Jaime Soto

Miltefosine for New World Cutaneous Leishmaniasis

The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala.

Topical Paromomycin/Methylbenzethonium Chloride Plus Parenteral Meglumine Antimonate as Treatment for American Cutaneous Leishmaniasis: Controlled Study

We determined the efficacy of the combination of the topical formulation 15% paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.

Primaquine Prophylaxis against Malaria in Nonimmune Colombian Soldiers: Efficacy and Toxicity: A Randomized, Double-Blind, Placebo-Controlled Trial

Malaria prophylaxis is required for nonimmune persons who enter malaria-endemic regions. Although mefloquine and doxycycline are highly effective for malaria prophylaxis [1], the actual or perceived toxicities of these drugs and the possibility of mefloquine resistance have prompted the evaluation of other prophylactic regimens. Fryauff and colleagues [2] investigated primaquine, a drug normally used to clear latent stages of Plasmodium vivax from the liver. In a 52-week study of persons who had recently immigrated to an endemic area of Indonesia, these investigators found that approximately 30 mg of primaquine per day was 95% protective against P. falciparum infection and 90% protective against P. vivax infection [2]. Because the indication for prophylaxis is to prevent disease in nonimmune travelers to all endemic regions, trials should be performed in persons in several regions of the world who are completely inexperienced with (that is, are not immune to) malaria. The clinical end point should be malaria (parasitemia plus symptoms) rather than parasitemia alone. We performed a randomized, double-blind, placebo-controlled clinical trial of primaquine prophylaxis against clinical malaria in nonimmune Colombian soldiers on patrol in a region in which P. falciparum and P. vivax malaria is endemic. Methods The study was performed between 18 April and 19 September 1997 in the province of Uraba, Colombia. Participants were 176 soldiers in the Colombian army. On specific questioning, all participants denied previous exposure to a malaria-endemic area. Eligible participants were male; were 18 to 42 years of age; did not have important medical problems as determined by history, physical examination, and routine laboratory tests (complete blood count and measurement of blood urea nitrogen, glutamic oxalacetic aminotransferase, and methemoglobin); and were not G6PD deficient (G6PDH Diagnostic Test, Sigma, St. Louis, Missouri). The study was conducted according to the regulations of the Colombian Army and was approved by the institutional review board of the Universidad Militar Nueva Granada. Written informed consent was required from all participants. Drug Administration Patients were randomly allocated to receive prophylaxis with primaquine diphosphate (two tablets of 15-mg base each, for a total of 30 mg/d) or matching placebo (two tablets) in a 2:1 allocation. Primaquine (Parmamed, Ltd., Malta) and placebo (Sanofi-Winthrop, New York, New York) were identical-looking brown-orange tablets obtained by the Colombian Ministry of Health. Investigators and participants were unaware of the randomization code and remained blinded to treatment group assignment throughout the study. On 16 May 1997, participants began 15 weeks of patrol in Mutapa, a malaria-endemic region of Uraba province, after which they returned to barracks duty in Carepa, a nonmalarial area. Prophylaxis (two tablets) was taken daily from 15 May, the day before patrol, during the 15 weeks of patrol, and for 7 days after the return to Carepa. Colombian soldiers on patrol have access only to items issued by their commanders and therefore could not acquire or take unauthorized antimalarial agents. Each day, immediately before a breakfast of coffee, bread, and, sometimes, an egg, the senior sergeant personally gave two tablets to each soldier from a bag labeled with the soldiers patient number and watched the soldier swallow the tablets. At the end of each week, the number of pills remaining in the bags was counted and recorded. Determination of Infection During the 15 weeks of exposure and for 4 weeks after the soldiers returned to the barracks, thick and thin smears were obtained weekly or sooner if participants had symptoms compatible with malaria infection. Giemsa-stained smears were read by a microscopist blinded to the symptom status of the participant. A smear was considered negative if no parasites were found in 200 fields of x1000 magnification. All positive smears were combined with two negative smears and were reread by a second microscopist blinded to participant status. Discordant readings were resolved by a third blinded reader in Bogota. There were no discordant readings for smears that resulted in study end points. Diagnosis of Malaria A participant was considered to have malaria if he had parasitemia of at least 1500 Plasmodia organisms/L or lesser parasitemia with at least two symptoms compatible with malaria (fever, headache, myalgia, nausea, vomiting, diarrhea, or icterus). Determination of Drug Toxicity Each day, participants were asked, Do you feel at all sick? Do you have any complaints? If the answer was no, questioning was stopped. If the answer was yes, the complaints were recorded. Toxicity was graded as severe if the side effects of the drug caused the participant to withdraw from the trial, moderate if the complaints resulted in some impairment of normal duty, and mild if duty was not impaired. Laboratory tests other than G6PD were repeated during 2 to 4 weeks of follow-up. End Points Study end points were prophylaxis failure, indicated by P. falciparum or P. vivax malaria, and withdrawal from the study because of severe drug toxicity, other medical reasons, or noncompliance (defined as missing more than 2 days of drug administration in any 2-week period). All end points and toxicity grades were assigned before the code was broken. Statistical Analysis Protective efficacy was based on the rate of disease. This rate was calculated by dividing the total number of cases by the total number of weeks during which the drug was administered (primaquine group, 2137 weeks; placebo group, 709 weeks). For each participant, the number of weeks of drug administration was the week of the study in which an end point was reached or the week just before an end point was reached. Protective efficacy was defined as 1 [(rate in primaquine group)/(rate in placebo group)]. Values are expressed as the estimate of efficacy with 95% CIs (calculated by using the method of Ederer and Mantel [3]). On the basis of assumptions of 50% incidence of malaria in the placebo group, 90% prophylactic efficacy of primaquine, a desired lower limit of confidence of the prophylactic efficacy of 70%, and a 2:1 allocation ratio, the sample size was approximately 120 participants in the primaquine group and 60 participants in the placebo group. Results Patient Characteristics One hundred seventy-nine volunteers were screened for this study. Because 3 volunteers declined to participate, 176 persons (mean age, 23.6 years) were enrolled. One hundred twenty-two (69%) participants were randomly allocated to the primaquine group and 54 (31%) were randomly allocated to the placebo group. Compliance and Withdrawal Of the 16 821 doses intended to be administered, 16 789 doses (99.8%) were observed by the senior sergeant to have been swallowed. A total of 32 pills were not taken by a total of 6 participants. Ten participants withdrew (Table 1). Table 1. Efficacy and Toxicity of Primaquine and Placebo* Efficacy The protective efficacy, based on the rate of all malaria, was 89% (95% CI, 75% to 96%). All patients had fever (temperature 38.3 C) and two to four of the other six symptoms of malaria (chills, headache, myalgia, nausea, vomiting, and icterus). The protective efficacy for P. falciparum infection was 94% (CI, 78% to 99%). Two participants in the primaquine group became parasitemic in week 6. Eleven participants who received placebo became parasitemic (2 in week 5, 1 in week 7, 2 in week 8, 1 in week 10, 3 in week 12, 1 in week 13, and 1 in week 14. The protective efficacy of primaquine against P. vivax infection was 85% (CI, 57% to 95%). Six participants in the primaquine group became parasitemic (2 in week 5, 2 in week 7, 1 in week 8, and 1 in week 17). Among participants who received placebo, 13 became parasitemic (3 in week 4, 2 in week 5, 1 in week 6, 1 in week 7, 1 in week 8, 2 in week 9, 1 in week 10, 1 in week 13, and 1 in week 18). Toxicity Three participants in the primaquine group (2.5% [CI, 0.2% to 5.2%]) had epigastric pain, abdominal pain, or vomiting of sufficient severity that they had to withdraw from the study. Six other participants in the primaquine group (5.0% [CI, 1.0% to 9.0%]) had mild or moderate gastrointestinal symptoms. In contrast, only one placebo recipient (2.0% [CI, 3.0% to 7.0%]) had mild gastrointestinal symptoms. Discussion Prophylaxis with primaquine, 30 mg/d, or placebo was administered to nonimmune Colombian soldiers on patrol in a malaria-endemic area. The treatments were begun 1 day before the start of patrol, were administered during the 15 weeks of patrol, and were continued for 1 week after return to base camp. Participants were followed for parasitemia and symptoms for the 16 weeks of drug administration and for 3 more weeks at base camp. The protective efficacy of primaquine was 89% against all types of malaria, 94% against P. falciparum malaria, and 85% against P. vivax malaria. Members of the military are tightly supervised. Troops that patrol malaria-endemic regions often come from malaria-free regions. Using participants in the military made it possible to fulfill our aims of conducting the trial according to exacting protocol conditions, adopting the clinically relevant criterion of disease as the end point, and performing the study in nonimmune persons who reflect the population requiring prophylaxis. Although primaquine was administered immediately before a modest breakfast, moderate gastrointestinal toxicity occurred. Our results contrast with the lack of increased gastrointestinal distress due to primaquine seen in other studies [2]. Other side effects of this regimen that are listed in the literature but were not evaluated in this study are an increase in methemoglobin value to a mean of 0.06% (range, 0.01% to 0.13%) without clinical manifestations [2] and, rarely, cases of leukopenia and arrhythmias [4]. Acute intravascular

Intralesional Antimony for Single Lesions of Bolivian Cutaneous Leishmaniasis

BACKGROUND Cutaneous leishmaniasis is an ultimately self-curing disease for which systemic therapy with pentavalent antimony (Sb) is effective but with side effects. We evaluated 2 local treatments, intralesional (IL) Sb and cryotherapy, for single lesions due to Bolivian Leishmania (v.) braziliensis in a placebo-controlled study. METHODS Patients were randomized between IL Sb (650 µg/mm(2) of lesion area on days 1, 3, and 5), cryotherapy (days 1 and 14), and placebo cream (daily for 20 days) in a 3:2:3 allocation. Lesion area was measured prior to therapy, and at 1, 3, and 6 months after therapy. The criteria for lesion cure were as follows: not doubling in size at 1 month, at least 50% diminution in size at 3 months, and complete reepithelialization at 6 months. Local adverse effects were recorded. RESULTS Cure rates were 21 of 30 (70%; 95% confidence interval [CI], 52%-83%) for IL Sb, 4 of 20 (20%; 95% CI, 8%-42%) for cryotherapy, and 5 of 30 (17%; 95% CI, 7%-34%) for placebo cream (P < .001 for IL Sb vs each other group). IL Sb adverse events were limited to injection site pain, with a mean value of 1.0 (mild). CONCLUSIONS The comparative cure rate, small amount of drug administered, and tolerance data for IL Sb suggest that if local therapy for single L. braziliensis lesions is chosen, this treatment is attractive. Given the difficulties of performing placebo-controlled trials in the New World, the combined placebo and cryotherapy cure rate (18%; 95% CI, 10%-31%) is likely to become the standard against which future interventions for L. braziliensis are compared. CLINICAL TRIALS REGISTRATION NCT01300975.

Double-blind, randomized, placebo-controlled assessment of chloroquine/ primaquine prophylaxis for malaria in nonimmune Colombian soldiers

To improve upon the efficacy of primaquine prophylaxis for malaria (94%, Plasmodium falciparum malaria; 85%, Plasmodium vivax malaria), we administered chloroquine (300 mg weekly) in combination with primaquine (30 mg daily) to nonimmune Colombian soldiers during 16 weeks of patrol in a region of endemicity and for a further 1 week in base camp. The occurrence of symptomatic parasitemia was determined during those 17 weeks and during a further 3 weeks in base camp. The protective efficacy for the chloroquine/primaquine treatment group of 100 subjects, compared with that for the placebo treatment group of 51 subjects, was 88% (95% confidence interval [CI], 76-94) against all types of malaria, 89% (95% CI, 61-97) against P. falciparum malaria, and 88% (95% CI, 58-93) against P. vivax malaria. Two chloroquine/primaquine recipients had severe gastrointestinal distress. Comparison of these data with data from a previous study indicates that the addition of chloroquine did not increase the prophylactic efficacy of primaquine.

Intralesional Pentamidine: A Novel Therapy for Single Lesions of Bolivian Cutaneous Leishmaniasis.

A novel therapy, intralesional (IL) pentamidine, was compared to intralesional therapy with antimony (ILSb), a World Health Organization-recommended therapy, for single Bolivian Leishmania braziliensis lesions. In Study 1, 90 patients were randomized equally between three injections of ILSb over 5 days, five injections of ILSb over 11 days, and three injections of IL pentamidine (120 μg/mm(2)lesion area [ILPenta-120-3]) over 5 days. Cure rates at 6 months were 57% for ILSb-3 injections, 73% for ILSb-5 injections, and 72% for ILPenta-120-3 injections. Adverse effects were local irritation and injection-site pain-ILSb (60 patients): mild (25), moderate (4); IL pentamidine (30 patients): mild (4), moderate (3). In Study 2, 60 patients were randomized equally between five injections of ILSb and three injections of a double dose of IL pentamidine (240 μg/mm(2)[ILPenta-240-3]). In Study 2, cure rates were 67% for ILSb-5 injections and 73% for ILPenta-240-3. For three IL injections of pentamidine, efficacy was optimized at a dose of 120 μg/mm(2)lesion area. The cure rate of that regimen was similar to that for ILSb-5 injections and nonstatistically larger than that of ILSb-3 injections. IL pentamidine is an attractive alternative to ILSb on the basis of efficacy for Bolivian L. braziliensis, the threat of Sb-resistant parasites, tolerance, and patient convenience of three visits over 5 days.

Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation

Introduction Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL). Materials and methods Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings. Results Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized. Conclusions The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments.

Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial

BACKGROUND Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION NCT03096457.

Miltefosine Combined with Intralesional Pentamidine for Leishmania braziliensis Cutaneous Leishmaniasis in Bolivia

Bolivian cutaneous leishmaniasis due to Leishmania braziliensis was treated with the combination of miltefosine (150 mg/day for 28 days) plus intralesional pentamidine (120 μg/mm2 lesion area on days 1, 3, and 5). Ninety-two per cent of 50 patients cured. Comparison to historic controls at our site suggests that the efficacy of the two drugs was additive. Adverse effects and cost were also additive. This combination may be attractive when a prime consideration is efficacy (e.g., in rescue therapy), avoidance of parenteral therapy, or the desire to treat locally and also provide systemic protection against parasite dissemination.