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

Author summary Why was this study done? is the most geographically widespread human malaria species; outside of sub-Saharan Africa, it almost invariably coexists with . . A recent systematic review of 153 studies across 21 countries revealed that within 63 days of being treated for . monoinfection, more than 15% of patients treated with an artemisinin-based combination therapy (ACT) had an episode of . malaria, far greater than expected for patients in similar locations who do not have acute malaria. We hypothesised that patients presenting with . in coendemic locations are at high risk of carrying . dormant liver stages (hypnozoites) and would therefore potentially benefit from presumptive radical cure. What did the researchers do and find? We undertook an individual patient data meta-analysis to define the risk of vivax parasitaemia (blood stream infection) after treatment of . malaria in different coendemic environments and to explore the factors underlying these risks. In total, 42 studies enrolling 15,341 patients were included in the analysis. By day 63, the risk of . ranged from 12.8% following dihydroartemisinin-piperaquine (DP) to 42.4% following artesunate-amodiaquine (AA). The highest rate of . malaria was in patients residing in areas with high risk of relapses and those who were slow to clear their initial parasitaemia. What do these findings mean? There is a high risk of vivax malaria after treatment of falciparum infection after all ACTs, although the risk varies substantially between locations. The correlation between the risk of . and the initial clearance of . raises the possibility that the host response to acute malaria may be triggering the reactivation of . dormant liver stages. Universal radical cure with treatment to kill the liver stages may be warranted for reducing . , but the benefits will vary considerably between geographical locations, and further prospective clinical efficacy studies will be needed to determine the risks and benefits of such a strategy. 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.