Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis

Abstract

Background: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy.

Methods: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected.

Results: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.

Conclusions: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Keywords: Plasmodium falciparum; gametocytemia; single low-dose primaquine.

Figure 1.

Forest plots of difference in proportions of participants with gametocytes (risk difference) on each day of follow-up. Only individuals with gametocytes at enrolment were included. Day 3, heterogeneity χ ² = 14.90 (df = 8); P = .061; I² = 46.3. Day 7, heterogeneity χ ² = 45.75 (df = 8); P < .001; I² = 82.5%. Day 14, heterogeneity χ ² = 70.21 (df = 8); P < .001; I² = 88.6%. Studies were excluded if no data were collected on a specific day, except for study 8, which only included PQ arms (all days), and study 14 (day 3) in which PQ was administered on day 3. Abbreviations: CI, confidence interval; PQ, primaquine; RD, risk difference.

Figure 2.

Predicted relationship between probability of gametocyte carriage on days 7 (A) and 14 (B) post treatment initiation and PQ dose. The dashed line represents this relationship for individuals treated with AL and the solid line for individuals treated with DP. Shaded areas correspond to 95% confidence intervals. Median values for other variables were assumed. Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine; PQ, primaquine.

Figure 3.

Results of membrane feeding experiments on different days of follow-up, in relation to starting treatment (A and C) and time of PQ administration (B and D). Whiskers represent 95% confidence intervals adjusted for clustering within patients (A and B) and within feeding experiments (C and D). Red boxes represent data for PQ arms and blue boxes for arms without PQ administration. This figure includes all data combined from AL, DP, and SPAQ treatment arms. Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine; PQ, primaquine; SPAQ, sulfadoxine-pyrimethamine and amodiaquine.

Figure 4.

Predicted risk of infecting at least 1 mosquito in the membrane feeding experiment, after administration of 0.25-mg/kg dose of PQ (red line) or without PQ administration (blue line). Gametocytemia of 100 gametocytes per microliter was assumed at the time of sampling. Results are presented for patients treated with AL (A) or DP (B). Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine; PQ, primaquine.