medic examines infant, Cambodia

Vivax Adherence Study Group

Analysis of the effect of adherence to primaquine on the risk of recurrence in patients with Plasmodium vivax malaria.

Update and overview

The Vivax Adherence Study Group is an extension of The Vivax Recurrence Study Group, which was established in April 2016 (1).  A systematic review was undertaken in 2017 and the relevant research groups were contacted, and the available data collated. The systematic review was updated to include all studies up until May 2019 and any additional data sets were curated and added to.


Malaria is a leading cause of morbidity and mortality, with approximately 200 million clinical cases each year throughout the world. The WHO Global Technical Strategy for Malaria 2016–2030 has set the following ambitious goals for 2030: reducing malaria case incidence and mortality rates by at least 90% and eliminating malaria in at least 35 countries (2). Efficacious treatment of malaria is one of the key factors to achieve these goals. In this regard, adherence to antimalarial drugs is an important, but less emphasised factor, since clinical trials usually focus on the safety and efficacy of antimalarial drugs (3).

Most recommended antimalarial regimens for P. vivax require a three-day treatment of blood schizontocidal drugs plus a prolonged course of primaquine for hypnozoitocidal treatment. Since the primary aim of most clinical studies is to define or compare the efficacy of antimalarial regimens, treatment is usually supervised, particularly for the acute management of the blood stage infection, when the patient is clinically unwell. However, trials tend to vary in their approach to supervising the prolonged course of primaquine.

Pooled clinical trials of P. vivax will enable us to investigate how adherence to these regimens influences the treatment efficacy. These findings will be incorporated into within-host malaria mathematical models that link drug concentration profile with drug action within a patient, to investigate the impact of missing doses on parasite clearance and recurrent episodes of malaria.


1. To assess the effect of variable adherence on P. vivax efficacy:

  • Determine the association between P. vivax recurrence (defined as a recurrent episode between day 7 and 42) and imperfect adherence to schizontocidal and hypnozonticidal regimens
  • Identify the key patient factors that contribute to imperfect adherence

2. To develop a pharmacokinetic-pharmacodynamic within-host mathematical model for P. vivaxtreatment: 

  • Quantify the impact of missing dose(s) on the pharmacokinetic profile of primaquine
  • Using a simulation framework, assess the effect of imperfect adherence on P. vivaxrecurrence between day 7 and 42
  • Propose new efficacious primaquine dosing regimens that are easier to adhere to compared with the standard 14-day regimen

Essential inclusion criteria

  • Prospective clinical efficacy studies of uncomplicated vivax malaria with a minimum 28 days follow up:

    - Multi-day primaquine administered with schizontocidal treatments (chloroquine or artemisinin-based combination therapy) and commenced before day 3

    - Information on dose of schizontocidal treatment

    - Information on supervision, timing and dose of primaquine

Desirable criteria

  • Presence of fever at baseline and during follow-up
  • Mg/Kg dosing
  • Weight of the patient
  • Number of days of symptoms before enrolment
  • Haemoglobin or haematocrit measured on day 0 and during follow-up
  • Malnutrition as gauged by weight and age +/– height or MUAC
  • Qualitative or quantitative assessment of G6PD status

Data standardisation and analysis

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

Assessment of the risk of vivax recurrence with respect to level of adherence (adjusted and unadjusted for geographic location) will be performed in a variety of subgroups after controlling for known confounding factors. In particular, the effect of i) complete and partial primaquine mg/kg dosing and ii) whether a study is supervised or unsupervised, on parasite recurrence between day 7 and 42 will be estimated (4).

A detailed statistical analysis plan has been developed.

Study group governance

The Vivax Adherence Study Group 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. Parinaz Mehdipour, Professor Julie Simpson, Dr Saber Dini, Rob Commons and the WWARN statistician(s) will oversee the statistical analyses. The Study Group collectively makes decisions with respect to including additional studies, and plans for publication. Participating investigators will be recognized in publication as contributors under the banner of the Vivax Adherence Study Group. The Study Group will assign a Writing Committee to coordinate activities including data analysis, and drafting of publications and reports for complete group review. The Writing Committee will comprise a group of interested investigators 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: rob [dot] commons [at] wwarn [dot] org