Finger-prick of child for malaria blood slide

DP Dose Impact Study Group

Assessing the effect of mg/kg dosing strategies on the risk of treatment failure in patients treated with the currently recommended dose of dihydroartemisinin-piperaquine (DP)

 

Update and overview

The Dihydroartemisinin-Piperaquine (DP) Dose Impact Study Group found that the dihydroartemisinin-piperaquine demonstrates excellent efficacy in a wide range of transmission settings. However, treatment failure is associated with a lower dose of piperaquine, particularly in young children. This suggests potential to further optimise treatment regimens. The results of the Study Group were published in December 2013 in PLOS Medicine.

In the final analysis 7,072 patients from 26 published studies conducted in 2004-2013 were included. These studies represent 70 per cent of the targeted published literature on DP. Of these patients 39.7 per cent were from 12 studies conducted in Asia, 56.7 per cent from 13 studies from Africa, and 3.6 per cent from one study conducted in South America. The DP Dose Impact Study Group was formed in October 2011, with an open invitation to interested researchers with relevant data sets. A meeting of potential study group participants was held at the December 2011 ASTMH Annual Meeting to discuss the Study Group governance and publication policy. The study group closed December 2012. The manuscript was submitted August 2013 to PLOS Medicine.

Results from this study group provided evidence for the revised recommendations for optimal use of artemisinin combination therapies included in the updated WHO ‘Guidelines for the Treatment of Malaria in June 2015. Download a presentation from the DP Dose Impact Study Group.

Publication details:

WWARN DP Study Group. The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data. PLoS Med. 2013 Dec;10(12):e1001564 doi: 10.1371/journal.pmed.1001564 PubMedID: 24311989

Rationale

Artemisinin Combination Therapies (ACTs) efficacy is influenced by both the artemisinin derivative and the partner drug. The drugs should cure patients and also prevent the survival and spread of artemisinin resistant strains of Plasmodium. One of the most common partner drugs currently prescribed for uncomplicated malaria is piperaquine. The dosage of partner drugs must be sufficient to ensure that blood concentrations exceed the minimum inhibitory concentration of the parasite until all parasites have been killed. Although target doses are usually given as a total mg/kg over three days, in practice, manufacturers’ recommendations are often pragmatic and based upon weight ‘banding’. This approach inevitably results in some patients at the margins receiving either lower or higher dosages. Young children are particularly vulnerable to extreme total dosages especially when drug administration is based on tablets rather than paediatric formulations or suspensions. The problem is further confounded when dosing is recommended according to age bands rather than actual body weight. Preliminary modelling of dosing strategies according to known ‘weight for age’ demographics in malaria patients, suggests that the wide range of mg/kg dosing used may impact significantly on treatment efficacy and possibly safety. 

Objectives

  • Determine the mg/kg dosing range of dihydroartemisinin and piperaquine (DP)
  • Investigate the effects of dihydroartemisinin (DHA) and piperaquine (PIP) mg/kg dosing on early parasite response
  • Investigate the effects of DHA mg/kg dosing on gametocyte carriage
  • Investigate the effect of PIP mg/kg dosing on late parasitological response

Inclusion criteria

  • Published and unpublished studies enrolling patients treated with DP evaluated prospectively for clinical efficacy against P. falciparum (either alone or mixed infections), for a minimum of 28 days
  • Studies with information on the treatment dose administered, the age and weight of the patient, and if necessary, genotyping results to distinguish between new infections and recrudescent infections
  • Only patients completing a full 3-day treatment regimen included in the meta-analysis

Desirable criteria (not required for inclusion)

  • Drug manufacturer
  • Whether all doses were supervised
  • Whether drugs were administered with fat

Data standardisation and analysis

  • Data from selected studies compiled and standardised using WWARN standard methodology: Clinical Module: Data Management and Statistical Analysis Plan Version 1.2
  • Meta-analysis based on a priori data management and statistical analytical plan: Statistical Analysis Plan DHA-PQP Dose Impact Study Group. Version 1.9
  • Mg/kg dose of DHA and PIP administered calculated from the individual number of tablets administered to each patient daily or back-calculated based on the dosing strategy presented in the study protocol
  • Primary endpoint: PCR- adjusted risk of P. falciparum recrudescence at the end of study follow-up
  • Secondary endpoints: new infections of P. falciparum, parasitological clearance rates and gametocyte carriage
  • Incidence risk of the primary and secondary endpoints at day 28, day 42 and day 63 computed using survival analysis [Kaplan-Meier estimates (K-M)].
  • Univariable and multivariable analysis of risk factors associated with the primary and secondary endpoints conducted using Cox proportional hazards model with shared frailties on study sites to account for heterogeneous nature of the data
  • Population attributable risks (PARs) associated with recrudescent failures assessed
  • Relationship between drug dose and gastrointestinal side effects explored using logistic regression with random effects fitted for individual study & sites

Outcome

  • Twenty four published and two unpublished studies (N=7,072 patients) were included in the analysis 
  • Fifty seven percent patients from Africa, 40% from Asia and 3% from South America
  • Overall PCR-adjusted efficacy: 98.8% at day 28, 97.6% at day 42 and 97.0%  at day 63
  • Lower efficacy in children 1 to < 5 years at day 63:  94.4%
  • Overall: 22% of the patients exposed to a PIP dose < 48mg/kg (WHO recommended therapeutic range is 48 – 78 mg/kg)
  • Children aged 1 to <5 years at greater risk of exposure  to a dose below recommended dose range for DHA and PIP
  • Low Dose of DP was significant predictor of parasite positivity on day 3
  • A lower dose of DHA associated with gametocyte carriage on day 7
  • Main risk factors for PCR-confirmed recrudescence: age (1 up to 5 years), high baseline parasitemia and mg/kg dose of PIP
  • In children 1 up to 5 years, increasing the minimum target dose of PIP from 48 mg/kg to 59 mg/kg leads to a cure rate > 95%

Study Group governance

The Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. The Study Group will identify one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review. It is proposed that Prof Ric Price leads the Study Group ad interim

Acknowledgements

WWARN would like to thank the investigators who contributed individual patient data from published or unpublished clinical studies to the DP Dose Impact Study Group (see Related Documents for listing).

For further information, please contact the WWARN clinical team (clinical [at] wwarn [dot] org).

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