Breaking the cycle: investigating recurrent relapses in VL-HIV co-infected patients, their role in transmission and novel therapeutic strategies

Visceral leishmaniasis (VL), a deadly neglected tropical disease annually affecting thousands,
presents significant treatment hurdles when there is HIV-coinfection. Despite antiretroviral therapy
and anti-leishmanial treatment, recurrent VL episodes (up to 48) are common, raising concerns
about emerging drug-resistant parasites and transmission risks. Our recent studies highlight immune
exhaustion induced by PD(L)-1 overexpression on T-cells, suggesting a pivotal role in disease
recurrence. We hypothesize that recurrent VL-HIV patients act as super-spreaders of drug-resistant
Leishmania, fueling transmission. Additionally, we believe that blocking the PD(L)-1 pathway via
immunochemotherapy could prevent relapse by restoring the anti-Leishmania T cell response.
Leveraging our research platform in Ethiopia, we will establish a VL-HIV cohort to monitor parasite
drug susceptibility, conduct xenodiagnosis to measure infectiousness and identify patients most likely
to benefit from PD(L)-1 inhibition. Finally, a clinical trial will assess the efficacy of PD(L)-1 inhibitors
alongside anti-leishmanial therapy. This multidisciplinary pioneering project aims to provide critical
insights into the underlying causes of recurrent VL episodes chronic VL-HIV patients, their role in
transmission dynamics, and strategies to interrupt the cycle of relapse.