HIV co-infection is an important factor that impedes the elimination of visceral leishmaniasis. Uncontrolled HIV infection will unmask many asymptomatically infected individuals to develop VL and they also contribute to ongoing disease transmission. Higher doses of LipoAmpho B are typically required for the treatment of VL and HIV coinfection (30-40 mg/kg cumulative dose) and addition of miltefosine has some benefits based on two large retrospective data (CID. 2015;61(8):1255, PLoSNegl Trop Dis. 2014;8(6):e2869.). WHO recommends high dose (40 mg/kg) liposomal amphotericin as the first line of therapy. This RCT compared AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) among Ethiopian VL patients coinfected with HIV. It used a complicated sequential design which basically had flexible sample size which was titrated to the evolving data from the trial probably secondary to low number of patients with HIV VL coinfection. 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. 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. The rescue treatment in patients who did not respond was sodium stibogluconate and paromomycin combinationation therapy. The following schematic representation may explain the trial flow.
In short, most of the patients required an extended treatment with the trial drugs. The combination arm with Ambisome (30mg/kg) with miltefosine performed better overall. This trial has potential treatment implications – however the relative poor performance of high dose Ambisome is surprising. A similar trial is underway in the Indian setting as well.