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

Published: November 19, 2020

Citation

Hossain MS, Commons RJ, Douglas NM, Thriemer K, Alemayehu BH, Amaratunga C, Anvikar AR, Ashley EA, Asih PBS, Carrara VI, Lon C, D’Alessandro U, Davis TME, Dondorp AM, Edstein MD, Fairhurst RM, Ferreira MU, Hwang J, Janssens B, Karunajeewa H, Kiechel JR, Ladeia-Andrade S, Laman M, Mayxay M, McGready R, Mueller I, Newton PN, Thuy-Nhien NT, Noedl H, Nosten F, Phyo AP, Poespoprodjo JR, Saunders DL, Smithius F, Spring MD, Stepniewska K, Suon S, Suputtamongkol Y, Syafruddin D, Tran HT, Valecha N, Van Herp M, Van Vugt M, White NJ, Guerin PJ, Simpson JA, Price RN (2020) The risk of Plasmodium vivax parasitaemia after Pfalciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network. PLOS Medicine 17(11): e1003393. https://doi.org/10.1371/journal.pmed.1003393

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 Pvivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of Pvivax 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 Pfalciparum monoinfection and 1,195 (7.8%) mixed infection with Pfalciparum and Pvivax. 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 Pfalciparum 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 Pvivax 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 Pvivax parasitaemia after treatment of Pfalciparum malaria that varied significantly between studies. These Pvivax 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.