saquinavir and Malaria--Falciparum

 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..  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..  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..  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.

Topics: Animals; Anopheles; Anti-HIV Agents; Antimalarials; Dose-Response Relationship, Drug; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Nevirapine; Plasmodium falciparum; Reverse Transcriptase Inhibitors; Saquinavir; Trimethoprim, Sulfamethoxazole Drug Combination

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.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Liver; Lopinavir; Malaria, Falciparum; Nevirapine; Plasmodium falciparum; Reverse Transcriptase Inhibitors; Saquinavir

The 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.

Topics: Animals; Antimalarials; Biological Transport; Chloroquine; Drug Combinations; Drug Synergism; Female; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Membrane Transport Proteins; Mutation; Oocytes; Plasmodium falciparum; Protozoan Proteins; Ritonavir; Saquinavir; Tritium; Xenopus laevis

Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.

Topics: Animals; Antimalarials; Drug Resistance, Multiple; Gene Dosage; Genes, MDR; Genes, Protozoan; HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Malaria, Falciparum; Malaria, Vivax; Parasitic Sensitivity Tests; Plasmodium falciparum; Plasmodium vivax; Ritonavir; Saquinavir

The antimalarial activity of several antiretroviral protease inhibitor combinations was investigated. Data demonstrate that ritonavir and saquinavir behave synergistically with chloroquine and mefloquine. These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins.

Topics: Animals; Antimalarials; Chloroquine; Drug Synergism; HIV Protease Inhibitors; Humans; Malaria, Falciparum; Mefloquine; Parasitic Sensitivity Tests; Plasmodium falciparum; Ritonavir; Saquinavir

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Topics: Alkynes; Amodiaquine; Antimalarials; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Burkina Faso; Chromatography, High Pressure Liquid; Cyclopropanes; Cytochrome P-450 CYP2C8; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Genotype; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Models, Biological; Polymorphism, Genetic; Pyridines; Pyrimidinones; Pyrones; Reverse Transcriptase Inhibitors; Saquinavir; Spectrophotometry, Ultraviolet; Sulfonamides; Treatment Outcome; Trimethoprim

Synergy between HIV and malaria is being increasingly recognized. We examined the antimalarial activity of sera from subjects receiving chloroquine, no drugs or HAART. Sera from subjects taking ritonavir-boosted saquinavir or lopinavir significantly inhibited parasite growth (median of 55 and 69% inhibition, respectively). These results indicate that patients on protease inhibitors may be afforded some protection from malaria. The clinical relevance of these observations will require confirmation in controlled studies in malaria-endemic regions.

Topics: Animals; Antimalarials; Antiretroviral Therapy, Highly Active; Chloroquine; Drug Synergism; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Plasmodium falciparum; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Outcome