Blood parasite load as an early marker to predict treatment response in visceral leishmaniasis in Eastern Africa


Background: In order to expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes.

Methods: Data from three clinical trials were combined in this study, where Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during and up to six months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at six months.

Results: The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within six months of follow-up at a cut-off of 20 parasites/mL (AUC 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ= 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a >80% power to detect a difference in cure rate between treatment regimens if this difference was high (>50%) and when minimally 30 patients were included per regimen.

Conclusion: Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.

Clinical Infectious Diseases