Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria

Abstract

BACKGROUND Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.” METHODS We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, −4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123.)

Tafenoquine for the radical cure and prevention of malaria: the importance of testing for G6 PD deficiency

“…It should be noted that these trials did not account for reduced adherence and effectiveness of a prolonged primaquine regimen under programmatic conditions and did not compare tafenoquine with high dose primaquine regimens (eg, 0.5 mg/kg/day for 14 days), which are recommended in East Asia and Oceania . Safety profiles for tafenoquine and primaquine were similar in these studies, when treatment was restricted to patients with normal G6PD activity (≥ 70%) …”

“…Since tafenoquine is eliminated slowly, it can cause more prolonged exposure to oxidative stress that cannot be mitigated by drug cessation. Therefore, the recommended threshold of enzyme activity for tafenoquine prescription is more stringent, and females with intermediate G6PD activity (< 70% enzymatic activity) should be excluded based on the pivotal clinical studies performed for the licensing of tafenoquine for radical cure …”

“…Tafenoquine has been shown to be non‐inferior to low dose primaquine regimens (15 mg daily or about 0.25 mg/kg/day for 14 days) for radical cure of P. vivax in multicentre randomised controlled trials . It should be noted that these trials did not account for reduced adherence and effectiveness of a prolonged primaquine regimen under programmatic conditions and did not compare tafenoquine with high dose primaquine regimens (eg, 0.5 mg/kg/day for 14 days), which are recommended in East Asia and Oceania .…”

Malaria in Gold Miners in the Guianas and the Amazon: Current Knowledge and Challenges

“…Although the risk of emergence of resistant P. falciparum has been the main concern until now, the increasing proportion of P. vivax cases leads to other challenges: the control of hypnozoites with the prevention of relapses and the emergence of choloroquine-resistant P. vivax [, [64][65][66]. The role of tafenoquine for hard-to-reach populations could be discussed for future strategies [67,68].…”

Defeating malaria: new weapons against one of our deadliest foes

“…A single dose of 300mg tafenoquine, taken on the first or second day of treatment of the blood stage, should ensure very good compliance. 17,18 Tafenoquine will be made available for the radical cure of relapsing P. vivax malaria, at a not-for-profit, not-for-loss price to make it affordable for economically disadvantaged communities. "…”