Drug regimens for visceral leishmaniasis in Mediterranean countries

Until the early 1990s, pentavalent antimony was the only documented first-line drug employed for the treatment of zoonotic visceral leishmaniasis (VL) in the Mediterranean, with reported cure rates exceeding 95% in immunocompetent patients. The emergence of antimony resistance in other endemic settings and the increase in drug options have stimulated re-evaluation of the current therapeutic approaches and outcomes in Mediterranean countries. A scientific consortium ('LeishMed' network) collected updated information from collaborating clinical health centres of 11 endemic countries of Southern Europe, Northern Africa and the Middle East. In contrast with the previous situation, VL is now treated differently in the region, basically through three approaches: (1) In Northern Africa and in part of the Middle East, pentavalent antimony is still the mainstay for therapy, with no alternative drug options for treating relapses; (2) In some European countries and Israel, both pentavalent antimony and lipid-associated amphotericin B (AmB) formulations are used as first-line drugs, although in different patients' categories; (3) In other countries of Europe, mainly liposomal AmB is employed. Importantly, cure rates exhibited by different drugs, including antimonials in areas where they are still in routine use, are similarly high (>/=95%) in immunocompetent patients. Our findings show that antimony resistance is not an emerging problem in the Mediterranean. A country's wealth affects the treatment choice, which represents a balance between drug efficacy, toxicity and cost, and costs associated with patient's care.     

Successful treatment of cutaneous leishmaniasis with lipid formulations of amphotericin B in two immunocompromised patients

Pentavalent antimonial drugs are habitually the first choice for treating leishmaniasis, although they possess well-known toxicity and may present some therapeutic failure. Lipid formulations of amphotericin B (LFAB) have been increasingly used for treating several types of leishmaniasis. However, the administration of such lipid formulations specifically to patients with cutaneous leishmaniasis (CL) is still rare, including immunocompromised patients to whom standard treatments are more frequently contraindicated. We describe here two cases of immunocompromised patients with CL, one of them with AIDS, representing the first case of AIDS and CL co-infection treated with LFAB described in the literature. The patient achieved therapeutic success with a total 1.500 mg dose of amphotericin B colloidal dispersion. The other had diabetes mellitus as well as kidney failure and was under dialysis, having obtained the healing of lesion with a total dose of 600 mg of liposomal amphotericin B. Thus, the authors suggest that LFAB can represent a safe, efficient and less toxic therapeutic alternative to pentavalent antimonials, as well as to the so-called second line drugs, pentamidine and amphotericin B deoxycholate.     

Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study Group.

BACKGROUND: Visceral leishmaniasis is common in patients with HIV infection living in endemic areas, but the most effective and safe treatment remains unknown. OBJECTIVE: To compare the efficacy and safety of meglumine antimoniate versus amphotericin B in HIV-infected patients with first episodes of visceral leishmaniasis (VL). DESIGN: An open, multicentre, prospective and randomized trial. SETTING: Twelve tertiary hospitals. PATIENTS: Eighty-nine consecutive HIV-infected patients diagnosed with VL. Patients were randomly assigned to treatment with either meglumine antimoniate (20 mg pentavalent antimony per kilogram of body weight per day) or amphotericin B (0.7 mg/kg per day) both for 28 days. Treatment was considered successful if a bone marrow aspirate performed 1 month after the end of therapy did not detect parasites. Relapse was defined as the reappearance of parasites after an initial cure. RESULTS: An initial cure was attained in 29 of 44 patients (65.9%) randomly assigned to treatment with meglumine antimoniate and 28 of 45 (62.2%) randomly assigned to treatment with amphotericin B. The incidence of moderate to severe adverse events was similar in both groups. The patients treated with meglumine antimoniate had higher incidences of cardiotoxicity (14 versus 0%, P = 0.02) and chemical pancreatitis (30 versus 0%, P < 0.01). However, in the amphotericin B group, nephrotoxicity was more frequent (36 versus 5%, P < 0.01). There was no difference in survival or relapse-free interval according to the allocated group of therapy. CONCLUSION: Treatment of VL with meglumine antimoniate or amphotericin B was shown to have similar efficacy and toxicity rates in Spanish HIV-infected patients. The differences in the toxicity patterns could be useful in choosing one of these agents as first-line treatment.     

Oral miltefosine treatment in children with visceral leishmaniasis: a brief review.

Visceral leishmaniasis (VL) or kala-azar is an infection disease caused by hemiflagellate protozoan parasites (Leishmania donovani) and transmitted to humans by the phlebotomine sandfly. Leishmaniasis is distributed worldwide and 13 million people are estimated to be infected, with about 1.8 million new cases each year. All antileishmanial drugs are toxic and most have to be used parenterally for prolonged period. The therapy has been further complicated by large number of infected children and declining effectiveness of pentavalent antimonial compounds. Although the lipid formulations of amphotericin B are an important advance in therapy, their high cost precludes their use. Miltefosine, a phosphocholine analogue originally developed as antimalignant drug, has been found to be highly active against Leishmania in vitro and in animal model. Based on these experiences this drug was tried against human visceral leishmaniasis and found to be highly effective in children. The aim of this review is to evidence the pharmacodymamic and pharmacokinetic characteristics and the safety, tolerance and efficacy of this drug for treatment of visceral leishmaniasis in children.     

Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome).

Visceral leishmaniasis (VL) is a rare disease in renal transplant recipients. Liposomal amphotericin B (AmBisome) is known to be effective against VL. However, previously there has been no experience with administration of such treatment to renal transplant recipients. We report herein four patients with VL complicating renal transplantation who were treated successfully with liposomal amphotericin B (total dose, 23-40 mg/kg). Neither adverse reactions nor clinical relapses of VL were observed.     

Comparison of the efficacy and pharmacology of formulations of amphotericin B used in treatment of leishmaniasis

PURPOSE OF REVIEW: Several lipid-based formulations of the antifungal and antiparasitic drug amphotericin B are now available on the market. The purpose of this review is to assess their efficacy against leishmaniasis in both experimental and clinical settings, and to point out new developments in the formulation of this antibiotic. RECENT FINDINGS: The development of resistance to pentavalent antimony compounds has shifted the emphasis to amphotericin B for the treatment of visceral leishmaniasis in India. Lipid formulations show good efficacy but are expensive. The treatment period with lipid formulations is shorter, however, which reduces hospitalization costs. As a result, in developed countries where these costs are an important proportion of the treatment, lipid formulations are preferred, whereas they remain largely inaccessible in developing countries. Lipid-associated amphotericin B has been found to be effective for secondary prophylaxis in HIV-positive patients, in studies carried out in European countries bordering the Mediterranean. SUMMARY: The reduced toxicity of lipid-based formulations of amphotericin B is no longer in doubt. In India, their efficacy against visceral leishmaniasis and shorter treatment periods compared with the conventional formulation with deoxycholate has to be counter-balanced against the very high cost. By contrast, in developed countries around the Mediterranean, where leishmaniasis occurs mainly in immunocompromised individuals, lipid formulations have become the treatment of choice for visceral disease. The efficacy against cutaneous lesions is variable, however, and in some reports oral miltefosine was active after failure of treatment with amphotericin B.     

Risk factors for in-hospital mortality of visceral leishmaniasis patients in eastern Uganda

Objective  To identify risk factors for in-hospital mortality in patients treated for visceral leishmaniasis (VL) in Uganda.
Methods  Retrospective analysis of VL patients' clinical data collected for project monitoring by Médecins Sans Frontières in Amudat, eastern Uganda.
Results  Between 2000 and 2005, of 3483 clinically suspect patients, 53% were confirmed with primary VL. Sixty-two per cent were children <16 years of age with a male/female ratio of 2.2. The overall case-fatality rate during pentavalent antimonial ( n  = 1641) or conventional amphotericin B treatment ( n  = 217) was 3.7%. There was no difference in the case-fatality rate between treatment groups ( P  > 0.20). The main risk factors for in-hospital death identified by a multivariate analysis were age <6 years and >15 years, concomitant tuberculosis or hepatopathy, and drug-related adverse events. The case-fatality rate among patients >45 years of age was strikingly high (29.0%).
Conclusion  Subgroups of VL patients at higher risk of death during treatment with drugs currently available in Uganda were identified. Less toxic drugs should be evaluated and used in these patients.     

Short-Course Treatment Regimen of Indian Visceral Leishmaniasis with an Indian Liposomal Amphotericin B Preparation (Fungisome?)

India bears the burden of about half of global visceral leishmaniasis (VL) cases with emerging problems of stibanate resistance. Liposomal preparations have improved treatment outcome through shorter duration of therapy and lower toxicity compared with conventional amphotericin B. We report the efficacy of two short-course regimens of an Indian preparation of liposomal amphotericin B (Fungisome™) for VL caused by Leishmania donovani in India. An open-label, randomized, single-center comparative study was undertaken from 2008 to 2011, involving 120 treatment naive non–human immunodeficiency virus VL patients randomly allocated to two groups. Fungisome™ was given, in groups A (N = 60), 5 mg/kg daily for 2 days and B (N = 60), 7.5 mg/kg daily for 2 days, as intravenous infusion. Initial cure rate was 100% in both the groups after 1 month posttreatment. At 6 months after completion of treatment, definitive cure rate was group A 90% (54/60, 95% confidence interval (CI): 80.55–95.72%); group B: 100% (95% CI: 95.92–100%); (P = 0.027). No serious adverse events occurred in either group. The short-course, 2-day regimen of 15 mg/kg Fungisome™ infusion is easy to administer, effective, and safe for treatment of VL caused by L. donovani in India.     

Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis

Treatment options for cutaneous leishmaniasis in the United States are problematic because the available products are either investigational, toxic, and/or of questionable effectiveness. A retrospective review of patients receiving liposomal amphotericin B through the Walter Reed Army Medical Center for the treatment of cutaneous leishmaniasis during 2007-2009 was conducted. Twenty patients who acquired disease in five countries and with five different strains of Leishmania were treated, of whom 19 received a full course of treatment. Sixteen (84%) of 19 experienced a cure with the initial treatment regimen. Three patients did not fully heal after an initial treatment course, but were cured with additional dosing. Acute infusion-related reactions occurred in 25% and mild renal toxicity occurred in 45% of patients. Although the optimum dosing regimen is undefined and the cost and toxicity may limit widespread use, liposomal amphotericin B is a viable treatment alternative for cutaneous leishmaniasis.     

Visceral leishmaniasis in those infected with HIV: clinical aspects and other opportunistic infections

Cases of visceral leishmaniasis (VL) in HIV-positive individuals have been reported from most areas of the world where the geographical distributions of the two infections overlap. The majority of the co-infected cases that have been recorded, however, live around the Mediterranean basin. In these subjects, the length of the incubation period of VL is presumably very short, particularly in those who have severe immunodepression. At diagnosis, almost all cases of VL/HIV co-infection have been found to have fewer than 200 CD4+ cells/microl blood, and about 50% meet the AIDS-defining criteria during their first episode of VL. The clinical manifestations of VL in HIV-infected individuals may be similar to those seen in HIV-negative cases; fever, pancytopenia and hepato-splenomegaly, for example, are found in 75% of all the HIV-positive cases. Following the dissemination of the parasites, however, the HIV-positive cases may develop unusual, multi-organ pathology. Almost all the cases of co-infection are very prone to VL relapses, even after carefully managed antileishmanial treatment. The opportunistic infections that are often seen in HIV-positives frequently develop during VL episodes, the signs and symptoms of the leishmaniasis then confusingly overlapping with those of the other infections.     

Leishmaniasis among organ transplant recipients

Leishmaniasis is a rarely reported disease among transplant recipients; however, the number of published cases has quadrupled since the beginning of the 1990s. Most cases have been observed in patients living in countries of the Mediterranean basin. Leishmaniasis is most commonly associated with kidney transplantation (77%), and cases are also recorded among patients undergoing liver, heart, lung, pancreas, and bone marrow transplantation. Visceral leishmaniasis (VL) is the most frequently observed clinical presentation, followed by mucosal leishmaniasis and more rarely cutaneous leishmaniasis. Transplant recipients with VL develop the classic clinical form of the disease, which is a febrile hepatosplenic and pancytopenic syndrome. Immunodepression seems to predispose to development of mucosal leishmaniasis caused by viscerotropic strains. Early diagnosis of VL is crucial for patient therapy and outcome; however, this is frequently overlooked or delayed in transplant patients. Pentavalent antimonials are the most commom form of treatment for VL, but have a high incidence of toxicity (34%). Although used in fewer patients, liposomal amphotericin B seems to be better tolerated and should be considered as first-line therapy in transplant recipients.     

Leishmaniasis in the United States: treatment in 2012

Although civilian physicians in the United States seldom encounter patients with leishmaniasis, therapeutic advances in endemic regions have opened the door to approaches that can be applied in this country. Advances revolve around the use of oral miltefosine in all forms of leishmaniasis and the use of short-course intravenous liposomal amphotericin B in visceral and possibly cutaneous infection. Lengthy, traditional intravenous treatment with pentavalent antimony (sodium stibogluconate) still has a role in the United States; however, although expensive, miltefosine and liposomal amphotericin B are considerably more appealing selections for initial therapy.     

Drug resistance in Indian visceral leishmaniasis

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.     

Rapid clearance of circulating Leishmania kinetoplast DNA after treatment of visceral leishmaniasis

With the aim of evaluating the utility of the detection of Leishmania kDNA in peripheral blood for the cure assessment of visceral leishmaniasis (VL), a PCR based method was performed in patients with confirmed VL at three follow-up periods after specific chemotherapy with pentavalent antimonial. In 16 out of 17 (94.1%) patients with pre-treatment detectable kDNA that were clinically cured, the PCR turned negative up to 37 days after the initiation of treatment, remaining negative over 90 days after treatment. The clearance of Leishmania kDNA from peripheral blood of patients with VL hints to occur during or shortly after treatment concurring or preceding clinical recovery.     

Long-term remission of human immunodeficiency virus-associated visceral leishmaniasis after initiation of potent combination antiretroviral treatment: report of two cases

We describe two cases of human immunodeficiency virus-infected patients with visceral leishmaniasis in whom no clinical and parasitological disease relapses were observed after liposomal amphotericin B therapy combined with potent antiretroviral treatment.     

USEFULNESS OF kDNA PCR IN THE DIAGNOSIS OF VISCERAL LEISHMANIASIS REACTIVATION IN CO-INFECTED PATIENTS

SUMMARY

It is important to develop new methods for diagnosing relapses in the co-infection of visceral leishmaniasis (VL) and HIV to enable earlier detection using less invasive methods. We report a case of a co-infected patient who had relapses after VL treatment, where the qualitative kDNA PCR showed a good performance. The kDNA PCR seems to be a useful tool for diagnosing VL and may be a good marker for predicting VL relapses after treatment of co-infected patients with clinical symptoms of the disease.     

A species-specific approach to the use of non-antimony treatments for cutaneous leishmaniasis

We used a species-specific approach to treat 10 patients with cutaneous leishmaniasis diagnosed using polymerase chain reaction. Non-antimony treatments (oral miltefosine, ketoconazole, and liposomal amphotericin B) were chosen as an alternative to pentavalent antimony drugs based on likely or proven drug efficacy against the infecting species. Leishmania Viannia panamensis was diagnosed in three patients and treated successfully with oral ketoconazole. Miltefosine treatment cured two patients with L. infantum chagasi. A wide variety of Leishmania responded to liposomal amphotericin B administered for 5-7 days. Three patients with L. V. braziliensis, one patient with L. tropica, and two patients with L. infantum chagasi were treated successfully. One person with L. V. braziliensis healed slowly because of a resistant bacterial superinfection, and a second patient with L. infantum chagasi relapsed and was retreated with miltefosine. These drugs were reasonably well-tolerated. In this limited case series, alternative non-antimony-based regimens were convenient, safe, and effective.     

Central nervous system toxicity associated with liposomal amphotericin B therapy for cutaneous leishmaniasis

AmBisome (liposomal amphotericin B) is used for prophylaxis and treatment of fungal infections, treatment of visceral leishmaniasis, and more recently, treatment of cutaneous leishmaniasis. Although the package insert cites neurologic toxicities in up to 20% of cases, review of the literature did not reveal any specific cases describing this side effect, particularly in a patient without comorbidities. We describe a healthy 38-year-old male treated with liposomal amphotericin B for cutaneous leishmaniasis acquired during military duties in Iraq. Shortly after completion of his treatment course, he reported memory difficulties and confusion. Further evaluation revealed no other source, and his cognitive issues were attributed to liposomal amphotericin B toxicity. These issues resolved over a few weeks, which is consistent with data about the drug's tissue penetration and metabolism available in the literature. This is a potential side effect of liposomal amphotericin B that can be observed in otherwise healthy patients.     

From the Cover: Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg⋅mL⁻¹ Pentostam compared with the control passage group (38.5 μg⋅mL⁻¹) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.Visceral leishmaniasis (VL) is a systemic illness caused by the obligate intracellular protozoan parasites Leishmania donovani and Leishmania infantum. The parasite, in amastigote form, multiplies within macrophages of the spleen, liver, and bone marrow causing fever, anorexia, weight loss, and hepatosplenomegaly (1). Effective chemotherapy for this condition is essential because untreated VL is fatal and accounts for 41,000 deaths per year (2). Currently, there are four main antileishmanial drugs available: antimonial preparations, amphotericin B, miltefosine, and paromomycin (3). Antimonial preparations have been used for almost a century and remain an essential part of the treatment of VL in South America and sub-Saharan Africa (2). However, by the end of the twentieth century, their efficacy in Bihar, which houses 90% of India’s large VL burden (4), had decreased to cure rates of less than 50% (5). Consequently, use of antimonial drugs is no longer recommended in the Indian subcontinent (6).The underlying reasons for this epidemic of resistance in Bihar are not fully understood. In our previous publication we proposed that the presence of arsenic in drinking water in Bihar has contributed to the gradual decline in efficacy of antimonial preparations for VL in this region (7). Subsequent to the 1970s, when there was a large-scale insertion of shallow tube wells to provide clean drinking water in India, it was found that the Bihari population was at risk from arsenic exposure due to contamination from naturally occurring trivalent arsenic in the groundwater accessed by these wells (8). The elements antimony and arsenic have a long therapeutic history, are closely related in the periodic table, and share many similar chemical properties (9). In the 1980s, when Leishmania antimonial resistance was first suspected, parasitologists used stepwise exposure to trivalent arsenic in the laboratory to induce antimonial cross-resistance and study mechanisms of resistance (10). Our hypothesis is that a similar selection process could occur in VL patients who have been chronically exposed to environmental arsenic, such that selection for parasite resistance to arsenic would result in cross-resistance to antimonial drugs.The incidence of arsenic contamination, VL, and antimonial resistance from all of the available data from surveys, journals, and Web sites was previously collated by our group (7). These data showed that in 10 out of 38 districts in Bihar, arsenic exposure, endemic VL, and reported antimonial resistance coexist. Thus, in these areas, arsenic contamination of the groundwater has the potential to contribute to the development of Leishmania parasite antimonial resistance, giving epidemiological plausibility to the hypothesis.In this study we test our hypothesis using a mouse model of arsenic exposure and chronic VL. Our findings demonstrate that Leishmania parasites resistant to pentavalent antimonials can be created through oral exposure to arsenic in drinking water of mice infected with L. donovani.     

Efficacy of second line drugs on antimonyl-resistant amastigotes of Leishmania infantum

In a previous paper we have demonstrated that the induction, by direct drug pressure, of a resistance to Sb(III) antimony at physiological concentration in the amastigote stage of the parasite, led to a high cross-resistance to Sb(V) species in the form of Glucantime. In this paper, further chemoresistant clones were characterized. Axenic amastigotes of Leishmania infantum were adapted to survive in culture medium containing 4, 20, 30 and 120 microg/ml of potassium antimonyl tartrate Sb(II). These mutants were 12, 28, 35 and 44-fold more resistant to Sb(III) than the parental wild-type clone. They were able to resist at concentrations of Glucantime Sb(V) as high as 160 microg/ml when growing in THP-1 cells. We have investigated the efficacy of second line drugs in clinical use (pentamidine and amphotericin B) on the antimony-resistant mutants. Amphotericin B was toxic for both wild-type and chemoresistant mutants at concentrations ranging from 0.05 to 0.15 microM. Pentamidine which is extensively used when the first course of antimonial pentavalent compounds is unsuccessful, was more toxic for all the chemoresistant organisms than for the wild-type clone. In the same way, chemoresistant amastigotes growing within THP-1 cells were more susceptible to pentamidine than the wild-type clone. Our results showed that the resistance of the mutants was restricted to the antimony containing drugs and did not led to a cross-resistance against the other clinically relevant drugs. These results confirmed that these two drugs (pentamidine and amphotericin B) are good candidates to treat pentavalent antimonial unresponsiveness.