Piperaquine Monotherapy of Drug-Susceptible Plasmodium falciparum Infection Results in Rapid Clearance of Parasitemia but Is Followed by the Appearance of Gametocytemia

Abstract

Background: Piperaquine, coformulated with dihydroartemisinin, is a component of a widely used artemisinin combination therapy. There is a paucity of data on its antimalarial activity as a single agent. Such data, if available, would inform selection of new coformulations.

Methods: We undertook a study in healthy subjects, using the induced blood stage malaria (IBSM) model to test the antimalarial activity of single doses of piperaquine (960, 640, and 480 mg) in 3 cohorts. In a pilot study in the third cohort, gametocyte clearance following administration of 15 mg, or 45 mg or no primaquine was investigated.

Results: Parasite clearance over the 48-hour period after piperaquine administration was more rapid in the 960 mg cohort, compared with the 640 mg cohort (parasite reduction ratio, 2951 [95% confidence interval {CI}, 1520-5728] vs 586 [95% CI, 351-978]; P < .001). All 24 subjects developed gametocytemia as determined by pfs25 transcripts. Clearance of pfs25 was significantly faster in those receiving primaquine than in those not receiving primaquine (P < .001).

Conclusions: Piperaquine possesses rapid parasite-clearing activity, but monotherapy is followed by the appearance of gametocytemia, which could facilitate the spread of malaria. This new information should be taken into account when developing future antimalarial coformulations.

Clinical trials registration: ACTRN12613000565741.

Keywords: P. falciparum; gametocytemia; malaria; piperaquine clinical trial.

Figure 1.

Trial profile. Abbreviations: BMI, body mass index; ECG, electrocardiography; PCR, polymerase chain reaction.

Figure 2.

Mean parasitemia level (18S) before and after piperaquine treatment for cohort 1 (960 mg), cohort 2 (640 mg), and cohort 3 (480 mg). Day 0 corresponds to inoculation day. Piperaquine was administered to subjects in cohorts 1 and 3B on day 7 and to subjects in cohorts 2 and 3A on day 8. The scale of the x-axis is expanded on days 9–13 to better illustrate the course of parasitemia immediately after piperaquine treatment.

Figure 3.

Course of gametocytemia after piperaquine treatment. A, Cohort 1 (960 mg). Subjects in cohort 1 received primaquine 21 days after piperaquine treatment. B, Cohort 2 (640 mg). Subjects in cohort 2 received primaquine 19 days after piperaquine treatment. C, Cohort 3 (480 mg). In cohort 3A (R013–R018), all subjects but R016 received a second dose of piperaquine 9 days after the first piperaquine dose. Subject R016 received a second dose of piperaquine 8 days after the first piperaquine dose. In cohort 3B (R019–R024), subjects who had recrudescence received a second dose of piperaquine (4, 16, and 20 days after the first piperaquine dose for subjects R019, R020, and R023, respectively). Subjects in cohort 3 were randomized in 3 arms to receive 15 mg of primaquine, 45 mg of primaquine, or no primaquine. Subjects in the 15 mg and 45 mg arms received primaquine treatment 14 or 17 days after the first piperaquine dose (indicated with an arrow). Subjects in the no-treatment arm only received primaquine treatment at the end of the study (25 or 27 days after the first piperaquine dose). Dashed lines in the figure represent gametocytemia after randomization for primaquine treatment. Dashed lines in blue correspond with 15 mg primaquine treatment arm; dashed lines in red correspond to the 45 mg primaquine treatment arm; dashed lines in black correspond to the no-treatment arm (control group). For the control group, clearance of gametocytemia following primaquine treatment at the end of study is not shown.

Figure 4.

Confirmation of gametocytemia. A, A Giemsa-stained female gametocyte detected on a thick blood smear. B, Gating strategy for gametocyte detection for flow cytometry. Abbreviations: P12/P13, gametocytes; P14, red blood cells; P15, reticulocytes.