are uncommon; they include elevated liver function enzymes (≥3 times the upper limit of normal in 6 percent of patients), reversible ototoxicity (2 percent), and renal insufficiency (1 percent) [137].

Acquisition of resistance during therapy is a theoretical risk (since resistance can be induced in vitro), although thus far, no clinically acquired resistance has been reported [141]. Given the parenteral administration and relatively short half-life, the risk of inducing paromomycin resistance is likely lower than for miltefosine.

Combination therapy — There is a broad consensus among experts that antileishmanial therapy in endemic regions should move toward combination drug regimens to (1) protect the limited armamentarium of antileishmanial agents from development of acquired resistance, and (2) establish shorter treatment courses with high efficacy to improve compliance and decrease treatment costs [109,142]. However, published data are sparse and recommendations for specific combination regimens do not yet exist [23].

Several small trials or observational studies of paromomycin (12 to 18 mg/kg/day) combined with SSG (20 mg/kg/day) have demonstrated good parasitological response rates for dosing schedules of 17 to 21 days [138-140,143]. In a dose-finding study in India, regimens that combined single dose liposomal amphotericin (5 mg/kg) with miltefosine (100 mg daily) for 7, 10, or 14 days showed efficacy rates of 96 to 98 percent [144].

A subsequent trial among 634 patients in India with nonsevere VL demonstrated 97 to 98 percent efficacy for each of three combination regimens: single IV infusion of liposomal amphotericin (5 mg/kg) plus miltefosine (50 mg per day for seven days), single IV infusion of liposomal amphotericin (5 mg/kg) plus intramuscular paromomycin (11 mg/kg/day for 10 days), and miltefosine (50 mg per day for 10 days) plus intramuscular paromomycin (11 mg/kg/day for 10 days) [145].

SSG plus paromomycin combination is considered the first-line treatment for immunocompetent patients in East Africa [19], based on results of a randomized trial in East Africa comparing three regimens: paromomycin (20 mg/kg/day for 21 days), paromomycin 15 mg/kg/day plus SSG 20 mg/kg/day for 17 days, and SSG 20 mg/kg/day for 30 days [26]. The efficacy of paromomycin monotherapy was significantly lower than SSG (84.3 versus 94.1 percent; difference 9.7 percent; 95% CI 3.6 to 15.7 percent). The efficacy of SSG plus paromomycin was comparable with SSG (91 versus 94 percent). The safety profile for the three treatment regimens was comparable. These data are a promising step in the shift to combination therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leishmaniasis".)

SUMMARY AND RECOMMENDATIONS

Clinical approach – Treatment of visceral leishmaniasis (VL) varies by region due to variable drug susceptibility (table 2).(See 'Clinical approach' above.)

Europe/North America/South America – We suggest treatment of VL with liposomal amphotericin B (Grade 2C).

India/Nepal/Bangladesh – We suggest liposomal amphotericin B as the first-line treatment due to widespread high-level resistance to antimonial drugs (Grade 2C). A move to combination regimens for first-line treatment is under active discussion.

East Africa – We suggest combination treatment with sodium stibogluconate and paromomycin (Grade 2C).

Treatment of VL in patients with HIV

Primary treatment −Patients with VL should be evaluated for HIV coinfection; if found, HIV-VL coinfection should be treated aggressively with antiparasitic therapy and antiretroviral therapy. (See 'HIV coinfection' above.)

-For patients with HIV-VL coinfection in East Africa, we suggest liposomal amphotericin B (5 mg/kg intravenously administered on days 1, 3, 5, 7, 9, and 11) with miltefosine (100 mg orally daily for 28 days) (Grade 2C). If miltefosine is not available, monotherapy with liposomal amphotericin B (5 mg/kg intravenously on days 1-5, 10, 17, and 24) is an appropriate alternative. (See 'Antiparasitic therapy' above.)

-For patients with HIV-VL coinfection in South Asia, we suggest liposomal amphotericin B (5 mg/kg intravenously administered on days 1, 3, 5, 7, 9, and 11) with miltefosine (100 mg orally daily for 14 days) (Grade 2C). If miltefosine is not available, monotherapy with liposomal amphotericin B (5 mg/kg intravenously on days 1-4, 8, 10, 17, and 24) is an appropriate alternative. (See 'Antiparasitic therapy' above.)

-For patients with HIV-VL coinfection in the Mediterranean or the Americas, we suggest liposomal amphotericin B (40 mg/kg administered in eight equal doses over 24 days) monotherapy (Grade 2C).

Initiation of antiretroviral therapy − Antiretroviral therapy (ART) should be initiated or optimized as soon as the patient is sufficiently able to tolerate it (eg, either during or soon after the initial course of therapy for VL) as it has been shown to improve mortality.

Secondary prophylaxis − Following antiparasitic therapy, we administer secondary prophylaxis to prevent relapses. In the absence of effective immune reconstitution, treatment response is poor in patients with HIV-VL coinfection. (See 'Secondary prophylaxis' above.)

-For patients in East Africa, we suggest pentamidine isethionate (4 mg/kg [300 mg for adults] intravenously every three to four weeks) (Grade 2C).

-For patients in South Asia, we suggest liposomal amphotericin B (3 to 5 mg/kg intravenously every three to four weeks) (Grade 2C). If liposomal amphotericin B is not available, amphotericin B deoxycholate at 1 mg/kg intravenously every three to four weeks can be used.

-For patients in the Mediterranean or the Americas, we suggest liposomal amphotericin B (3 to 5 mg/kg intravenously every three to four weeks) (Grade 2C). If liposomal amphotericin B is not available, amphotericin B deoxycholate at 1 mg/kg intravenously every three to four weeks can be used.

Treatment of VL in pregnant patients – VL infection in the setting of pregnancy has been associated with congenital infection and fetal death. We suggest liposomal amphotericin B for treatment of VL in pregnancy (Grade 2C). Alternative choices include amphotericin B deoxycholate and pentavalent antimony. Miltefosine is contraindicated in pregnancy. (See 'Pregnancy' above.)

Assessing response to treatment – Response to treatment is generally assessed clinically, based on resolution of fever, decrease in spleen size, and weight gain. Serologic tests are not useful tests of cure, as they remain positive for months to years after treatment. (See 'Assessing response to treatment' above.)

Post kala-azar dermal leishmaniasis – Management of post kala-azar dermal leishmaniasis requires prolonged treatment; the optimal approach is uncertain and clinical trial data are limited. (See 'Post kala-azar dermal leishmaniasis' above.)

Therapeutic agents – Liposomal amphotericin has the highest therapeutic efficacy and the most favorable safety profile for treatment of VL. Other agents with activity against VL include pentavalent antimonial drugs, paromomycin (a parenteral aminoglycoside), and miltefosine (the first oral drug for treatment of VL) (table 2 and table 3). (See 'Therapeutic agents' above.)

  1. Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis 2016; 63:e202.
  2. Jeronimo SMB, de Queiroz Sousa A, Pearson RD. Leishmaniasis. In: Tropical Infectious Diseases: Principles, Pathogens and Practice, 3rd ed, Guerrant RL, Walker DH, Weller PF (Eds), Saunders Elsevier, Philadelphia 2011. p.696.
  3. Kuhls K, Keilonat L, Ochsenreither S, et al. Multilocus microsatellite typing (MLMT) reveals genetically isolated populations between and within the main endemic regions of visceral leishmaniasis. Microbes Infect 2007; 9:334.
  4. Desjeux P. Leishmaniasis. Public health aspects and control. Clin Dermatol 1996; 14:417.
  5. Sen Gupta PC. History of kala-azar in India. Indian Medical Gazette 1947; 82:281.
  6. Collin S, Davidson R, Ritmeijer K, et al. Conflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in southern Sudan. Clin Infect Dis 2004; 38:612.
  7. Alvar J, Aparicio P, Aseffa A, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008; 21:334.
  8. Laguna F. Treatment of leishmaniasis in HIV-positive patients. Ann Trop Med Parasitol 2003; 97 Suppl 1:135.
  9. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines (Accessed on July 25, 2023).
  10. Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol 2006; 61:223.
  11. Bern C, Adler-Moore J, Berenguer J, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006; 43:917.
  12. Sundar S, Mehta H, Suresh AV, et al. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis 2004; 38:377.
  13. Murray HW. Treatment of visceral leishmaniasis in 2004. Am J Trop Med Hyg 2004; 71:787.
  14. World Health Organization. Control of the leishmaniases. World Health Organ Tech Rep Ser 2010; :xii.
  15. Shahriar AA, Alpern JD. Antiparasitic Drugs in the United States-Two Roads to High Prices. Front Sociol 2020; 5:540478.
  16. Das VN, Siddiqui NA, Pandey K, et al. A controlled, randomized nonblinded clinical trial to assess the efficacy of amphotericin B deoxycholate as compared to pentamidine for the treatment of antimony unresponsive visceral leishmaniasis cases in Bihar, India. Ther Clin Risk Manag 2009; 5:117.
  17. Diro E, Ritmeijer K, Boelaert M, et al. Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study. PLoS Negl Trop Dis 2015; 9:e0004087.
  18. Diro E, Ritmeijer K, Boelaert M, et al. Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial. Clin Infect Dis 2018; 66:444.
  19. Sundar S, Singh A. Recent developments and future prospects in the treatment of visceral leishmaniasis. Ther Adv Infect Dis 2016; 3:98.
  20. Alves F, Bilbe G, Blesson S, et al. Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives. Clin Microbiol Rev 2018; 31.
  21. Sundar S, More DK, Singh MK, et al. Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. Clin Infect Dis 2000; 31:1104.
  22. Rijal S, Chappuis F, Singh R, et al. Treatment of visceral leishmaniasis in south-eastern Nepal: decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline. Trans R Soc Trop Med Hyg 2003; 97:350.
  23. den Boer ML, Alvar J, Davidson RN, et al. Developments in the treatment of visceral leishmaniasis. Expert Opin Emerg Drugs 2009; 14:395.
  24. Goyal V, Das VNR, Singh SN, et al. Long-term incidence of relapse and post-kala-azar dermal leishmaniasis after three different visceral leishmaniasis treatment regimens in Bihar, India. PLoS Negl Trop Dis 2020; 14:e0008429.
  25. Kimutai R, Musa AM, Njoroge S, et al. Safety and Effectiveness of Sodium Stibogluconate and Paromomycin Combination for the Treatment of Visceral Leishmaniasis in Eastern Africa: Results from a Pharmacovigilance Programme. Clin Drug Investig 2017; 37:259.
  26. Musa A, Khalil E, Hailu A, et al. Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial. PLoS Negl Trop Dis 2012; 6:e1674.
  27. Musa AM, Younis B, Fadlalla A, et al. Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study. PLoS Negl Trop Dis 2010; 4:e855.
  28. 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.
  29. Wasunna M, Njenga S, Balasegaram M, et al. Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial. PLoS Negl Trop Dis 2016; 10:e0004880.
  30. Musa AM, Mbui J, Mohammed R, et al. Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial. Clin Infect Dis 2023; 76:e1177.
  31. Guideline for the treatment of leishmaniasis in the Americas. Pan American Health Organization. June 2022. https://www.paho.org/en/documents/guideline-treatment-leishmaniasis-americas-second-edition (Accessed on June 30, 2022).
  32. Romero GAS, Costa DL, Costa CHN, et al. Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. PLoS Negl Trop Dis 2017; 11:e0005706.
  33. Carnielli JBT, Monti-Rocha R, Costa DL, et al. Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil. Am J Trop Med Hyg 2019; 101:789.
  34. Olivier M, Badaró R, Medrano FJ, Moreno J. The pathogenesis of Leishmania/HIV co-infection: cellular and immunological mechanisms. Ann Trop Med Parasitol 2003; 97 Suppl 1:79.
  35. Tremblay M, Olivier M, Bernier R. Leishmania and the pathogenesis of HIV infection. Parasitol Today 1996; 12:257.
  36. van Griensven J, Carrillo E, López-Vélez R, et al. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014; 20:286.
  37. World Health Organization, 2007. Report of the 5th Consultative Meeting on Leishmania/HIV Coinfection. WHO Technical Report Series WHO/CDS/NTD/IDM/2007.5.
  38. ter Horst R, Collin SM, Ritmeijer K, et al. Concordant HIV infection and visceral leishmaniasis in Ethiopia: the influence of antiretroviral treatment and other factors on outcome. Clin Infect Dis 2008; 46:1702.
  39. Akuffo H, Costa C, van Griensven J, et al. New insights into leishmaniasis in the immunosuppressed. PLoS Negl Trop Dis 2018; 12:e0006375.
  40. 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.
  41. WHO guideline for the treatment of visceral leishmaniasis in HIV co-infected patients in East Africa and South-East Asia. World Health Organization: Control of Neglected Tropical Diseases, Guidelines Review Committee. June 2022. https://www.who.int/publications/i/item/9789240048294 (Accessed on June 14, 2022).
  42. van Griensven J, Diro E. Visceral Leishmaniasis: Recent Advances in Diagnostics and Treatment Regimens. Infect Dis Clin North Am 2019; 33:79.
  43. Diro E, Blesson S, Edwards T, et al. A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia. PLoS Negl Trop Dis 2019; 13:e0006988.
  44. Burza S, Mahajan R, Kazmi S, et al. AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial. Clin Infect Dis 2022; 75:1423.
  45. Mahajan R, Das P, Isaakidis P, et al. Combination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in India. Clin Infect Dis 2015; 61:1255.
  46. Abongomera C, Diro E, de Lima Pereira A, et al. The initial effectiveness of liposomal amphotericin B (AmBisome) and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: A retrospective cohort study. PLoS Negl Trop Dis 2018; 12:e0006527.
  47. 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.
  48. Laguna F, López-Vélez 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; 13:1063.
  49. Meyerhoff A. U.S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999; 28:42.
  50. Sudarshan M, Weirather JL, Wilson ME, Sundar S. Study of parasite kinetics with antileishmanial drugs using real-time quantitative PCR in Indian visceral leishmaniasis. J Antimicrob Chemother 2011; 66:1751.
  51. Davidson RN, Di Martino L, Gradoni L, et al. Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med 1994; 87:75.
  52. Laguna F, Videla S, Jiménez-Mejías 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; 52:464.
  53. Russo R, Nigro LC, Minniti S, et al. Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin B (AmBisome). J Infect 1996; 32:133.
  54. Laguna F, Torre-Cisneros J, Moreno V, et al. Efficacy of intermittent liposomal amphotericin B in the treatment of visceral leishmaniasis in patients infected with human immunodeficiency virus. Clin Infect Dis 1995; 21:711.
  55. Sindermann H, Engel KR, Fischer C, et al. Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection. Clin Infect Dis 2004; 39:1520.
  56. Pintado V, Martín-Rabadán P, Rivera ML, et al. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine (Baltimore) 2001; 80:54.
  57. de la Rosa R, Pineda JA, 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; 32:633.
  58. Tortajada C, Pérez-Cuevas B, Moreno A, 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; 30:364.
  59. Abongomera C, Diro E, Vogt F, et al. The Risk and Predictors of Visceral Leishmaniasis Relapse in Human Immunodeficiency Virus-Coinfected Patients in Ethiopia: A Retrospective Cohort Study. Clin Infect Dis 2017; 65:1703.
  60. Verrest L, Kip AE, Musa AM, et al. Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa. Clin Infect Dis 2021; 73:775.
  61. Alvar J, Cañavate C, Gutiérrez-Solar B, et al. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997; 10:298.
  62. Ribera E, Ocaña I, de Otero J, et al. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients. Am J Med 1996; 100:496.
  63. López-Vélez R, Videla S, Márquez 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; 53:540.
  64. Mira 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; 70:298.
  65. Casado JL, Lopez-Velez R, Pintado V, et al. Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy. Eur J Clin Microbiol Infect Dis 2001; 20:202.
  66. Goswami RP, Goswami RP, Basu A, et al. Protective Efficacy of Secondary Prophylaxis Against Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients Over the Past 10 Years in Eastern India. Am J Trop Med Hyg 2017; 96:285.
  67. Meinecke CK, Schottelius J, Oskam L, Fleischer B. Congenital transmission of visceral leishmaniasis (Kala Azar) from an asymptomatic mother to her child. Pediatrics 1999; 104:e65.
  68. Gradoni L, Gaeta GB, Pellizzer G, et al. Mediterranean visceral leishmaniasis in pregnancy. Scand J Infect Dis 1994; 26:627.
  69. Pagliano P, Carannante N, Rossi M, et al. Visceral leishmaniasis in pregnancy: a case series and a systematic review of the literature. J Antimicrob Chemother 2005; 55:229.
  70. Utili R, Rambaldi A, Tripodi MF, Andreana A. Visceral leishmaniasis during pregnancy treated with meglumine antimoniate. Infection 1995; 23:182.
  71. Sundar S, Sinha P, Jha TK, et al. Oral miltefosine for Indian post-kala-azar dermal leishmaniasis: a randomised trial. Trop Med Int Health 2013; 18:96.
  72. Ghosh S, Das NK, Mukherjee S, et al. Inadequacy of 12-Week Miltefosine Treatment for Indian Post-Kala-Azar Dermal Leishmaniasis. Am J Trop Med Hyg 2015; 93:767.
  73. Ramesh V, Singh R, Avishek K, et al. Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India. PLoS Negl Trop Dis 2015; 9:e0004093.
  74. Zijlstra EE, Musa AM, Khalil EA, et al. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis 2003; 3:87.
  75. Thakur CP, Kumar K, Sinha PK, et al. Treatment of post-kala-azar dermal leishmaniasis with sodium stibogluconate. Br Med J (Clin Res Ed) 1987; 295:886.
  76. Thakur CP, Narain S, Kumar N, et al. Amphotericin B is superior to sodium antimony gluconate in the treatment of Indian post-kala-azar dermal leishmaniasis. Ann Trop Med Parasitol 1997; 91:611.
  77. Musa AM, Khalil EA, Mahgoub FA, et al. Efficacy of liposomal amphotericin B (AmBisome) in the treatment of persistent post-kala-azar dermal leishmaniasis (PKDL). Ann Trop Med Parasitol 2005; 99:563.
  78. Abongomera C, Gatluak F, Buyze J, Ritmeijer K. A Comparison of the Effectiveness of Sodium Stibogluconate Monotherapy to Sodium Stibogluconate and Paromomycin Combination for the Treatment of Severe Post Kala Azar Dermal Leishmaniasis in South Sudan - A Retrospective Cohort Study. PLoS One 2016; 11:e0163047.
  79. den Boer M, Das AK, Akhter F, et al. Safety and Effectiveness of Short-Course AmBisome in the Treatment of Post-Kala-Azar Dermal Leishmaniasis: A Prospective Cohort Study in Bangladesh. Clin Infect Dis 2018; 67:667.
  80. Moulik S, Chaudhuri SJ, Sardar B, et al. Monitoring of Parasite Kinetics in Indian Post-Kala-azar Dermal Leishmaniasis. Clin Infect Dis 2018; 66:404.
  81. Ramesh V, Dixit KK, Sharma N, et al. Assessing the Efficacy and Safety of Liposomal Amphotericin B and Miltefosine in Combination for Treatment of Post Kala-Azar Dermal Leishmaniasis. J Infect Dis 2020; 221:608.
  82. 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.
  83. Bern C, Haque R, Chowdhury R, et al. The epidemiology of visceral leishmaniasis and asymptomatic leishmanial infection in a highly endemic Bangladeshi village. Am J Trop Med Hyg 2007; 76:909.
  84. Sundar S, Rai M. Laboratory diagnosis of visceral leishmaniasis. Clin Diagn Lab Immunol 2002; 9:951.
  85. Boelaert M, El-Safi S, Hailu A, et al. Diagnostic tests for kala-azar: a multi-centre study of the freeze-dried DAT, rK39 strip test and KAtex in East Africa and the Indian subcontinent. Trans R Soc Trop Med Hyg 2008; 102:32.
  86. Mollett G, Bremer Hinckel BC, Bhattacharyya T, et al. Detection of Immunoglobulin G1 Against rK39 Improves Monitoring of Treatment Outcomes in Visceral Leishmaniasis. Clin Infect Dis 2019; 69:1130.
  87. Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des 2002; 8:319.
  88. Lazanas MC, Tsekes GA, Papandreou S, et al. Liposomal amphotericin B for leishmaniasis treatment of AIDS patients unresponsive to antimonium compounds. AIDS 1993; 7:1018.
  89. Torre-Cisneros J, Villanueva JL, Kindelan JM, et al. Successful treatment of antimony-resistant visceral leishmaniasis with liposomal amphotericin B in patients infected with human immunodeficiency virus. Clin Infect Dis 1993; 17:625.
  90. Adler-Moore J, Proffitt RT. AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother 2002; 49 Suppl 1:21.
  91. Adler-Moore J, Proffitt RT. Effect of tissue penetration on AmBisome efficacy. Curr Opin Investig Drugs 2003; 4:179.
  92. Davidson RN, di Martino L, Gradoni L, et al. Short-course treatment of visceral leishmaniasis with liposomal amphotericin B (AmBisome). Clin Infect Dis 1996; 22:938.
  93. di Martino L, Davidson RN, Giacchino R, et al. Treatment of visceral leishmaniasis in children with liposomal amphotericin B. J Pediatr 1997; 131:271.
  94. Syriopoulou V, Daikos GL, Theodoridou M, et al. Two doses of a lipid formulation of amphotericin B for the treatment of Mediterranean visceral leishmaniasis. Clin Infect Dis 2003; 36:560.
  95. Berman JD, Badaro R, Thakur CP, et al. Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries. Bull World Health Organ 1998; 76:25.
  96. Seaman J, Mercer AJ, Sondorp HE, Herwaldt BL. Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under wartime conditions and with limited resources. Ann Intern Med 1996; 124:664.
  97. Sundar S, Jha TK, Thakur CP, et al. Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study. Am J Trop Med Hyg 2002; 66:143.
  98. Thakur CP. A single high dose treatment of kala-azar with Ambisome (amphotericin B lipid complex): a pilot study. Int J Antimicrob Agents 2001; 17:67.
  99. Thakur CP, Pandey AK, Sinha GP, et al. Comparison of three treatment regimens with liposomal amphotericin B (AmBisome) for visceral leishmaniasis in India: a randomized dose-finding study. Trans R Soc Trop Med Hyg 1996; 90:319.
  100. Gradoni L, Gramiccia M, Scalone A. Visceral leishmaniasis treatment, Italy. Emerg Infect Dis 2003; 9:1617.
  101. Kafetzis DA, Velissariou IM, Stabouli S, et al. Treatment of paediatric visceral leishmaniasis: amphotericin B or pentavalent antimony compounds? Int J Antimicrob Agents 2005; 25:26.
  102. Sundar S, Jha TK, Thakur CP, et al. Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study. Clin Infect Dis 2003; 37:800.
  103. Sundar S, Chakravarty J, Agarwal D, et al. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010; 362:504.
  104. World Health Organization. Report of a WHO Informal Consultation on Liposomal Amphotericin B in the Treatment of Visceral Leishmaniasis, Rome, Italy, April 2005. WHO/CDS/NTD/IDM/2007.4 Geneva: WHO, 2007.
  105. Mondal D, Alvar J, Hasnain MG, et al. Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: a feasibility study. Lancet Glob Health 2014; 2:e51.
  106. Walsh TJ, Goodman JL, Pappas P, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001; 45:3487.
  107. Sundar S, Chakravarty J, Rai VK, et al. Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions. Clin Infect Dis 2007; 45:556.
  108. Sundar S, Singh A, Agarwal D, et al. Safety and efficacy of high-dose infusions of a preformed amphotericin B fat emulsion for treatment of Indian visceral leishmaniasis. Am J Trop Med Hyg 2009; 80:700.
  109. den Boer M, Davidson RN. Treatment options for visceral leishmaniasis. Expert Rev Anti Infect Ther 2006; 4:187.
  110. Ritmeijer K, Veeken H, Melaku Y, et al. Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome. Trans R Soc Trop Med Hyg 2001; 95:668.
  111. Veeken H, Ritmeijer K, Seaman J, Davidson R. A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan. Trop Med Int Health 2000; 5:312.
  112. Moore E, O'Flaherty D, Heuvelmans H, et al. Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya. Bull World Health Organ 2001; 79:388.
  113. Rijal S, Chappuis F, Singh R, et al. Sodium stibogluconate cardiotoxicity and safety of generics. Trans R Soc Trop Med Hyg 2003; 97:597.
  114. Sundar S, Sinha PR, Agrawal NK, et al. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 1998; 59:139.
  115. Frézard F, Demicheli C, Ribeiro RR. Pentavalent antimonials: new perspectives for old drugs. Molecules 2009; 14:2317.
  116. Baiocco P, Colotti G, Franceschini S, Ilari A. Molecular basis of antimony treatment in leishmaniasis. J Med Chem 2009; 52:2603.
  117. Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46:296.
  118. Chulay JD, Spencer HC, Mugambi M. Electrocardiographic changes during treatment of leishmaniasis with pentavalent antimony (sodium stibogluconate). Am J Trop Med Hyg 1985; 34:702.
  119. Gasser RA Jr, Magill AJ, Oster CN, et al. Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis. Clin Infect Dis 1994; 18:83.
  120. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19:111.
  121. Sundar S. Drug resistance in Indian visceral leishmaniasis. Trop Med Int Health 2001; 6:849.
  122. Centers for Disease Control and Prevention: Parasites - Leishmaniasis http://www.cdc.gov/parasites/leishmaniasis/health_professionals/index.html#tx-vl (Accessed on March 25, 2014).
  123. Monge-Maillo B, López-Vélez R. Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clin Infect Dis 2015; 60:1398.
  124. Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002; 347:1739.
  125. Sundar S, Jha TK, Sindermann H, et al. Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 2003; 22:434.
  126. Bhattacharya SK, Sinha PK, Sundar S, et al. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 2007; 196:591.
  127. Rijal S, Ostyn B, Uranw S, et al. Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis 2013; 56:1530.
  128. Sundar S, Singh A, Rai M, et al. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis 2012; 55:543.
  129. Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ. Optimal dosing of miltefosine in children and adults with visceral leishmaniasis. Antimicrob Agents Chemother 2012; 56:3864.
  130. 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.
  131. Mbui J, Olobo J, Omollo R, et al. Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial. Clin Infect Dis 2019; 68:1530.
  132. Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for the treatment of Indian visceral leishmaniasis. Trans R Soc Trop Med Hyg 2006; 100 Suppl 1:S26.
  133. Sundar S, Murray HW. Availability of miltefosine for the treatment of kala-azar in India. Bull World Health Organ 2005; 83:394.
  134. Pandey BD, Pandey K, Kaneko O, et al. Relapse of visceral leishmaniasis after miltefosine treatment in a Nepalese patient. Am J Trop Med Hyg 2009; 80:580.
  135. Davidson RN, den Boer M, Ritmeijer K. Paromomycin. Trans R Soc Trop Med Hyg 2009; 103:653.
  136. Jha TK, Olliaro P, Thakur CP, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 1998; 316:1200.
  137. Sundar S, Jha TK, Thakur CP, et al. Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med 2007; 356:2571.
  138. Thakur CP, Kanyok TP, Pandey AK, et al. A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 2000; 94:429.
  139. Chunge CN, Owate J, Pamba HO, Donno L. Treatment of visceral leishmaniasis in Kenya by aminosidine alone or combined with sodium stibogluconate. Trans R Soc Trop Med Hyg 1990; 84:221.
  140. Melaku Y, Collin SM, Keus K, et al. Treatment of kala-azar in southern Sudan using a 17-day regimen of sodium stibogluconate combined with paromomycin: a retrospective comparison with 30-day sodium stibogluconate monotherapy. Am J Trop Med Hyg 2007; 77:89.
  141. Jhingran A, Chawla B, Saxena S, et al. Paromomycin: uptake and resistance in Leishmania donovani. Mol Biochem Parasitol 2009; 164:111.
  142. Bryceson A. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health 2001; 6:928.
  143. Seaman J, Pryce D, Sondorp HE, et al. Epidemic visceral leishmaniasis in Sudan: a randomized trial of aminosidine plus sodium stibogluconate versus sodium stibogluconate alone. J Infect Dis 1993; 168:715.
  144. Sundar S, Rai M, Chakravarty J, et al. New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis 2008; 47:1000.
  145. Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 2011; 377:477.
Topic 5710 Version 44.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟