The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

Abstract

Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.

Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.

Results: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL.

Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.

Trial registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

Keywords: Chloroquine; Haemoglobin; Haemolysis; Plasmodium vivax; Pooled analysis; Primaquine.

Conflict of interest statement

AAn reports grants from USAID Iniciativa Amazónica contra la Malaria/Red Amazónica de la Vigilancia de las Drogas Antimaláricas AMI/RAVREDA and personal fees from Pan American Health Organization PWR (BOL). NMA reports grants from the Australian Government, National Health and Medical Research Council. DBP reports grants from GSK outside the submitted work. PJdV reports personal fees from ACE Pharma outside the submitted work. All other authors declare that they have no competing interests.

Figures

Fig. 1

Study flowchart

Fig. 2

Mean haemoglobin-time profiles for a any baseline haemoglobin, b baseline ≥ 11.5 g/dL, c baseline < 11.5 g/dL and d normal G6PD status. Figures derived from the linear mixed effects model with fractional polynomial terms for time. Profiles for chloroquine (CQ) alone and chloroquine plus primaquine (CQ+PQ) adjusted to the same baseline haemoglobin. Shaded regions show 95% confidence intervals. In total, 1975 patients were treated with CQ alone and 1446 with CQ+PQ; in patients with baseline Hb ≥ 11.5 g/dL, the corresponding figures were 1277 and 1063; in patients with baseline Hb < 11.5 g/dL, the corresponding figures were 698 and 383; and in patients with normal G6PD status, the corresponding figures were 856 and 836

Fig. 3

Relationship between haemoglobin at baseline and day 7 as a fractional change and b absolute change. One thousand two hundred twenty-two patients were treated with chloroquine (CQ) alone and 539 with chloroquine plus primaquine (CQ+PQ). The open circle represents the single patient with a clinically significant fall > 25% to < 7 g/dL at day 7 (female patient with normal G6PD status). The dashed orange line represents a fractional fall of 25%. The baseline Hb correlated negatively with the fractional change in Hb at day 7 (r = − 0.521 [95% CI − 0.554 to − 0.486], p < 0.0001)

Fig. 4

Fractional change in haemoglobin between baseline and day 7 following a chloroquine and b chloroquine plus primaquine. In patients treated with chloroquine alone, 608 had normal G6PD status and 588 had unknown G6PD status. In patients treated with chloroquine plus primaquine, 389 had normal G6PD status and 150 had unknown G6PD status. The open circle represents the single patient with a clinically significant fall > 25% to < 7 g/dL at day 7 (female patient with normal G6PD status). The dashed orange line represents a fractional fall of 25%