A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia

Background: Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment. Methodology/Principal findings: An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Conclusions/Significance: The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa. Trial registration number: www.clinicaltrials.gov NCT02011958. Author summary: Visceral Leishmaniasis is a complex parasitological disease and is particularly challenging to treat in patients coinfected with human immunodeficiency virus (HIV). Antimonial drugs used in first-line treatments for immunocompetent patients in eastern Africa are more toxic in immunocompromised patients. In 2010, a WHO expert committee recommended a lipid formulation of amphotericin B as first line treatment for HIV/VL co-infected patients, based on a single clinical trial conducted in Spain and empirical information obtained from scattered case reports using AmBisome (liposomal amphotericin B). In addition, Médecins Sans Frontières began a compassionate use regimen combining AmBisome and miltefosine a in a treatment centre in Northwest Ethiopia with encouraging results. Here, we report the results of a trial to assess the efficacy and safety of both the currently internationally recommended treatment of AmBisome monotherapy and the new AmBisome-miltefosine combination regimen, in Ethiopian patients. The results of this trial show that one course of treatment with either regimen could be insufficient to clear parasites in a high proportion of patients and that an extended treatment strategy, of administrating a second course of treatment, could lead to a high parasite clearance rate in patients treated with the combination regimen.