Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial

Abstract

BackgroundThere is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.MethodsA multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.Results378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).ConclusionsDue to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.Trial registrationClinicalTrials.gov NCT01310738

The direct costs of treating human visceral leishmaniasis in Brazil

“…In Brazil, the Ministry of Health (MH) recommends the following drugs for VL treatment: N-methylglucamine antimoniate, amphotericin B deoxycholate, and liposomal amphotericin B. N-methylglucamine antimoniate has an efficacy of 83.1-96.9% [4][5][6][7] , and is recommended as the first-line treatment for VL, despite its recognized toxicity 8 . Amphotericin B deoxycholate, which is the second choice for the VL treatment is also highly toxic.…”

“…Its estimated efficacy ranges from 85.0-90.0% 8,9 . Romero et al 6 conducted a randomized clinical study trial in Brazil and observed high toxicity in patients treated with amphotericin B deoxycholate, which led to the discontinuation of that arm of the study. Liposomal amphotericin B is indicated for patients with severe disease, those presenting comorbidities or immunodeficiencies, pregnant women, and those with renal or cardiac toxicity caused by the first-and second-line VL drugs 10 .…”

“…Liposomal amphotericin B is indicated for patients with severe disease, those presenting comorbidities or immunodeficiencies, pregnant women, and those with renal or cardiac toxicity caused by the first-and second-line VL drugs 10 . Liposomal amphotericin B has strong leishmanicidal activity, and its estimated efficacy varies between 62.0-91.2% 6,11 .…”

Treatment for human visceral leishmaniasis: a cost‐effectiveness analysis for Brazil

“…Our decision‐making models were constructed with epidemiological parameters with a high level of evidence, since they came from a multicenter, randomised, open‐label trial that assessed the efficacy and safety of the drugs used for the treatment of VL in Brazil . Regarding the costs, the study used data that reflect the Brazilian reality, as they were obtained from a the cost‐of‐illness study of VL care in Brazil, that used data from national official information systems .…”

“…In this study, treatment with the drug AMBD was not considered, since, although it is available at SUS, it is only intended for patients who cannot be treated with MA or LAMB [10]. Incidentally, the therapeutic arm evaluating AMBD in the study by Romero et al (2017) was suspended following the recommendation of the data safety monitoring board due to safety issues [10]. Also, the evidence on efficacy and safety of AMDB in Brazil is restricted to one clinical trial comparing AMBD with MA in children aged 6 months to 12 years [11].…”