Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial

Abstract

BackgroundRecent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia.Methods and findingsPatients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42.The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%–10.4%) after CQ treatment and 0% (95% CI 0%–4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%–20.6%) following AL alone and 2.3% (95% CI 0.6%–9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%–28.0%) after CQ, 1.2% (95% CI 0.2%–8.0%) after CQ+PQ, 29.9% (95% CI 21.6%–40.5%) after AL, and 5.9% (95% CI 2.4%–13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0–3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9–9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6–11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms.The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia.ConclusionsDespite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y.Trial registrationClinicalTrials.gov NCT01680406

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study

“…Since the symptoms of malaria usually subside within 2 or 3 days of initiation of treatment, the incentive to take all doses of primaquine is low. Recent randomized controlled trials conducted in Thailand and Ethiopia demonstrated that directly observed primaquine therapy was associated with a 3-to-4-fold lower rate of vivax recurrence when compared to unsupervised therapy [ 7 , 27 ]. In our study, primaquine effectiveness was highest in young children, and this may reflect parental encouragement and supervision of tablet administration.…”

Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial

“…The current standard for the treatment of P. vivax malaria includes chloroquine administration for 3 days followed by 15 mg primaquine once daily for 14 days to prevent relapse; this dose may be increased up to 30 mg once daily primaquine for 14 days in some cases ( 2 , 3 ). This 14-day regimen of primaquine leads to poor patient compliance ( 4 ). Additionally, primaquine can cause hemolytic toxicity in subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency ( 5 ).…”

Low risk of recurrence following artesunate–Sulphadoxine–pyrimethamine plus primaquine for uncomplicated Plasmodium falciparum and Plasmodium vivax infections in the Republic of the Sudan

“…Sub-optimal drug dosage was defined as a total dose below 4 mg/kg for AS, below 25 mg/kg for Sulphadoxine and 1.25 mg/kg for pyrimethamine [ 13 , 14 ]. The sub-optimal PQ dose was defined as below 0.15 mg/kg in the Pf-PQ1 arm and below 2.5 mg/kg total dose of primaquine in the Pv-PQ14 arm [ 25 ].…”