Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 76, Issue 5, Pages 1258-1268Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkab013
Keywords
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Funding
- Drugs for Neglected Diseases initiative from the European Union Seventh Framework Programme [305178]
- Dutch Ministry of Foreign Affairs (DGIS), the Netherlands [PDP15CH21]
- Federal Ministry of Education and Research (BMBF through KfW), Germany
- Medicor Foundation, Liechtenstein [FL0001.526.038-3]
- Swiss Agency for Development and Cooperation (SDC), Switzerland [81017718]
- Dutch Research Council (NWO)/ZonMw Veni grant [91617140]
- Medecins Sans Frontieres/Doctors without Borders, International
- UK aid, UK [204075-101]
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This study found low antileishmanial drug exposure in HIV-VL co-infected patients, with correlated levels of miltefosine and amphotericin B, and generally stable ARV drug concentrations during treatment.
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.
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