Short-course, high-dose primaquine regimens for the treatment of liver-stage vivax malaria in children.

OBJECTIVES: To assess the pharmacokinetics, safety, and tolerability of two high-dose, short-course primaquine (PQ) regimens compared with standard care in children with Plasmodium vivax infections. METHODS: We performed an open-label pediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal glucose-6-phosphate dehydrogenase activity were allocated to one of three PQ treatment regimens in a stepwise design (group A: 0.5 mg/kg once daily for 14 days, group B: 1 mg/kg once daily for 7 days, and group C: 1 mg/kg twice daily for 3.5-days). The study assessments were completed at each treatment time point and fortnightly for 2 months after PQ administration. RESULTS: Between August 2013 and May 2018, 707 children were screened and 73 met the eligibility criteria (15, 40, and 16 allocated to groups A, B, and C, respectively). All children completed the study procedures. The three regimens were safe and generally well tolerated. The pharmacokinetic analysis indicated that an additional weight adjustment of the conventionally recommended milligram per kilogram PQ doses is not necessary to ensure the therapeutic plasma concentrations in pediatric patients. CONCLUSIONS: A novel, ultra-short 3.5-day PQ regimen has potential benefits for improving the treatment outcomes in children with vivax malaria that warrants further investigation in a large-scale clinical trial.

A Randomized Open-Label Evaluation of the Antimalarial Prophylactic Efficacy of Azithromycin-Piperaquine versus Sulfadoxine-Pyrimethamine in Pregnant Papua New Guinean Women.

Emerging malaria parasite sulfadoxine-pyrimethamine (SP) resistance has prompted assessment of alternatives for intermittent preventive treatment in pregnancy (IPTp). The objective was to evaluate the tolerability and prophylactic efficacy of azithromycin (AZ) plus piperaquine (PQ) in pregnant women in Papua New Guinea. The study was an open-label, randomized, parallel-group trial. A total of 122 women (median gestation, 26 weeks [range, 14 to 32 weeks]) were randomized 1:1 to three daily doses of 1 g AZ plus 960 mg PQ tetraphosphate or single-dose SP (4,500 mg sulfadoxine plus 225 mg pyrimethamine), based on computer-generated block randomization. Tolerability was assessed to day 7, and efficacy was assessed to day 42 (when participants were returned to usual care) and at delivery. Data for 119 participants (AZ-PQ, n = 61; SP, n = 58) were analyzed. Both regimens were well tolerated, but AZ-PQ was associated with more gastrointestinal side effects (31%) and dizziness (21%). Eight women (6.7%) were parasitemic at recruitment but all were aparasitemic by 72 h. There were no differences in blood smear positivity rates between AZ-PQ and SP up to day 42 (0% versus 5.2%; relative risk [RR], 0.14 [95% confidence interval [CI], 0.01 to 2.58] [P = 0.18]; absolute risk reduction [ARR], 5.2% [95% CI, -1.3 to 11.6%]) and at the time of delivery (0% versus 8.7%; RR, 0.11 [95% CI, 0.01 to 2.01] [P = 0.14]; ARR, 8.7% [95% CI, -0.2 to 17.6%]). Of 92 women who were monitored to parturition, 89 (97%) delivered healthy babies; there were 3 stillbirths (SP, n = 1; AZ-PQ, n = 2 [twins]). There was a higher live birth weight (mean ± standard deviation) in the AZ-PQ group (3.13 ± 0.42 versus 2.88 ± 0.55 kg [P = 0.016]; mean difference, 0.25 kg [95% CI, 0.02 to 0.48 kg]). AZ-PQ is a promising candidate for IPTp.