Vivax Haematological Study Group: Part 2

Vivax Haematological Study Group: Part 2

An analysis of the effect of recurrences and primaquine dose on haematological recovery.

Medical staff working with blood samples
Update and overview

The Vivax Haematological Study Group: Part 2 was formed in May 2019. Research groups with relevant data sets were contacted. Data gathering and curation are nearly finalised.


Recurrent P. vivax causes a cumulative risk of severe anaemia and attributable morbidity and mortality.  The haematological profile following vivax malaria is complex and related to the absolute risk of recurrent parasitaemia, the timing and frequency of these recurrences and the co-administration of primaquine. Following an acute episode of malaria, the mean Hb falls to a nadir on day 2-3 before recovering to baseline values at about day 28 to 42. Patients with recurrent parasitaemia have a lower Hb compared to those patients who remain aparasitaemic.  Although recurrent malaria can be prevented by co-administration with primaquine, these patients can have a greater initial fall in Hb compared to those treated with schizontocidal treatment (chloroquine or ACT) alone.

A recent large pooled analysis of the haematological response in patients with vivax malaria, focused on clinical trials in which patients were followed until the first recurrent episode of malaria.  Most of these studies had a duration of 42 days or less.  Whilst these data provide valuable insights into the early risks of anaemia they do not reflect the importance of the timing of recurrence over a prolonged follow up period and the effect of multiple recurrences.

This study aims to investigate the complex interaction between vivax recurrence and haemoglobin profile following treatment of the initial P. vivax infection.

  1. Investigate the effect of primaquine use and dose on i) haematological decline and recovery and ii) the risk of moderate and moderately severe anaemia.
  2. Quantify the association between the number and timing of recurrences and i) haematological decline and recovery and ii) the risk of moderate and moderately severe anaemia.
  3. Determine the effect of slowly and rapidly eliminated blood schizontocidal treatments on i) haematological decline and recovery and ii) the risk of moderate and moderately severe anaemia.
Essential inclusion criteria
  • Prospective clinical efficacy studies of uncomplicated vivax malaria with a minimum 90 days follow up:
    • Treatment with chloroquine or one of four common artemisinin-based combination therapies (artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, dihydroartemisinin-piperaquine) with or without primaquine (given over multiple days and commencing within seven days of blood schizontocidal treatment)
    • Follow up of patients irrespective of malaria recurrence(s) occurring (ie to study completion)
    • Information on dose of schizontocidal treatment
    • Information on use, timing and dose of primaquine
  • Study meta-data as described in the Clinical Data Management and Statistical Analysis Plan
  • Baseline data on patient age and gender
  • Parasite density at day 0
  • Parasite presence during follow up
  • Haemoglobin (hb) or hematocrit (hct) measured on day 0 and at least one further point throughout follow up
Desirable criteria
  • Information on dose of schizontocidal treatment
  • Weight
  • Individual tablet or mg dosing
  • Data on dose adherence
  • Documentation on the supervision of drug administration
  • Malnutrition as gauged by weight and age +/- height or MUAC
  • Qualitative or quantitative assessment of G6PD status
  • CYP2D6 status
  • History of malaria within the past 28 days
  • History of fever
  • Genotyping to potentially distinguish recrudescence and reinfection
  • Symptoms at recurrence
Data standardisation and statistical analysis

After upload to the WWARN Data Repository, WWARN will standardise data sets according to the WWARN Clinical Data Management and Statistical Analysis Plan and pool all primary data sets into a single database of quality-assured individual patient data.

Confounders will be selected using a causal diagram framework.

a) The proportion of patients with mild or moderate anaemia at day 90, 180 and 360 will be determined and described stratified by the use and dose of primaquine, number of recurrences, timing of recurrences, and antimalarial elimination half-life. 

b) Linear mixed effects modelling will be used to assess the impact of primaquine on haemoglobin over time, with estimation of the effect of primaquine on haemoglobin at the outcome day (day 90, 180 and 360) derived from the model

c) A Poisson regression model to assess incidence rate of moderate anaemia over 12 months will be undertaken on the subset of studies that followed patients actively and measured haemoglobin at least monthly.

d) Cox regression analysis for the time to first episode of moderate and moderately severe anaemia during follow-up (90, 180 and 360 days) will be performed separately, with shared frailty for study-site.

e) The effect of the total number of malaria episodes prior to the outcome day and timing of recurrences prior to the haemoglobin on the outcome day at day 90, 180 and 360 will be assessed using separate multivariable linear mixed-effects modelling. 

f) The effect of antimalarial half-life on haemoglobin at the outcome day (day 60, 90, 180 and 360) will be assessed using multivariable linear mixed-effects modelling. 

g) The analyses described in d) to f) above will be repeated using the clinical threshold of anaemia as the outcome using a multivariable logistic mixed effects model.

A detailed statistical analysis plan has been developed.

Study group governance

The Vivax Haematology Study Group: Part 2 comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the investigator and will not be shared without their consent. The WWARN statistician(s) will oversee the statistical analyses. Participating investigators will be recognised in publication as contributors under the banner of the Vivax Haematology Study Group: Part 2. A Writing Committee will coordinate activities including data analysis and drafting of publications and reports for complete group review. The Writing Committee will comprise Rob Commons, Julie Simpson, Nick Douglas, Cindy Chu, Nick White, Ric Price and other interested investigators. They are responsible for undertaking the data analysis and preparation of the manuscript. Authors will be recognised according to the ICMJE guidelines and the WWARN publication policy.

For further information, please contact Rob Commons on email: