Antimalarial effects of human immunodeficiency virus protease inhibitors in rhesus macaques

Abstract

The antimalarial activity of the human immunodeficiency virus protease inhibitors indinavir and saquinavir was evaluated in rhesus macaques for the first time. Indinavir effectively suppressed the growth of Plasmodium cynomolgi and Plasmodium knowlesi in vivo after a 7- or 3-day treatment, respectively, with clinically relevant doses, whereas saquinavir showed only weak activity against P. cynomolgi.

Fig. 1.

Efficacy of indinavir against P. cynomolgi in rhesus macaques. Monkeys infected with 1 × 10⁷ P. cynomolgi-parasitized RBCs were treated intragastrically, three times daily, for seven consecutive days with different doses of indinavir (IDV) or the control as follows: 80 mg/kg (A), 40 mg/kg (B), 20 mg/kg (C), or control saline buffer (D). The parasitemia was recorded daily by examining Giemsa-stained thick and thin blood smears. The gray areas and the area between dotted lines indicate the duration of indinavir and buffer treatment, respectively. An open symbol indicates oral treatment of the monkey with artesunate to control the parasitemia. The significance of differences in comparison with the control group during treatment (days 8 to 14) was analyzed with the nonparametric Kruskal-Wallis test with Dunn's posttest (80 mg/kg, P < 0.01; 40 mg/kg, P < 0.01; and 20 mg/kg, P > 0.05).

Fig. 2.

Efficacies of indinavir and saquinavir against P. cynomolgi in rhesus macaques. Monkeys infected with 1 × 10⁷ P. cynomolgi-parasitized RBCs were treated intragastrically, three times daily, for seven consecutive days with either 30 mg/kg indinavir (IDV) (A), 22.5 mg/kg saquinavir (SQV) (B), or control saline buffer (C). After the 7-day treatment, chloroquine phosphate (CQ) (25 mg/kg body weight) was administered once a day for 3 days to eliminate the parasites. The level of parasitemia was recorded daily. The gray areas and the area between the dotted line and the dotted-gray area indicate the duration of indinavir, saquinavir, or buffer treatment, as indicated. The dotted-gray areas indicate the duration of the chloroquine phosphate treatment. The significance of differences in comparison with the control group during treatment (days 11 to 17) was analyzed with the nonparametric Kruskal-Wallis test with Dunn's posttest (IDV, P < 0.01, and SQV, P > 0.05).

Fig. 3.

Efficacy of indinavir against P. knowlesi in rhesus macaques. One macaque inoculated with 1 × 10⁷ P. knowlesi-parasitized RBCs was treated intragastrically with 40 mg/kg indinavir (IDV) three times daily for three consecutive days starting on day 5 after the inoculation. To eliminate the parasites, chloroquine phosphate (CQ) was administered. The gray area indicates the duration of the indinavir treatment. The dotted area indicates the duration of the chloroquine phosphate treatment.