Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial

Tine, Roger; Sylla, Khadime; Faye, Babacar; Poirot, Eugenie; Fall, Fatou; Sow, Doudou; Wang, Duolao; Ndiaye, Magatte; Ndiaye, Jean Louis; Greenwood, Brian; Gaye, Oumar; Milligan, Paul

doi:10.1093/cid/cix355

Cited by 27 publications

(50 citation statements)

References 32 publications

(39 reference statements)

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“…Ten new publications described seven new trials published since the last revision ( Dicko 2016 ; Gonçalves 2016a ; Gonçalves 2016b ; Mwaiswelo 2016 ; Okebe 2016 ; Lin 2017 ; Tine 2017 ). The Goncalves study is regarded as two trials because the two phases had different inclusion criteria ( Gonçalves 2016a ; Gonçalves 2016b ).…”

Section: Resultsmentioning

confidence: 99%

“…Five trials with artemisinin partners reported area under curve (AUC) or log(10)AUC as a summary combined measure of gametocyte prevalence and density over time, using PCR estimates of density ( Shekalaghe 2007 ; Eziefula 2013 ; Dicko 2016 ; Gonçalves 2016b ; Tine 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“… Participants with severe haemolysis as defined by the trial authors. It was defined as drop of ≥ 25% ( Dicko 2016 ; Mwaiswelo 2016 ), ≥ 2 g ( Gonçalves 2016b ), or ≥ 2 g of haemoglobin ( Tine 2017 ) over the course of follow‐up. …”

Section: Methodsmentioning

confidence: 99%

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Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Graves

Choi

Gelband³

et al. 2018

Cochrane Database of Systematic Reviews

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Background The 8‐aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low‐transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose‐6‐phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short‐course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘malaria*', ‘falciparum', ‘primaquine', ‘8‐aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi‐RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non‐artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi‐RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non‐artemisinin treatments (13 arms), and two trials included both artemisinin and non‐artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials ev...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Graves

Choi

Gelband³

et al. 2018

Cochrane Database of Systematic Reviews

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“…Occassionally, moderate or severe transient anaemia was observed after a single PQ-dose of 0.75 mg/kg [ 16 ]. More recently, the safety of the 0.25 mg/kg PQ dose was reported as ancillary analysis after a malaria elimination campaign on the Thai-Myanmar border [ 24 ], in a gametocyte clearance efficacy study in Tanzania [ 25 ], and in a randomized controlled safety trial in Senegal [ 26 ]. The first two studies observed mean relative reductions in hemoglobin of 4–8% 5–8 days after 0.25 mg/kg PQ in a subpopulation of G6PDd participants [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…While all studies suggested the WHO-recommended PQ dose was safe, only the study from Tine et al . intensively monitored G6PDd individuals who have a higher risk of hemolysis [ 26 ]. Markers of hemolysis, including reticulocyte counts, lactate dehydrogenase (LDH), haptoglobin and bilirubin concentrations were not examined.…”

Section: Introductionmentioning

confidence: 99%

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

et al. 2018

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BackgroundPrimaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria.Methods and findingsIn Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined.In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ.ConclusionsSingle low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy.Trial registrationClinicaltrials.gov NCT02174900Clinicaltrials.gov NCT02654730

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Migration Medicine

Greenaway

Castelli

2019

Infectious Disease Clinics of North America

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Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial

Cited by 27 publications

References 32 publications

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

Migration Medicine

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