UMSP ANTIMALARIAL DRUG STUDIES

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UMSP ANTIMALARIAL DRUG STUDIES

• Adoke Yeka
• Uganda Malaria Surveillance Project Kampala,
  Uganda

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Introduction

• Malaria control in Africa largely relies on
  effective case management.
• This effort is compromised by the rapidly
  increasing resistance to the cheap and widely
  used drugs CQ and SP.
• Use of ACTs is strongly advocated, but concerns
  remain regarding cost and availability.
• There is limited comparative data on the efficacy
  and safety of ACTs in Africa.

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Objectives

• Compare the efficacy of combination regimens
• for the treatment of uncomplicated malaria at
• multiple sites in Uganda
• CQ SP
• AQ SP
• AQ AS

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Study Methodology

• Randomized, single blinded, clinical trials at 7
  sites with varying transmission intensity around
  Uganda
• Patient were followed up for 28-days
• Genotyping was done to distinguish recrudescence
  from new infections
• There were 2 comparative study designs
• 2-arm studies CQ SP vs. AQ SP
• 3-arm studies CQ SP vs. AQ SP vs. AQ AS

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Study Methodology

• Inclusion criteria
• Age gt 6 months
• Fever or history of fever in past 24 hours
• P. falciparum mono-infection
• Parasite density 2000/µl 200,000/µl
• No severe disease or other febrile illness
• Patients were randomised to receive
• CQ (25 mg/kg over 3 days) plus SP (25 mg/kg
  sulfadoxine, 125 mg/kg pyrimethamine, single
  dose)
• AQ (25 mg/kg over 3 days) plus SP
• AQ plus AS (4 mg/kg daily for 3 days).
• All treatment was directly observed.

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Assessment of Treatment Efficacy

• Outcomes classified according to 2003 WHO
  guidelines
• Early treatment failure (ETF)
• Late clinical failure (LCF)
• Late parasitological failure (LPF)
• Adequate clinical and parasitological response
  (ACPR)
• Risk of recurrent parasitemia (unadjusted by
  genotyping)
• Proportion of patients with ETF, LCF or LPF
• Risk of recrudescence (adjusted by genotyping)
• Risk of ETF or LCF/LPF due to recrudescent
  parasites using Kaplan-Meier product limit
  formula (new infections censored)

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BASELINE CHARACTERISTICS
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KANUNGU SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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MUBENDE SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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KYENJOJO SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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Summary of 2 arm studies

• Risk of recurrent parasitemia after 28 days is
  alarmingly high, underscoring the impact of new
  infections on antimalarial drug efficacy in
  Africa
• Risk of failure with CQ SP is alarmingly high
  in Uganda
• AQ SP was much more efficacious than CQ SP
• AQ SP greatly reduces the risk of recurrent
  parasitaemia.
• AQ SP greatly reduces the risk of recrudescence.

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JINJA SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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APAC SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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TORORO SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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ARUA SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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Summary of 3 arm studies

• Risk of recurrent parasitemia after 28 days is
  alarmingly high.
• New infections have a big impact on recurrent
  parasitemia even with ACT regimens.
• CQ SP is failing badly in Uganda
• AQ SP or AQ AS are much more efficacious
• AQ AS lowered risk of recrudescence
• AQ SP lowered risk of recurrent parasitemia,
  especially at the sites with the highest
  transmission intensity
• There is minimal difference in the risk of
  recrudescence between AQ SP and AQ AS

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AQAS vs AL STUDY

• Study conducted at Tororo in 2004 - 5 to assess
  efficacy and safety of proposed 1st line ACT
  regimens in Uganda.
• Randomised single blinded trial with 28 day
  follow up.
• Micro-satellites used for genotyping
• Recruited 200 patients per treatment arm
• Recruitment criteria similar for previous studies
  except
• Age 1-10 years
• Weight gt 10 kg.
• Directly observed therapy (6 dose for AL)

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TORORO SITERisk of treatment failure
Recrudescence
Recurrent Parasitemia
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Conclusion

• Risk of treatment failure with CQ SP was
  unacceptably high at all sites
• AQ SP was much more efficacious than CQ SP
• AL and AQAS were highly efficacious
• For both ACT regimens, the high rate of
  re-infection and the implications of frequent
  retreatment are a major concern.
• High malaria endemicity in Africa may impact on
  effectiveness of ACTs.
• For ACTs to be maximally effective, they may need
  to be combined with measures aimed to reduce
  transmission intensity

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Future studies.

• Efficacy and safety of ACTs (AL, DP, CDA etc)
• Efficacy and effectiveness of quinine as second
  line drug for uncomplicated malaria.
• Study deployment of ACTs
• Health facility vs HBMF
• Use of RDTs
• Pharmacovigilance for safety

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Thank You