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<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>There is a high risk of <jats:italic>Plasmodium vivax</jats:italic> parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methods and findings</jats:title> <jats:p>A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic> between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic> parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> monoinfection and 1,195 (7.8%) mixed infection with <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> and <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic>. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic> parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p &lt; 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p &lt; 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Conclusions</jats:title> <jats:p>In this meta-analysis, we found a high risk of <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic> parasitaemia after treatment of <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> malaria that varied significantly between studies. These <jats:italic>P</jats:italic>. <jats:italic>vivax</jats:italic> infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.</jats:p> </jats:sec>

Original publication

DOI

10.1371/journal.pmed.1003393

Type

Journal

PLOS Medicine

Publisher

Public Library of Science (PLoS)

Publication Date

19/11/2020

Volume

17

Pages

e1003393 - e1003393