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Background: Primaquine is necessary for the radical cure of Plasmodium vivax malaria, but the optimum duration of treatment and best partner drug are uncertain. A randomized controlled trial was performed to compare the tolerability and radical curative efficacy of 7-day versus 14-day high-dose primaquine regimens (total dose 7mg/kg) with either chloroquine or dihydroartemisinin-piperaquine., Methods: Patients with uncomplicated P. vivax malaria on the Thailand-Myanmar border were randomized to either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine, either 0.5 mg/kg/day for 14 days or 1 mg/kg/day for 7 days. Adverse events within 42 days and 1-year recurrence rates were compared and their relationship with day 6 drug concentrations assessed., Results: Between February 2012 and July 2014, 680 patients were enrolled. P. vivax recurrences (all after day 35) occurred in 80/654 (12%) patients; there was no difference between treatments. Compared to the 7-day primaquine groups the pooled relative risk of recurrence in the 14-day groups was 1.15 (95% confidence interval 0.7 to 1.8). Hematocrit reductions were clinically insignificant except in G6PD female heterozygotes, 2 of whom had hematocrit reductions to <23% requiring blood transfusion., Conclusion: Radical cure should be deployed more widely. The radical curative efficacy in vivax malaria of 7-day high-dose primaquine is similar to the standard 14-day high-dose regimen. Chloroquine and dihydroartemisinin-piperaquine are both highly effective treatments of the blood stage infection. Quantitative point of care G6PD testing would ensure safe use of the 7-day high-dose primaquine regimen in G6PD heterozygous females., Clinical Trials Registration: NCT01640574., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Chloroquine has been recommended for Plasmodium vivax infections for >60 years, but resistance is increasing. To guide future therapies, the cumulative benefits of using slowly eliminated (chloroquine) vs rapidly eliminated (artesunate) antimalarials, and the risks and benefits of adding radical cure (primaquine) were assessed in a 3-way randomized comparison conducted on the Thailand-Myanmar border., Methods: Patients with uncomplicated P. vivax malaria were given artesunate (2 mg/kg/day for 5 days), chloroquine (25 mg base/kg over 3 days), or chloroquine-primaquine (0.5 mg/kg/day for 14 days) and were followed for 1 year. Recurrence rates and their effects on anemia were compared., Results: Between May 2010 and October 2012, 644 patients were enrolled. Artesunate cleared parasitemia significantly faster than chloroquine. Day 28 recurrence rates were 50% with artesunate (112/224), 8% with chloroquine (18/222; P < .001), and 0.5% with chloroquine-primaquine (1/198; P < .001). Median times to first recurrence were 28 days (interquartile range [IQR], 21-42) with artesunate, 49 days (IQR, 35-74) with chloroquine, and 195 days (IQR, 82-281) with chloroquine-primaquine. Recurrence by day 28, was associated with a mean absolute reduction in hematocrit of 1% (95% confidence interval [CI], .3%-2.0%; P = .009). Primaquine radical cure reduced the total recurrences by 92.4%. One-year recurrence rates were 4.51 (95% CI, 4.19-4.85) per person-year with artesunate, 3.45 (95% CI, 3.18-3.75) with chloroquine (P = .002), and 0.26 (95% CI, .19-.36) with chloroquine-primaquine (P < .001)., Conclusions: Vivax malaria relapses are predominantly delayed by chloroquine but prevented by primaquine., Clinical Trials Registration: NCT01074905.

Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings., Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310., Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8-35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69-0·97; p=0·021) and in children younger than 5 years (0·59, 0·41-0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1-7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05-0·17; p<0·0001)., Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax., Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Methylene blue, once discarded due to its unsettling yet mild side effects, has now found a renewed place in the pharmacopoeia of modern medicine. The continued spread of drug-resistant Plasmodium vivax and Plasmodium falciparum has also led to a recent re-examination of methylene blue's potent antimalarial properties. Here we examine the ex vivo susceptibility profile of Plasmodium spp. isolates to methylene blue; the isolates were from a region on the Thai-Myanmar border where there are increasing rates of failure when treating vivax malaria with chloroquine., Methods: To do this we used a newly developed ex vivo susceptibility assay utilizing flow cytometry and a portable flow cytometer with a near-UV laser., Results: P. vivax (median methylene blue IC50 3.1 nM, IQR 1.7-4.3 nM) and P. falciparum (median methylene blue IC50 1.8 nM, IQR 1.6-2.3 nM) are susceptible to methylene blue treatment at physiologically relevant levels. Unfortunately, the addition of chloroquine to combination treatments with methylene blue significantly reduces the ex vivo effectiveness of this molecule., Conclusions: Our data support further efforts to employ methylene blue as a safe, low-cost antimalarial to treat drug-resistant malaria., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and Findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Primaquine is the only licensed antimalarial for the radical cure of Plasmodium vivax infections. Many countries, however, do not administer primaquine due to fear of hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In other settings, primaquine is given without G6PD testing, putting patients at risk of hemolysis. New rapid diagnostic tests (RDTs) offer the opportunity to screen for G6PD deficiency prior to treatment with primaquine. Here we assessed the cost-effectiveness of using G6PD RDTs on the Thailand-Myanmar border and provide the model as an online tool for use in other settings. Methods/Principal findings: Decision tree models for the management of P. vivax malaria evaluated the costs and disability-adjusted life-years (DALYs) associated with recurrences and primaquine-induced hemolysis from a health care provider perspective. Screening with G6PD RDTs before primaquine use was compared to (1) giving chloroquine alone and (2) giving primaquine without screening. Data were taken from a recent study on the impact of primaquine on P. vivax recurrences and a literature review. Compared to the use of chloroquine alone, the screening strategy had similar costs while averting 0.026 and 0.024 DALYs per primary infection in males and females respectively. Compared to primaquine administered without screening, the screening strategy provided modest cost savings while averting 0.011 and 0.004 DALYs in males and females respectively. The probabilistic sensitivity analyses resulted in a greater than 75% certainty that the screening strategy was cost-effective at a willingness to pay threshold of US$500, which is well below the common benchmark of per capita gross domestic product for Myanmar. Conclusions/Significance: In this setting G6PD RDTs could avert DALYs by reducing recurrences and reducing hemolytic risk in G6PD deficient patients at low costs or cost savings. The model results are limited by the paucity of data available in the literature for some parameter values, including the mortality rates for both primaquine-induced hemolysis and P. vivax. The online model provides an opportunity to use different parameter estimates to examine the validity of these findings in other settings. [ABSTRACT FROM AUTHOR]

Introduction: Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections. Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria. A review was conducted with publications in English, French, Portuguese and Spanish using the search terms 'P. vivax' and 'relapse'.Areas Covered: Hypnozoites causing relapses may be activated weeks or months after initial infection. Incidence and temporal patterns of relapse varies geographically. Relapses derive from parasites either genetically similar or different from the primary infection indicating that some derive from previous infections. Malaria illness itself may activate relapse. Primaquine is the only widely available treatment for radical cure. However, it is often not given because of uncertainty over the risks of primaquine induced haemolysis when G6PD deficiency testing is unavailable. Recommended dosing of primaquine for radical cure in East Asia and Oceania is 0.5 mg base/kg/day and elsewhere is 0.25 mg base/kg/day. Alternative treatments are under investigation. Expert commentary: Geographic heterogeneity in relapse patterns and chloroquine susceptibility of P. vivax, and G6PD deficiency epidemiology mean that radical treatment should be given much more than it is today. G6PD testing should be made widely available so primaquine can be given more safely. [ABSTRACT FROM AUTHOR]