Abstract
Recent WHO guidelines on control of human immunodeficiency virus (HIV) call for the widespread use of antiretroviral (AR) therapy (ART) for people living with HIV. Given the considerable overlap between infections by HIV and Plasmodium, the causative agent of malaria, it is important to understand the impact of AR compounds and ART regimens on infections by malaria parasites. We undertook a systematic approach to identify AR drugs and ART drug combinations with inhibitory activity against the obligatory hepatic stage of Plasmodium infection. Our in vitro screen of a wide array of AR drugs identified the non-nucleoside reverse transcriptase inhibitors efavirenz and etravirine (ETV), and the protease inhibitor nelfinavir, as compounds that significantly impair the development of the rodent malaria parasite P. berghei in an hepatoma cell line. Furthermore, we show that WHO-recommended ART drug combinations currently employed in the field strongly inhibit Plasmodium liver infection in mice, an effect that may be significantly enhanced by the inclusion of ETV in the treatment. Our observations are the first report of ETV as an anti-Plasmodial drug, paving the way for further evaluation and potential use of ETV-containing ARTs in regions of geographical overlap between HIV and Plasmodium infections.
Highlights
The most recent WHO guidelines for treatment and prevention of infection with human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), recommend that all people living with HIV should be provided with antiretroviral (AR) therapy (ART), toward achieving universal access to HIV treatment and care, and ending AIDS as a public health threat (WHO, 2016a,b)
Our results show that nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are the classes of AR compounds most active against Plasmodium hepatic infection, whereas no substantial activity was observed for the nucleoside reverse transcriptase inhibitors (NRTIs) nor the II tested
Our results show that the ARTs currently employed in HIV treatment have a significant impact on liver infection by Plasmodium parasites, an effect that may be further enhanced by replacing EFV by the alternative NNRTI ETV
Summary
The most recent WHO guidelines for treatment and prevention of infection with human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), recommend that all people living with HIV should be provided with antiretroviral (AR) therapy (ART), toward achieving universal access to HIV treatment and care, and ending AIDS as a public health threat (WHO, 2016a,b). HIV has been shown to increase the risk of development of severe P. falciparum malaria (Grimwade et al, 2004; Cohen et al, 2005; Patnaik et al, 2005; Otieno et al, 2006; Flateau et al, 2011), while malaria has been associated with a decline in CD4+ T cell counts (Patnaik et al, 2005), enhanced HIV-1 replication (Kublin et al, 2005) and increased HIV transmission (Abu-Raddad et al, 2006) In light of these observations, WHO’s “ART-for-all” recommendation warrants an in-depth understanding of HIV drug influence on Plasmodium infection. While several reports have focused on the impact of ART on clinical malaria (reviewed in Van Geertruyden, 2014; Hobbs and Parikh, 2017) and on pharmacokinetic interactions between AR and antimalarial drugs (reviewed in Fehintola et al, 2011; Van Geertruyden, 2014), fewer studies exist on the specific impact of AR drugs on the clinically silent, yet statutory hepatic stage of infection by Plasmodium parasites
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