The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Abstract

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.

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

“…Parasite clearance delayed beyond day 3 was recently shown to be significantly associated with a higher risk of P. vivax recurrence at day 28 (30). Here we confirm that subjects with parasitemia detected by PCR (but not by microscopy) at day 3 were more likely to have day 28 recrudescence detected by either microscopy or PCR.…”

“…These data are consistent with the notion that PQ synergizes the blood schizontocidal effect of CQ against parasites with low-grade resistance (15). Accordingly, a meta-analysis of pooled individual patients' data has shown a 90% reduction in recurrence rates over 42 days among patients given a CQ-PQ combination, compared with CQ alone (30). Moreover, in our study, CQ-PQ coadministration appeared to favor faster parasite clearance, with a lower positivity rate by PCR and a lower frequency of gametocyte-specific transcript carriage at day 3, than with CQ alone, although these differences did not reach statistical significance.…”

“…Here we confirm that subjects with parasitemia detected by PCR (but not by microscopy) at day 3 were more likely to have day 28 recrudescence detected by either microscopy or PCR. Nevertheless, not all subjects with treatment failure by day 28 had delayed parasite clearance characterized in our and other studies (30), indicating that a short, 3-day follow-up of CQ-treated subjects would be unable to predict treatment failure by day 28 with acceptable sensitivity.…”

Chloroquine–Primaquine Therapeutic Efficacy, Safety, and Plasma Levels in Patients with Uncomplicated Plasmodium vivax Malaria in a Colombian Pacific Region

“…It has been found that the combination of PQ-CQ compared with CQ alone reduced early recurrences before day 42 by 90%, probably explained by the prevention of early relapses; PQ possibly contributes to reducing recrudescence through its blood schizonticidal activity. 49 Because of difficulties in carrying out in vitro studies with P. vivax to test resistance, in vivo efficacy studies offer an acceptable alternative to approach this matter, requiring continuous surveillance through therapeutic outcomes because various reports suggest P. vivax emerging CQ resistance around the globe.…”

Mapeamento de <i>hotspots</i> de transmissão de malária utilizando geolocalização de pacientes

“…Dentre as estratégias mais utilizadas para redução do pool de parasitas está o tratamento dos pacientes com terapias que consistem na administração de medicamentos como cloroquina, primaquina e artemisinina, variando de acordo com a espécie causadora, fase do ciclo de vida em que se encontram os parasitas, gravidade do quadro, entre outros (ABAY, 2013;COMMONS et al, 2018) . Por sua vez, a aplicação de inseticidas associados ou não ao uso de redes de proteção (ALONSO et al, 1991;NTONIFOR;VEYUFAMBOM, 2016) , buscam, seja através da redução da população de vetores ou através do uso de barreiras físicas, reduzir a interface de contato entre os mosquitos e a população humana, nas áreas de risco.…”