Risk of Plasmodium vivax parasitaemia after Plasmodium falciparum infection: a systematic review and meta-analysis

Abstract

Background: A 14-day course of primaquine is used for radical cure of Plasmodium vivax and Plasmodium ovale malaria only. We quantified the risk of P vivax parasitaemia after treatment of Plasmodium falciparum with commonly used antimalarial drugs to assess the potential benefits of radical cure for all patients with uncomplicated malaria in co-endemic regions.

Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for prospective clinical studies in any language, published between Jan 1, 1960, and Jan 5, 2018, assessing drug efficacy in patients with uncomplicated P falciparum malaria in countries co-endemic for P vivax. Studies were included if the presence or absence of P vivax parasitaemia was recorded after treatment. The primary outcome was the risk of P vivax parasitaemia between day 7 and day 42 after initiation of antimalarial treatment for P falciparum, with the pooled risk calculated by random-effects meta-analysis. We compared the risk of P vivax parasitaemia after treatment with different artemisinin-based combination therapies (ACTs). This study is registered with PROSPERO, number CRD42017064838.

Findings: 153 of 891 screened studies were included in the analysis, including 31 262 patients from 323 site-specific treatment groups: 130 (85%) studies were from the Asia-Pacific region, 16 (10%) from the Americas, and seven (5%) from Africa. The risk of P vivax parasitaemia by day 42 was 5·6% (95% CI 4·0-7·4; I²=92·0%; 117 estimates). The risk of P vivax parasitaemia was 6·5% (95% CI 4·6-8·6) in regions of short relapse periodicity compared with 1·9% (0·4-4·0) in regions of long periodicity, and was greater after treatment with a more rapidly eliminated ACT: 15·3% (5·1-29·3) for artemether-lumefantrine compared with 4·5% (1·2-9·3) for dihydroartemisinin-piperaquine and 5·2% (2·9-7·9) for artesunate-mefloquine. Recurrent parasitaemia was delayed in patients treated with ACTs containing mefloquine or piperaquine compared with artemether-lumefantrine, but by day 63 the risk of vivax parasitaemia was more than 15% for all ACTs assessed.

Interpretation: Our findings show a high risk of vivax parasitaemia after treatment of falciparum malaria, particularly in areas with short relapse periodicity and after rapidly eliminated treatment. In co-endemic regions, universal radical cure for all patients with uncomplicated malaria has the potential to substantially reduce recurrent malaria.

Funding: Australian National Health and Medical Research Council, Royal Australasian College of Physicians, Wellcome Trust, and Bill & Melinda Gates Foundation.

Figure 1

Study selection * Citations and reasons for exclusion are given in the appendix (pp 21, 60–89). †As defined by the Malaria Atlas Project. ‡Countries that reported or were suspected to have cases of indigenous Plasmodium falciparum and Plasmodium vivax in 2016 according to WHO's World Malaria Report 2017. §Outcomes for two treatment groups in the study by Li and colleagues were not reported and these groups were also excluded. ¶Other reasons for exclusion are listed in the appendix (p 21).

Figure 2

Risk of Plasmodium vivax parasitaemia or any parasitaemia after Plasmodium falciparum infection by artemisinin-based combination therapy and day of follow-up Risk is the percentage of patients with P vivax parasitaemia or any parasitaemia. AL=artemether-lumefantrine. DP=dihydroartemisinin-piperaquine. AM=artesunate-mefloquine.

Figure 3

Risk of recurrent Plasmodium vivax parasitaemia by day 42 after Plasmodium falciparum infection by drug elimination half-life Red diamonds represent subtotals or totals. Full reference citations and study and record details are provided in the appendix pp 14–20, 22–36. As=artesunate. Qu=quinine. Dox=doxycycline. Tet=tetracycline. RE=random effects. AL=artemether-lumefantrine. Az=azithromycin. Hal=halofantrine. PNG=Papua New Guinea. At=atovaquone. Pg=proguanil. AQ=amodiaquine. SP=sulfadoxine-pyrimethamine. CQ=chloroquine. DP=dihydroartemisinin-piperaquine. AM=artesunate-mefloquine. MQ=mefloquine. Py=pyronaridine. PQ=primaquine. unsup=unsupervised. sup=supervised. Art=artemisinin. N=naphthoquine. Pqp=piperaquine. Am=artemether. Dha=dihydroartemisinin. *Treatment group described by drug with number of days given (total dose) if needed to distinguish from other treatment groups. †Data are number of patients with P vivax parasitaemia/total evaluable patients at day 42. ‡Risk is the percentage of patients with P vivax parasitaemia. §Asadabad, Afghanistan. ¶Jalalabad, Afghanistan. ||Multisite, Afghanistan. **Promoy (Pursat province), Cambodia. ††Tasanh (Battambang province), Cambodia. ‡‡Pailin City (Pailin province), Cambodia. §§Changlang, India. ¶¶Lunglei, India. ||||Gomati, India. ***Multiple antimalarials—studies with aggregated treatment data where drug elimination half-life varies; refer to appendix p 7 for drugs included in rapid, intermediate, and slow half-life elimination categories.

Figure 3

Risk of recurrent Plasmodium vivax parasitaemia by day 42 after Plasmodium falciparum infection by drug elimination half-life Red diamonds represent subtotals or totals. Full reference citations and study and record details are provided in the appendix pp 14–20, 22–36. As=artesunate. Qu=quinine. Dox=doxycycline. Tet=tetracycline. RE=random effects. AL=artemether-lumefantrine. Az=azithromycin. Hal=halofantrine. PNG=Papua New Guinea. At=atovaquone. Pg=proguanil. AQ=amodiaquine. SP=sulfadoxine-pyrimethamine. CQ=chloroquine. DP=dihydroartemisinin-piperaquine. AM=artesunate-mefloquine. MQ=mefloquine. Py=pyronaridine. PQ=primaquine. unsup=unsupervised. sup=supervised. Art=artemisinin. N=naphthoquine. Pqp=piperaquine. Am=artemether. Dha=dihydroartemisinin. *Treatment group described by drug with number of days given (total dose) if needed to distinguish from other treatment groups. †Data are number of patients with P vivax parasitaemia/total evaluable patients at day 42. ‡Risk is the percentage of patients with P vivax parasitaemia. §Asadabad, Afghanistan. ¶Jalalabad, Afghanistan. ||Multisite, Afghanistan. **Promoy (Pursat province), Cambodia. ††Tasanh (Battambang province), Cambodia. ‡‡Pailin City (Pailin province), Cambodia. §§Changlang, India. ¶¶Lunglei, India. ||||Gomati, India. ***Multiple antimalarials—studies with aggregated treatment data where drug elimination half-life varies; refer to appendix p 7 for drugs included in rapid, intermediate, and slow half-life elimination categories.

Figure 3

Risk of recurrent Plasmodium vivax parasitaemia by day 42 after Plasmodium falciparum infection by drug elimination half-life Red diamonds represent subtotals or totals. Full reference citations and study and record details are provided in the appendix pp 14–20, 22–36. As=artesunate. Qu=quinine. Dox=doxycycline. Tet=tetracycline. RE=random effects. AL=artemether-lumefantrine. Az=azithromycin. Hal=halofantrine. PNG=Papua New Guinea. At=atovaquone. Pg=proguanil. AQ=amodiaquine. SP=sulfadoxine-pyrimethamine. CQ=chloroquine. DP=dihydroartemisinin-piperaquine. AM=artesunate-mefloquine. MQ=mefloquine. Py=pyronaridine. PQ=primaquine. unsup=unsupervised. sup=supervised. Art=artemisinin. N=naphthoquine. Pqp=piperaquine. Am=artemether. Dha=dihydroartemisinin. *Treatment group described by drug with number of days given (total dose) if needed to distinguish from other treatment groups. †Data are number of patients with P vivax parasitaemia/total evaluable patients at day 42. ‡Risk is the percentage of patients with P vivax parasitaemia. §Asadabad, Afghanistan. ¶Jalalabad, Afghanistan. ||Multisite, Afghanistan. **Promoy (Pursat province), Cambodia. ††Tasanh (Battambang province), Cambodia. ‡‡Pailin City (Pailin province), Cambodia. §§Changlang, India. ¶¶Lunglei, India. ||||Gomati, India. ***Multiple antimalarials—studies with aggregated treatment data where drug elimination half-life varies; refer to appendix p 7 for drugs included in rapid, intermediate, and slow half-life elimination categories.