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Vivax Recurrence Study Group

Analysis of risk factors of Plasmodium vivax early and late recurrence. 

Update and overview

The Vivax Recurrence Study Group was formed in April 2016, with an invitation to interested researchers with relevant data sets. Research groups with relevant data sets were contacted in 2016. Data gathering and curation are now complete. Statistical analysis on parasite recurrence following chloroquine +/- primaquine has been completed, and the publication drafted in early 2018.

The study: The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis was published in The Lancet Infectious Diseases in July 2018. Analysis of parasite recurrence following artemisinin combination therapies has also commenced and was completed in 2018. The study: The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: a systematic review and individual patient data meta-analysis was published in PLOS Medicine in October 2019. 

Rationale

Plasmodium vivax remains widespread, and outside of Africa, it is becoming the dominant cause of malaria. There is increasing recognition that recurrent vivax malaria is associated with recurrent symptomatic illness and anaemia with attributable morbidity and mortality. Recurrent P. vivax can arise from recrudescence (treatment failure), reinfection (new infections from an infected mosquito bite) and relapse (reactivation from dormant liver stages). Whilst it is currently impossible to differentiate reliably between these alternatives, early recurrence is more likely to be due to recrudescence, whereas later recurrences are more likely to be due to relapse and reinfection. The risk, frequency and timing of recurrence is dependent upon host, parasite and drug factors including: antimalarial drug resistance, the pharmacokinetic profile of the antimalarial agents administered, the use of hypnozoiticidal drugs and the endemic setting (relapse patterns and endemicity). The relative contributions of these risk factors have not been comprehensively evaluated. If the risks and benefits of radical cure are to be quantified, there was a need to further understand the factors that impact on recurrence, with and without radical therapy. 

Objectives

The study group had two main objectives which required complementary but discrete analyses:

  1. To assess the risk of early vivax recurrence before day 42 and associated risk factors:
  • Identify key host, parasite and pharmacological determinants including:

               - The effect of different schizontocidal treatments including mg/kg dose

               - The effect of different primaquine treatments including mg/kg dose

  • Determine the relationship between parasite clearance and early vivax recurrence

2. To assess the risk of late vivax recurrence after day 42 with and without primaquine treatment:

  • Identifying key host, parasite, geographical and pharmacological determinants including the effect of different primaquine treatments including mg/kg dose

Essential inclusion criteria

  • Prospective clinical efficacy studies of uncomplicated vivax malaria with a minimum 28 days follow up:
    • 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, 1, 2 and 3

Desirable criteria

  • Mg/Kg dosing
  • Weight of the patient
  • Documentation on the supervision of drug administration
  • Genotyping to potentially distinguish recrudescence and reinfection
  • Day 7 drug levels
  • Number of days of symptoms before enrollment
  • Haemoglobin (hb) or hematocrit (hct) or red blood count (RBC) measured on day 0
  • Information on splenomegaly, hepatomegaly
  • Malnutrition as gauged by weight and age +/- height or MUAC
  • Additional comorbidities
  • Qualitative or quantitative assessment of G6PD status 

Data standardisation and statistical analysis

After upload to the WWARN Data Repository, WWARN standardised data sets according to the WWARN Clinical Data Management and Statistical Analysis Plan and pooled all primary data sets into a single database of quality-assured individual patient data. Baseline risk factors assessment for early and late recurrence (adjusted and unadjusted for geographic location) were performed in a variety of subgroups after controlling for known confounding factors. In particular, the effect of parasite clearance, chloroquine mg/kg dosing and primaquine mg/kg dosing and timing on early and late recurrence were analysed.

A detailed statistical analysis plan has been developed.

Study group governance

The Vivax Recurrence Study Group comprised participating investigators who contributed relevant data sets to the pooled analysis. Data sets remained the property of the investigator and will not be shared without their consent. The WWARN statistician(s) oversaw the statistical analyses. The Study Group collectively made decisions with respect to including additional studies, and publication decision-making. Participating investigators were recognised in publication as contributors under the banner of the Vivax Recurrence Study Group. The Study Group assigned a Writing Committee to coordinate activities including data analysis, and drafting of publications and reports for complete group review. The Writing Committee comprised a group of interested investigators undertaking the data analysis and preparation of the manuscript. Authors were recognised according to the ICMJE guidelines and the WWARN publication policy.

For further information, please contact Rob Commons clinical [at] wwarn [dot] org