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Meta-Analysis
. 2020 Nov 19;17(11):e1003393.
doi: 10.1371/journal.pmed.1003393. eCollection 2020 Nov.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network

Mohammad S Hossain  1   2   3   4 , Robert J Commons  1   2   5 , Nicholas M Douglas  2   3 , Kamala Thriemer  2 , Bereket H Alemayehu  6 , Chanaki Amaratunga  7 , Anupkumar R Anvikar  8 , Elizabeth A Ashley  9   10 , Puji B S Asih  11 , Verena I Carrara  9   12 , Chanthap Lon  13   14 , Umberto D'Alessandro  15 , Timothy M E Davis  16 , Arjen M Dondorp  9   17 , Michael D Edstein  18 , Rick M Fairhurst  7 , Marcelo U Ferreira  19 , Jimee Hwang  20   21 , Bart Janssens  22 , Harin Karunajeewa  23   24 , Jean R Kiechel  25 , Simone Ladeia-Andrade  26   27 , Moses Laman  16   28 , Mayfong Mayxay  9   10   29 , Rose McGready  9   12 , Brioni R Moore  16   30 , Ivo Mueller  31   32   33 , Paul N Newton  9   10   17 , Nguyen T Thuy-Nhien  34 , Harald Noedl  35 , Francois Nosten  9   12 , Aung P Phyo  12   36 , Jeanne R Poespoprodjo  37   38   39 , David L Saunders  40 , Frank Smithuis  9   36   41 , Michele D Spring  13 , Kasia Stepniewska  1   9 , Seila Suon  42 , Yupin Suputtamongkol  43 , Din Syafruddin  11   44 , Hien T Tran  9   34 , Neena Valecha  8 , Michel Van Herp  22 , Michele Van Vugt  12   17   45 , Nicholas J White  9   17 , Philippe J Guerin  1   9 , Julie A Simpson  1   3 , Ric N Price  1   2   9   17
Affiliations
Meta-Analysis

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network

Mohammad S Hossain et al. PLoS Med. .

Abstract

Background: There is a high risk of Plasmodium vivax 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.

Methods and findings: 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 P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax 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 P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. 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 P. falciparum 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 P. vivax 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 < 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 < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high.

Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax 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.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: RMF is employed currently by AstraZeneca but has no financial stake in the results of the current study. EAA and NJW are Academic Editors on PLOS Medicine's editorial board, and IM was previously an Academic Editor.

Figures

Fig 1
Fig 1. Study flowchart.
AA, artesunate-amodiaquine; ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AM, artesunate-mefloquine; DP, dihydroartemisinin-piperaquine; WWARN, WorldWide Antimalarial Resistance Network.
Fig 2
Fig 2. Cumulative risk (Kaplan–Meier analysis) of P. vivax parasitaemia following ACTs. *ACTs (AA, AL, AM, DP).
†P. vivax recurrence includes recurrences with P. vivax monoinfection or mixed-species infection. AA, artesunate-amodiaquine; ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AM, artesunate-mefloquine; DP, dihydroartemisinin-piperaquine.
Fig 3
Fig 3. Cumulative risk (Kaplan–Meier analysis) of P. vivax parasitaemia after P. falciparum infection by study for AL. AL, artemether-lumefantrine.
Fig 4
Fig 4. Cumulative risk (Kaplan–Meier analysis) of P. vivax parasitaemia after P. falciparum infection by study for AA. AA, artesunate-amodiaquine.
Fig 5
Fig 5. Cumulative risk (Kaplan–Meier analysis) of P. vivax parasitaemia after P. falciparum infection by study for AM. AM, artesunate-mefloquine.
Fig 6
Fig 6. Cumulative risk (Kaplan–Meier analysis) of P. vivax parasitaemia after P. falciparum infection by study for DP. DP, dihydroartemisinin-piperaquine.
Fig 7
Fig 7. Risk of P. vivax parasitaemia following falciparum infection between day 7 and day 42 according to treatment.
Dotted lines demonstrate 95% CIs. Figure adjusted for age, sex, baseline parasitaemia, regional relapse periodicity, P. falciparum gametocytes, mixed infection, and baseline Hb, assuming no study-site effect. AA, artesunate-amodiaquine; AL, artemether-lumefantrine; AM, artesunate-mefloquine; DP, dihydroartemisinin-piperaquine; Hb, haemoglobin.
Fig 8
Fig 8. Risk of P. vivax parasitaemia following falciparum infection between days 7 and 63 according to treatment and day of parasite clearance: (A) AL, (B) AA, (C) AM, and (D) DP.
Figure adjusted for age, sex, baseline parasitaemia, regional relapse periodicity, P. falciparum gametocytes, mixed infection at baseline, and Hb at baseline, assuming no study-site effect. AA, artesunate-amodiaquine; AL, artemether-lumefantrine; AM, artesunate-mefloquine; DP, dihydroartemisinin-piperaquine; Hb, haemoglobin.
Fig 9
Fig 9. Risk of P. vivax parasitaemia at day 42 following treatment with AL according to background subnational incidence of P. vivax (A) and P. falciparum (B).
rs = 0.676, p = 0.0029 (A) and rs = 0.607, p = 0.0098 (B). AL, artemether-lumefantrine.
See this image and copyright information in PMC

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