Low Antileishmanial Drug Exposure In Hiv-Positive Visceral Leishmaniasis Patients On Antiretrovirals: An Ethiopian Cohort Study

Background: Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown.Methods: HIV-VL co-infected patients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC-MS/MS.Results: Median (IQR) amphotericin B C-max on Day 1 was 24.6 mu g/mL (17.0-34.9 mu g/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) mu g/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) mu g/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz C-min was below the 1 mu g/mL therapeutic target for many patients.Conclusions: This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infected VL patients. Amphotericin B C-max was 2-fold lower than previously observed in non-VL patients. Miltefosine exposure in HIV-VL co-infected patients was 35% lower compared with adult VL patients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infected patients is especially important given the high proportion of relapses.