SummaryBackgroundChloroquine 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.MethodsA 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.FindingsOf 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).InterpretationChloroquine 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.FundingWellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

BackgroundControl of vivax malaria in endemic areas requires management of recurrence. The Brazilian National Malaria Surveillance System (SIVEP-Malária) records every case of malaria in Brazil, but is not designed to differentiate between primary and recurrent infections. The aim of this study was to explore whether the information provided by SIVEP-Malária could be used to identify Plasmodium vivax recurrences, its risk factors and evaluate the effectiveness of short course primaquine (7–9 days: total dose 3–4.2 mg/kg) in preventing relapses.MethodsIn this observational retrospective cohort study, data matching of SIVEP-Malária records was undertaken using bloom filters to identify potential recurrences defined as microscopically-confirmed P. vivax episodes from the same individual occurring within a year. Generalized Estimation Equation (GEE) models were used to determine predictors of recurrence. Extended Cox-based conditional Prentice–Williams–Peterson models (PWP) models were used to evaluate time to recurrence.ResultsBetween June 1, 2014 and May 31, 2015, 26,295 episodes fulfilled the criteria of potential recurrence among 154,970 reported malaria episodes. Age ≤ 3 years, being male, literate, not-indigenous and having domestic working activities were identified as risk factors for recurrence. There was no difference in time to recurrence or recurrence frequency between patients treated with 14-day or 7–9 day primaquine regimens (HR = 1.02, 0.96–1.09) and RR = 0.97 (0.90–1.04), respectively. The use of chloroquine alone was associated with a 1.43 (1.29–1.58, p < 0.0001) increased risk of P. vivax recurrence compared to patients who used chloroquine combined with short-course primaquine, the Brazilian standard of care. This was RR = 2.06 (1.48–2.86, p < 0.0001), RR = 1.90 (1.60–2.25, p = 0.0001) and RR = 1.14 (1.00–1.29, p = 0.05) for recurrences occurring between 3–28, 29–60 and > 60 days, respectively. PWP models showed that the time to recurrence was longer in recipients of both primaquine and artemisinin-based combination therapy (ACT) compared to patients treated with chloroquine alone or with concomitant primaquine, HR = 2.2 (1.62–2.99, p < 0.0001), HR = 1.27 (0.97–1.66, p = 0.08), respectively.ConclusionShort course primaquine was as effective as 14-day regimens and associated with a halving of the risk and delay in time to recurrence of P. vivax infections in comparison to chloroquine alone. The study demonstrates the feasibility of using record linkage on routine surveillance data to identify potential P. vivax recurrences, associated risk factors and impact of treatment.Electronic supplementary materialThe online version of this article (10.1186/s12936-019-2644-y) contains supplementary material, which is available to authorized users.

Background Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax . Methods A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was − 0.13 g/dL [− 0.27, 0.01] lower at day of nadir ( p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 ( p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration − 0.72 g/dL [− 0.90, − 0.54] lower than patients without recurrence ( p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial registration This trial was registered with PROSPERO: CRD42016053312 . The date of the first registration was 23 December 2016. Electronic supplementary material The online version of this article (10.1186/s12916-019-1386-6) contains supplementary material, which is available to authorized users.

BackgroundArtemisinin-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 findingsClinical 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.ConclusionsIn 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.

BackgroundStudies in South-East Asia have suggested that early diagnosis and treatment with artesunate (AS) and mefloquine (MQ) combination therapy may reduce the transmission of Plasmodium falciparum malaria and the progression of MQ resistance.MethodsThe effectiveness of a fixed-dose combination of AS and MQ (ASMQ) in reducing malaria transmission was tested in isolated communities of the Juruá valley in the Amazon region.Priority municipalities within the Brazilian Legal Amazon area were selected according to pre-specified criteria. Routine national malaria control programmatic procedures were followed. Existing health structures were reinforced and health care workers were trained to treat with ASMQ all confirmed falciparum malaria cases that match inclusion criteria. A local pharmacovigilance structure was implemented. Incidence of malaria and hospitalizations were recorded two years before, during, and after the fixed-dose ASMQ intervention. In total, between July 2006 and December 2008, 23,845 patients received ASMQ. Two statistical modelling approaches were applied to monthly time series of P. falciparum malaria incidence rates, P. falciparum/Plasmodium vivax infection ratio, and malaria hospital admissions rates. All the time series ranged from January 2004 to December 2008, whilst the intervention period span from July 2006 to December 2008.ResultsThe ASMQ intervention had a highly significant impact on the mean level of each time series, adjusted for trend and season, of 0.34 (95%CI 0.20 – 0.58) for the P. falciparum malaria incidence rates, 0.67 (95%CI 0.50 – 0.89) for the P. falciparum/P. vivax infection ratio, and 0.53 (95%CI 0.41 – 0.69) for the hospital admission rates. There was also a significant change in the seasonal (or monthly) pattern of the time series before and after intervention, with the elimination of the malaria seasonal peak in the rainy months of the years following the introduction of ASMQ. No serious adverse events relating to the use of fixed-dose ASMQ were reported.ConclusionsIn the remote region of the Juruá valley, the early detection of malaria by health care workers and treatment with fixed-dose ASMQ was feasible and efficacious, and significantly reduced the incidence and morbidity of P. falciparum malaria.

Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews Analysis 4.2. Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high-standard 0.5 mg/kg/day 14 days, Outcome 2: Recurrence by 12 months' follow-up subgrouped by geographical region.

Background Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s (http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/)

BackgroundMalaria remains a major public health problem, with half the world population at risk of contracting malaria. The effects of Plasmodium vivax on prosperity and longevity have been highlighted in several recent clinical case reports. The first line of vivax treatment drugs has seen no radical innovation for more than 60 years. This study introduces a subtle incremental innovation to vivax treatment: a chloroquine and primaquine co-blister. The co-blister includes a new chloroquine formulation incorporating coated tablets to mask the drug’s bitter taste and user-friendly packaging containing tablets of each drug, which may improve patient adherence and facilitate the appropriate use of the drugs. This new formulation will replace the non-coated chloroquine distributed in Brazil.MethodsPatients were orally treated with 150 mg coated chloroquine tablets for 3 days: an initial 450 mg dose, followed by two 300 mg doses. The patients were treated concomitantly with two 15 mg primaquine tablets for 7–9 days, according to their weight. The primary objective of this study was to prove parasitological and clinical cure rates above 90 % by day 28.ResultsThis single-arm open-label non-comparative trial was conducted according to the WHO recommended methodology for the surveillance of anti-malarial drug efficacy in the Brazilian Amazon. On day 28, the parasitological and clinical response was adequate in 98.8 % of patients (CI 95 % 93.4–100 %). The success rate on day 3 was 100 %, and the cumulative success rate by day 28 was 98.8 % (CI 95 % 91.7–99.8 %). There were no serious adverse events, with most adverse events classified as mild. The pharmacokinetic parameters of chloroquine analysed in whole blood dry spot samples showed mean (coefficient of variation) Cmax and AUC0–t values of 374.44 (0.35) and 3700.43 (0.36) ng/mL, respectively.DiscussionThis study reports an appropriate safety and efficacy profile of a new formulation of coated chloroquine tablets for vivax malaria treatment in the Brazilian Amazon. The cure rates meet the WHO efficacy criteria, supporting current Brazilian guidelines and the use of the formulation for vivax malaria treatment. Nevertheless, further studies should be conducted to address adherence and the effectiveness of the formulation.Trial registration RBR-77q7t3-UTN: U1111-1121-2982. Registered 10th May 2011Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1530-0) contains supplementary material, which is available to authorized users.