Single-Dose Tafenoquine to Prevent Relapse ofPlasmodium vivaxMalaria

Abstract

BACKGROUND Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed “radical cure”). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax . METHODS This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of prima-quine once daily for 14 days (129 patients). The primary outcome was the Kaplan– Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmith-Kline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167.)

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 .…”

Fever in a traveler returning from Ethiopia

“…It can be used for chemoprophylaxis against all Plasmodium species and, as a single dose, for presumptive antirelapse therapy. 25,26 Patients must be tested for glucose-6-phosphate dehydrogenase deficiency before receiving tafenoquine.…”

Determination of tafenoquine in human plasma by dispersive liquid‐liquid microextraction

“…haemolysis) prompted by primaquine . Regarding its pharmacological effects, TQ presents activity against hypnozoite forms of Plasmodium vivax and may also have a role in P. falciparum prophylaxis . However, its exact mechanism of action is unknown.…”