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Vivax After Falciparum Study Group

Exploration of the link between P. vivax recurrence and prior P. falciparum treatment, including increased risk of vivax parasitaemia due to acute malaria infection.

Overview

The Vivax After Falciparum Study Group was formed in March 2018, with an invitation to interested researchers with relevant data sets. Research groups with relevant data sets were contacted in early 2018, followed by data collation and analysis. The study group is now complete with the publication of: The risk of Plasmodium vivax parasitaemia after Pfalciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network in PLoS Medicine in November 2020.

Rationale

Recurrent P. vivax parasitaemia increases morbidity and the risk of ongoing transmission of malaria. In Thailand there is an increased risk of Plasmodium vivax parasitaemia after treatment of P. falciparum infection. This is hypothesized to be due to patients with falciparum malaria who have occult  P. vivax infection with the dormant liver stages (hypnozoites) being reactivated by acute malaria.

The risk of P. vivax after P. falciparum is likely to vary between regions. Dormant liver stages of P. vivax lead to relapse and the pattern of relapse varies with geographical region. The timing and frequency of relapse varies from weeks to months.

Chloroquine (CQ) is currently the first-line treatment for P. vivax infection, but in areas where CQ resistance is prevalent the World Health Organization recommends artemisinin-based combination therapy. In order to reduce the risk of P. vivax following P. falciparum in some co-endemic areas, there may be a significant benefit in providing universal radical cure with an ACT and primaquine to patients infected with either P. vivax or P. falciparum.

Objectives

1. To assess the risk of P. vivax parasitaemia up to day 63 following P. falciparum infection and compare to the risk of P. falciparum recurrence.

2. To quantify and compare the temporal distribution of P. vivax and P. falciparum recurrent parasitaemia.

3. To identify risk factors associated with P. vivax parasitaemia following the treatment of P. falciparum infection.

4. To compare the risk of P. vivax parasitaemia following P. falciparum infection with the expected background risk of P. vivax infection by location.

Essential inclusion criteria

- Prospective therapeutic efficacy trials of uncomplicated P. falciparum infection (including monoinfection and mixed P. falciparum and P. vivax infection)

- Study undertaken in a location co-endemic for P. vivax and P. falciparum

- Study observation period ≥28 days

- Available data on the patients age and gender

- Documented day of recurrence of all species of malaria

- Study meta-data as described in the Data Management and Statistical Analysis Plan

Desirable criteria:

- Baseline parasitaemia

- Baseline gametocytemia

- Haemoglobin or hematocrit measured on day 0

- Genotyping to potentially distinguish recrudescence and reinfection

- Mg/Kg dosing

- Malnutrition as gauged by weight and age +/- height or MUAC

Data standardisation and statistical analysis

After data upload in the WWARN Data Repository, according to the WWARN Clinical Data Management and Statistical Plan, they were standardised and pooled into a single database of quality-assured individual patient data. Baseline characteristics like parasitaemia, gametocytemia and haemoglobin were presented in a table. Risk of P. vivax parasitaemia and P. falciparum recurrence were investigated by Kaplan-Meier survival analysis. Risk factors for parasitaemia were investigated by multivariate Cox regression analysis with random effects for study site.

A detailed statistical analysis plan was developed and shared with all contributors.

Study group governance and ownership

The Study Group comprised participating investigators who contributed relevant data sets to the pooled analysis and technical experts. Data sets remain the property of the investigator. Prof Ric Price (ric [dot] price [at] wwarn [dot] org) is Study Group leader, with Robert Commons (rob [dot] commons [at] wwarn [dot] org) as Study Coordinator.

Publication

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, Moore BR, Mueller I, Newton PN, Thuy-Nhien NT, Noedl H, Nosten F, Phyo AP, Poespoprodjo JR, Saunders DL, Smithuis 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. The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network. PLoS Med. 2020 Nov 19;17(11):e1003393. doi: 10.1371/journal.pmed.1003393.