Chagas disease, caused by the flagellate parasite Trypanosoma cruzi, is a wellknown
neglected tropical disease. This parasitic illness affects 6-7 million people and can lead
to severe myocarditis and/or complications of the digestive tract. The changes in its epidemiology
facilitate co-infection with the Human Immunodeficiency Virus (HIV), making even
more difficult the diagnosis and prognosis. The parasitic infection is reactivated in
T. cruzi/HIV co-infection, with the appearance of unusual manifestations in the chronic phase
and the exacerbation of classical clinical signs. The therapeutic arsenal to treat Chagas disease,
in all its clinical forms, is restricted basically to two drugs, benznidazole and nifurtimox.
Both drugs are extremely toxic and the therapeutic efficacy is still unclear, making the clinical
treatment a huge issue to be solved. Therefore, it seems obvious the necessity of new tangible
approaches to combat this illness. In this sense, the repositioning of approved drugs appears
as an interesting and viable strategy. The discovery of Human Immunodeficiency Virus Aspartyl
Peptidase Inhibitors (HIV-PIs) represented a milestone in the treatment of Acquired
Immune Deficiency Syndrome (AIDS) and, concomitantly, a marked reduction in both the
incidence and prevalence of important bacterial, fungal and parasitic co-infections was clearly
observed. Taking all these findings into consideration, the present review summarizes the
promising and beneficial data concerning the effects of HIV-PIs on all the evolutionary forms
of T. cruzi and in important steps of the parasite’s life cycle, which highlight their possible
application as alternative drugs to treat Chagas disease.