Abstract
The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79–0.91; p<0.001) and 0.54 (0.41–0.70; p<0.001) respectively. By day 30, 14.15% (12.45–16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67–24.89) of patients treated without PQ; AHR = 0.66 (0.45–0.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21–0.35) in patients treated with PQ, compared to 0.38% (0.24–0.60) without PQ; AHR = 0.79 (0.43–1.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.
Highlights
In the last decade major gains have been made in malaria control, but successes have been less apparent for P. vivax than for P. falciparum
Primaquine (PQ) is currently the only widely available drug to kill hypnozoites, but its use is hampered by concerns over haemolysis in patients with Glucose-6-Dehydrogenase (G6PD) deficiency
At a recent round table discussion of the Asia Pacific Malaria Elimination Network (APMEN) policy makers prioritised further studies to determine the risk-benefit of PQ in different endemic settings
Summary
In the last decade major gains have been made in malaria control, but successes have been less apparent for P. vivax than for P. falciparum. Unlike P. falciparum, P. vivax forms dormant liver stages (hypnozoites) that can reactivate weeks to months after an initial infection, causing recurrent parasitaemia (relapses). The only widely available drug to kill hypnozoites and prevent relapsing infection is primaquine (PQ), which is administered with schizontocidal treatment in a combination known as radical cure. The effectiveness of PQ is limited by the prolonged treatment course (14 days) recommended by most national malaria control programs, and concerns over its safety, the risk of acute haemolysis in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency [5]. If G6PD testing is not available, the WHO guidelines recommend that a local risk-benefit assessment should guide antimalarial policy [7]. The risk-benefit considerations for PQ deployment depend on a variety of host, parasite and environmental factors, including the risk and frequency of relapse, access to healthcare, and the prevalence and local variants of G6PD deficiency
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