Case Series of Primaquine-Induced Haemolytic Events in Controlled Trials with G6PD Screening

Abstract

Primaquine for radical cure of Plasmodium vivax malaria poses a potentially life-threatening risk of haemolysis in G6PD-deficient patients. Herein, we review five events of acute haemolytic anaemia following the administration of primaquine in four malaria trials from Indonesia, the Solomon Islands, and Vietnam. Five males aged 9 to 48 years were improperly classified as G6PD-normal by various screening procedures and included as subjects in trials of anti-relapse therapy with daily primaquine. Routine safety monitoring by physical examination, urine inspection, and blood haemoglobin (Hb) assessment were performed in all those trials. Early signs of acute haemolysis, i.e., dark urine and haemoglobin drop >20%, occurred only after day 3 and as late as day 8 of primaquine dosing. All patients were hospitalized and fully recovered, all but one following blood transfusion rescue. Hb nadir was 4.7 to 7.9 g/dL. Hospitalization was for 1 to 7 days. Hb levels returned to baseline values 3 to 10 days after transfusion. Failed G6PD screening procedures in these trials led G6PD-deficient patients to suffer harmful exposures to primaquine. The safe application of primaquine anti-relapse therapy requires G6PD screening and anticipation of its failure with a means of prompt detection and rescue from the typically abrupt haemolytic crisis.

Plasmodium vivax Malaria and G6PD Testing

“…They report on five cases of PQ-induced acute haemolytic anaemia that occurred in G6PD deficient males enrolled in four clinical trials in Indonesia, the Solomon Islands, and Vietnam. These patients had been wrongly classified as G6PD normal, and in four of them, drug-induced haemolytic anemia was severe enough to require blood transfusion [21]. This paper illustrates that no diagnostic test is perfect; while all patients recovered without sequelae the outcome might have been different outside a well-conducted clinical trial.…”

“…Kosasih et al [21], with authors from Indonesia, Australia, France, the Solomon Islands, Thailand, and the UK, report the consequences of having missed a diagnosis of G6PD deficiency. They report on five cases of PQ-induced acute haemolytic anaemia that occurred in G6PD deficient males enrolled in four clinical trials in Indonesia, the Solomon Islands, and Vietnam.…”