Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data

Abstract

Background: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.

Methods: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.

Results: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms.

Conclusions: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients.

Trial registration: PROSPERO, CRD42019128185.

Keywords: Clinical trial; Haemoglobin; Haemoglobinuria adverse events; Individual patient data (IPD); Malaria; Meta-analysis; Primaquine; Safety; Systematic review.

Fig. 1

Study profile. Analysis datasets are not mutually exclusive

Fig. 2

Relationship between baseline haemoglobin and haematological endpoints on day 7. The shaded area shows 95% CI. Adjusted for all independent predictors (shown in Table 3) and shown for a child < 5 years of age, from low-transmission intensity area, normal G6PD status and baseline parasitaemia = 10,000/μL. A Absolute change in haemoglobin on day 7 evaluated in all patients. B Risk of > 25% drop in haemoglobin on day 7. C Risk of moderate/severe anaemia (Hb < 10 g/dL) on day 7. D Risk of severe anaemia (Hb < 7 g/dL) on day 7. E Absolute change in haemoglobin on day 7 evaluated in patients from sub-Saharan Africa. A–D used data from all locations. For the interpretation of the association in A and E, please refer to Additional file 3: Table S3.

Fig. 3

Estimated primaquine dose-response relationship. The shaded area shows 95% CI. Adjusted for all independent predictors (shown in Table 3) and shown for children < 5 years of age, from low-transmission intensity settings with parasitaemia of 10,000/μL, and for G6PD-deficient and G6PD-normal patients with different levels of baseline haemoglobin. A Moderate/severe anaemia (Hb < 10g/dL). B Severe anaemia (Hb < 7 g/dL) on day 7

Fig. 4

Classification of predicted frequency of severe anaemia (Hb < 7 g/dL, Hb < 5 g/dL) on day 7. Shown for Plasmodium falciparum malaria patients with G6PD deficiency in sub-Saharan Africa, treated with ACT (noPQ) or ACT + 0.25 mg/kg primaquine dose (PQ) shown for each value of baseline haemoglobin concentrations observed in G6PD-deficient population (y-axis). The results come from 100,000 simulated day 7 haemoglobin concentrations for each day 0 haemoglobin concentration value, age group, and transmission intensity from the AC7 model presented in Additional file 3: Table S12. Classification of AE frequency: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥ 1/1000 and < 1/100, rare ≥ 1/10,000 and < 1/1000, and very rare < 1/10,000