Low antileishmanial drug exposure in HIV-positive visceral leishmaniasis patients on antiretrovirals: an Ethiopian cohort study

Abstract

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 Cmax on Day 1 was 24.6 μg/mL (17.0-34.9 μg/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/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 Cmax 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.

Figure 1.

Median total amphotericin B (AMB) plasma concentration on the first treatment day (black lines) for monotherapy (n = 9) and combination therapy (n = 18) and the last treatment day (light grey lines) for monotherapy (Day 24, n = 10) and combination therapy (Day 11, n = 20). Error bars indicate the IQR.

Figure 2.

Miltefosine concentration–time curves for patients who were parasite negative at Day 29 (left, n = 10) and patients that were still parasite positive (right, n = 10) at the end of the first treatment cycle (Day 29, indicated with dashed vertical black line). The horizontal grey dashed line indicates the LLOQ of 10 ng/mL. For the 10 patients with positive parasitology at Day 29, one patient received rescue treatment (dashed line) and the others received an additional treatment cycle (until Day 56).

Figure 3.

Correlation between amphotericin B (AMB) accumulation and miltefosine exposure in patients receiving combination therapy. AMB accumulation is expressed in terms of D11/D1 AMB AUC_0–24h ratio, while miltefosine exposure is expressed in cumulative area under the contration–time curve until the end of the first treatment cycle (miltefosine AUC_0–D28). The black line indicates the linear regression line (P = 0.0313, R²=0.26), and the grey shaded area the 95% CI. Individual observations are indicated in solid triangles for patients who were parasite negative and open squares for patients still parasitologically positive after one treatment cycle (Day 29). The horizontal dashed line indicates the median D11/D1 AMB AUC_0–24h ratio of 2.4, while the vertical dashed line depicts the median miltefosine exposure AUC_0–D28 at 314 μg·day/mL. Two patients had aberrant sampling schedules and were excluded.

Figure 4.

Efavirenz C_min over time per patient during the treatment follow-up for combination therapy (n = 16) and monotherapy (n = 9). This figure also includes patients not yet on ART on the first antileishmanial treatment day and patients that had a treatment switch or otherwise showed undetectable ARV levels. The horizontal dashed black lines depict the 1–4 μg/mL therapeutic window previously described for efavirenz. FU, follow-up timepoint; EXT, additional extended treatment timepoint.

Figure 5.

Nevirapine C_max (left) and C_min (right) during the antileishmanial treatment period, per patient. Indicated with the black dashed line is the lower limit of the therapeutic window at 3.4 μg/mL. One patient had undetectable levels at FU2, probably due to non-adherence. FU, follow-up timepoint; EXT, additional extended treatment timepoint.