<i>In Vitro</i>
            Activity of Antiretroviral Drugs against Plasmodium falciparum

Nsanzabana, Christian; Rosenthal, Philip J.

doi:10.1128/aac.05130-11

Cited by 53 publications

(45 citation statements)

References 46 publications

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“…Consistent with prior reports (3,9), all tested compounds inhibited parasite growth. Lopinavir was the most potent inhibitor with an IC 50 of 1.9 M (Fig.…”

Section: Resultssupporting

confidence: 80%

“…A combination antiviral therapy that includes the HIV protease inhibitor (PI) lopinavir has been found to dramatically decrease malaria incidence in a pediatric clinical population, by 41%, suggesting a direct effect of PIs on parasite replication (2). Indeed, lopinavir has demonstrated in vitro activity (3) against Plasmodium falciparum, the protozoan species responsible for most malaria deaths (1,4). In addition, lopinavir reduces the malaria liver stage burden in infected rhesus monkeys in vivo at clinically relevant concentrations (5).…”

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confidence: 99%

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The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

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“…Consistent with prior reports (3,9), all tested compounds inhibited parasite growth. Lopinavir was the most potent inhibitor with an IC 50 of 1.9 M (Fig.…”

Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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“…ertain antiretroviral protease inhibitors (APIs) inhibit the growth of malaria parasites at clinically relevant concentrations (2,21,23,25,32). This observation may have clinically significant implications for the treatment of HIV-and malaria parasite-coinfected patients as well as for the development of a potent class of antimalarial agents possessing a novel mode of action.…”

mentioning

confidence: 99%

Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

Martin

Butterworth

Gardiner

et al. 2012

Antimicrob Agents Chemother

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eThe antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth of Plasmodium falciparum at clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasite in vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of the P. falciparum chloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using the Xenopus laevis oocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistant P. falciparum parasites. Certain antiretroviral protease inhibitors (APIs) inhibit the growth of malaria parasites at clinically relevant concentrations (2,21,23,25,32). This observation may have clinically significant implications for the treatment of HIV-and malaria parasite-coinfected patients as well as for the development of a potent class of antimalarial agents possessing a novel mode of action. While detailed clinical trials are required to determine whether the antiplasmodial activity of the APIs is beneficial in a coinfection setting, reports that these drugs act synergistically with selected antimalarial drugs both in vitro and in vivo (13,14,31) are promising, and further studies are clearly warranted.Initial studies demonstrated that chloroquine (CQ) acts synergistically with the APIs ritonavir (RTV) and saquinavir (SQV) against CQ-resistant Plasmodium falciparum parasites (31). These findings were confirmed and extended by the observation that CQ also acts synergistically with lopinavir (LPV), nelfinavir, and atazanavir against CQ-resistant P. falciparum (14). However, analysis of the activity of CQ-API combinations against CQ-sensitive P. falciparum parasites revealed that (i) the degree of synergy varies among the APIs, with RTV showing the greatest degree of synergism; (ii) the synergistic effect of RTV on CQ activity against CQ-resistant P. falciparum parasites is greater than that measured against CQ-sensitive parasites; and (iii) although LPV, SQV, nelfinavir, and atazanavir behave synergistically with CQ against CQ-resistant P. falciparum parasites, these combinations are additive when assessed with CQ-sensitive parasites (14).The mechanism underlying the different effects of CQ-API combinations against CQ-resistant parasites compared to CQsensitive parasites is not well understood, but one plausible explanation is that the APIs may act as CQ resistance reversers in P. falciparum. The primary determinant of CQ resistance in P. falciparum is mutation of the CQ resistance transporter (PfCRT) (5...

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“…[4][5][6]11,12 Considering clinically relevant effects of PIs, recent data are available from two randomized trials in humans and the results have been mixed. In secondary analyses of a multicenter trial of HIV-infected women randomized to either PI-based or NNRTI-based ART, there were no differences in the incidence of malaria, diagnosed clinically or with laboratory confirmation.…”

mentioning

confidence: 99%

“…The HIV protease inhibitors (PIs) have been shown to inhibit the growth of Plasmodium falciparum, the most common cause of malaria in Africa, in culture and in animal models. [4][5][6][7] In addition to activity against the asexual stage of the parasite, PIs have shown in vitro activity against gametoctyes, the sexual stage of the parasite responsible for transmission to mosquitoes. 8 However, there are limited clinical data on the effects of PIs on asymptomatic parasitemia and gametocytemia.…”

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confidence: 99%

Prevalence of Asymptomatic Parasitemia and Gametocytemia among HIV-Infected Ugandan Children Randomized to Receive Different Antiretroviral Therapies

Ikilezi

Achan²,

Kakuru³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. In a recent randomized controlled trial, the use of protease inhibitor (PI)-based antiretroviral therapy (ART) was associated with a significantly lower incidence of malaria compared with non-nucleoside reverse transcriptase inhibitor-based ART in a cohort of human immunodeficiency virus-infected Ugandan children living in an area of high malaria transmission intensity. In this report, we compared the prevalence of asymptomatic parasitemia and gametocytemia using data from the same cohort. The prevalence of asymptomatic parasitemia did not differ between the two ART treatment arms. The PI-based arm was associated with a lower risk of gametocytemia at the time of diagnosis of malaria (6.6% versus 14.5%, P = 0.03) and during the 28 days after malaria diagnosis (3.4% versus 6.5%, P = 0.04). Thus, in addition to decreasing the incidence of malaria, the use of PI-based ART may lower transmission, as a result of a decrease in gametocytemia, in areas of high malaria transmission intensity.The effects of human immunodeficiency virus (HIV) on malaria have been well documented and include increased malaria incidence, increased parasitemia, and worse clinical outcomes.1-3 Antiretroviral treatment (ART) for HIV that is also effective in preventing malaria and reducing transmission would have important public health implications for HIVinfected patients living in areas where malaria is highly endemic, such as sub-Saharan Africa. The HIV protease inhibitors (PIs) have been shown to inhibit the growth of Plasmodium falciparum, the most common cause of malaria in Africa, in culture and in animal models. [4][5][6][7] In addition to activity against the asexual stage of the parasite, PIs have shown in vitro activity against gametoctyes, the sexual stage of the parasite responsible for transmission to mosquitoes. 8 However, there are limited clinical data on the effects of PIs on asymptomatic parasitemia and gametocytemia.We recently published the results of an open-label randomized trial comparing PI-based versus non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART for the prevention of malaria among HIV-infected children living in Tororo, a highly malaria-endemic area of Eastern Uganda. 9 In this study the use of PI-based ART was associated with a 41% reduction in the incidence of malaria, largely attributable to ART-antimalarial drug interactions resulting in a significant reduction in the risk of recurrent malaria after treatment with artemether-lumefantrine (AL). In this report, we compare the prevalence of asymptomatic parasitemia and gametocytemia between ART treatment arms in this trial. Briefly, study participants were HIV-infected children 2 months to 5 years of age who were either eligible for ART initiation or already receiving first-line ART with virologic suppression. Participants were randomized to receive either an NNRTI-(nevirapine or efavirenz)-based or PI-(ritonavir-boosted lopinavir)-based regimen. Participants also received an insecticide-treated bed net at enrollment and daily trimethopr...

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In Vitro Activity of Antiretroviral Drugs against Plasmodium falciparum

Cited by 53 publications

References 46 publications

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

Prevalence of Asymptomatic Parasitemia and Gametocytemia among HIV-Infected Ugandan Children Randomized to Receive Different Antiretroviral Therapies

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