Macrophage Activation Marker Neopterin: A Candidate Biomarker for Treatment Response and Relapse in Visceral Leishmaniasis.

Anke E Kip,Jos H Beijnen,Fabiana Alves,Thomas P C Dorlo,Jan H M Schellens,Monique Wasunna,Ahmed M Musa,Eltahir A G Khalil

doi:10.3389/fcimb.2018.00181

Abstract

The Leishmania parasite resides and replicates within host macrophages during visceral leishmaniasis (VL). This study aimed to evaluate neopterin, a marker of macrophage activation, as possible pharmacodynamic biomarker to monitor VL treatment response and to predict long-term clinical relapse of VL. Following informed consent, 497 plasma samples were collected from East-African VL patients receiving a 28-day miltefosine monotherapy (48 patients) or 11-day combination therapy of miltefosine and liposomal amphotericin B (L-AMB, 48 patients). Neopterin was quantified with ELISA. Values are reported as median (inter-quartile range). Baseline neopterin concentrations were elevated in all VL patients at 98.8 (63.9–135) nmol/L compared to reported levels for healthy controls (<10 nmol/L). During the first treatment week, concentrations remained stable in monotherapy patients (p = 0.807), but decreased two-fold compared to baseline in the combination therapy patients (p < 0.01). In the combination therapy arm, neopterin concentrations increased significantly 1 day after L-AMB infusion compared to baseline for cured patients [137 (98.5–197) nmol/L, p < 0.01], but not for relapsing patients [84.4 (68.9–106) nmol/L, p = 0.96]. The neopterin parameter with the highest predictive power for VL relapse was a higher than 8% neopterin concentration increase between end of treatment and day 60 follow-up (ROC AUC 0.84), with a 93% sensitivity and 65% specificity. In conclusion, the identified neopterin parameter could be a potentially useful surrogate endpoint to identify patients in clinical trials at risk of relapse earlier during follow-up, possibly in a panel of biomarkers to increase its specificity.

Highlights

Visceral leishmaniasis (VL) is a systemic disease caused by the Leishmania parasite
A total of 497 plasma samples were available from 96 patients; 48 patients in combination therapy and 48 patients in monotherapy
Six patients in the combination therapy arm and nine patients in the monotherapy arm relapsed within 6 months after treatment

Summary

Introduction

Visceral leishmaniasis (VL) is a systemic disease caused by the Leishmania parasite. Affordable and safe treatments for this devastating disease are urgently needed. In a recently published clinical trial in Kenya and Sudan, 6–18% of patients relapsed within 6 months follow-up, depending on the treatment arm (Wasunna et al, 2016). As parasite recrudescence and clinical relapse is a longterm event, the follow-up period to determine efficacy of new VL treatment regimens is normally 6 or even 12 months. To speed up the process of assessing the efficacy of new treatment regimens, sensitive and specific early biomarkers are required to predict long-term clinical outcomes, e.g., to be used in an adaptive trial design with interim analysis. No longitudinal evaluations of pharmacodynamic markers have been performed in the evaluation of anti-leishmanial therapies (Kip et al, 2015)

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Conclusion