ABSTRACT
HIV and malaria overlap geographically, but the full impact of different antiretrovirals on malaria remains poorly understood. We examined the antimalarial activity of the HIV protease inhibitors lopinavir and saquinavir and the non-nucleoside reverse transcriptase inhibitor nevirapine on Plasmodium falciparum liver stages. Our results demonstrate that the HIV PI lopinavir inhibits liver stage parasites at clinically relevant concentrations, that is, at drug levels achieved in HIV-infected patients on standard dosing regimens. Because drugs that inhibit liver stages target parasites when they are present in lower numbers, these results might have implications for eradication efforts.
Subject(s)
HIV Protease Inhibitors/pharmacology , Liver/parasitology , Plasmodium falciparum/drug effects , Reverse Transcriptase Inhibitors/pharmacology , HIV Infections/complications , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Humans , In Vitro Techniques , Liver/drug effects , Lopinavir/pharmacology , Lopinavir/therapeutic use , Malaria, Falciparum/complications , Nevirapine/pharmacology , Nevirapine/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Saquinavir/pharmacology , Saquinavir/therapeutic useABSTRACT
BACKGROUND: Millions of individuals being treated for human immunodeficiency virus (HIV) live in malaria-endemic areas, but the effects of these treatments on malaria transmission are unknown. While drugs like HIV protease inhibitors (PIs) and trimethoprim-sulfamethoxazole (TMP-SMX) have known activity against parasites during liver or asexual blood stages, their effects on transmission stages require further study. METHODS: The HIV PIs lopinavir and saquinavir, the nonnucleoside reverse-transcriptase inhibitor nevirapine, and the antibiotic TMP-SMX were assessed for activity against Plasmodium falciparum transmission stages. The alamarBlue assay was used to determine the effects of drugs on gametocyte viability, and exflagellation was assessed to determine the effects of drugs on gametocyte maturation. The effects of drug on transmission were assessed by calculating the mosquito oocyst count as a marker for infectivity, using standard membrane feeding assays. RESULTS: Lopinavir and saquinavir have gametocytocidal and transmission blocking activities at or approaching clinically relevant treatment levels, while nevirapine does not. TMP-SMX is not gametocytocidal, but at prophylactic levels it blocks transmission. CONCLUSIONS: Specific HIV treatments have gametocyte killing and transmission-blocking effects. Clinical studies are warranted to evaluate these findings and their potential impact on eradication efforts.
