Severe haemolysis during primaquine radical cure of Plasmodium vivax malaria: two systematic reviews and individual patient data descriptive analyses

BackgroundPrimaquine (PQ) kills Plasmodium vivax hypnozoites but can cause haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. MethodsWe did two systematic reviews: the first used data from clinical trials to determine the spectrum of definitions and frequency of haematological serious adverse events (SAE) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management and outcome of severe PQ-associated haemolysis necessitating hospitalisation. FindingsIn the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 haematological SAEs amongst 9,824 patients with vivax malaria treated with PQ, 9 of which necessitated hospitalisation or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalised following PQ radical cure; 79.9% (123/154) of whom were prescribed PQ at [&ge;]0.5mg/kg/day. Overall, 101 patients were categorised as having probable or possible severe PQ-associated haemolysis, 96.8% of whom were G6PD deficient (<30% activity). The first symptoms of haemolysis were mostly reported on day 2 or 3 (45.5%) and all patients were hospitalised within 7 days of PQ commencement. 57.9% (77/133) of patients had blood transfusion. Seven (6.9%) patients with probable or possible haemolysis died. InterpretationEven when G6PD testing is available, enhanced monitoring for haemolysis is warranted following PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of haemolysis. More robust definitions of severe PQ-associated haemolysis are required. FundingWHO-TDR, Australian National Health and Medical Research (NHMRC), The Bill & Melinda Gates Foundation.