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

Abstract

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. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45-87%) in the unadjusted analysis, and 50% (95% CI 27-73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67-90%) and 67% (95% CI 48-82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32-78%) in the monotherapy arm, and 88% (95% CI 79-98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication.

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.

Fig 1. Treatment strategy.

Fig 2. Sequential analysis.

The vertical axis, (Z), is the number of observed treatment successes minus the number of expected successes. The higher the value represented on that vertical axis, the more favorable (better efficacy observed). The horizontal axis (V) is proportional to the number of patients who, over time, have been evaluated at day 29. Hence, over time, each arm’s data points extend to the right. Each arm starts inside the triangle (green area) and recruitment is stopped on crossing either the upper (blue area) or the lower boundary (pink area). Recruitment to the AmBisome monotherapy arm was stopped after the first interim analysis (I1) and to the combination arm after the second interim analysis (I2). Also shown are the final results for each arm, including those who had not reached the primary endpoint (day29) when the interim analysis was performed and the recruitment was stopped. These final results take the trajectory of each arm well away from the triangular boundary, which is known as ‘over-run'. The two numbers after each label are the numbers of patients included in that analysis and the number of these with treatment success at day 29.

Fig 3. Trial participant flow.

Fig 4. CD4-cell counts at baseline (D0), D29 and D58.

Categories are Cat 1 = <50, Cat 2 = 50–99, Cat 3 = 100–199, Cat 4 = 200–349, Cat 5 = ≥350 cells/μl. (A) AmBisome monotherapy arm (B) AmBisome+miltefosine combination arm.