Longitudinal Comparison of Combination Antimalarial Therapies in Ugandan Children: Evaluation of Saf

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Longitudinal Comparison of Combination
Antimalarial Therapies in Ugandan Children
Evaluation of Safety, Tolerability, and
Efficacy(UO1 Study)

• MU-UCSF Malaria Research Collaboration

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Study Aims

• Compare the safety, tolerability, and efficacy of
  combined antimalarial therapies using a
  longitudinal design
• Follow plasmodial genetic polymorphisms as
  longitudinal markers of antimalarial drug
  resistance
• Evaluate the roles of host genetic polymorphisms
  in the incidence of malaria and in antimalarial
  drug resistance

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Value of longitudinal studies

• Prospective data on disease incidence
• Evaluation of true impact of different therapies
  on population health
• Prospective data on molecular epidemiology of
  antimalarial drug resistance
• Incidence data allows search for associations
  with other factors (host genetics, geography,
  etc.)

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Study population

• Census survey of Mulago III Parish conducted July
  - August 2004
• Completed by a team of Makerere University
  students
• Included enumeration of all households and GPS
  mapping
• Results of census project and recruitment for
  cohort study
• Total of 5171 households 4931 completed the
  survey
• 16,172 persons in less than 1 sq km
• Randomized list of 582 households approached for
  recruitment to obtain a representative study
  cohort
• 743 children screened
• 601 children out of 322 households enrolled

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Study Design

• 601 children enrolled between November 2004
  April 2005
• All participants to be followed for 3 years
• Study clinic open every day to provide all health
  care for participants
• Malaria blood smear performed each time child
  presents with new episode of fever. If smear
  positive, child diagnosed with malaria
• Child randomized to therapy at the first episode
  of malaria. Same therapy given for all subsequent
  episodes of malaria.
• Therapy directly observed with standardized
  assessment of treatment response
• Routine follow-up
• Malaria blood smear done every 30 days
• Phlebotomy performed every 90 days including
  hemoglobin measurement

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Study treatment

• Uncomplicated Malaria
• Children are randomized to one of 3 combination
  regimens currently recommended by WHO for Africa
• Amodiaquine Sulfadoxine/Pyrimethamine
• Amodiaquine Artesunate
• Coartem (Artemether Lumefantrine)
• Complicated Malaria
• Quinine
• Treatment failures
• within 14 days of treatment with study drugs
  Quinine
• after 14 days of treatment with study drugs
  Study drugs
• Other routine treatments according to IMCI
  guidelines
• Mebendozole every 6 months
• Vitamin A every 6 months
• Iron sulfate for participants with Hb lt10 g/dL

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Preliminary Results (May 2006)

• 524 children of 601 remain in the study
• Observed 741 out of 795 potential person years of
  follow up (93)
• 776 treatments for malaria (incidence density
  1.05 per person year)
• 734 episodes treated with study drugs
• 18 episodes treated with quinine for first
  line therapy
• 24 episodes treated with quinine for treatment
  failure
• Other outcomes of interest
• Number of severe malaria episodes 0
• Number referred to hospital 47
• 19 complicated malaria (12 with convulsion)
• 6 bronchopneumonia
• 3 convulsion (2 diagnosed with epilepsy)
• 19 miscellaneous (fractures, asthma attack,
  chicken pox, fever of unknown origin, etc)
• Number of deaths 0

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Monthly incidence of malaria
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Incidence of malaria stratified by age group
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Risk of recurrent parasitemia

• Combined results for all 3 study therapies
• Day 14 3
• Day 28 16

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Risk of recurrent malaria
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Prevalence of asymptomatic parasitemia
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Prevalence of anemia (Hb lt10g/dL) in asymptomatic
children
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Future Directions

• Unblinding of data for analysis of comparative
  malaria incidence and safety of study treatments
• Distribution of one insecticide treated bed net
  per participant was completed between 1 May 6
  June 2006 drug efficacies will be compared after
  this intervention

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Sub-Studies

• Immunology studies
• Efficacy of rapid diagnostic tests (RDT) for
  malaria
• Predictors of malaria incidence
• Prevalence and duration of false HIV EIA in
  malaria
• Pharmacokinetics of study therapies

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Conclusions

• Prompt, effective treatment for malaria, as part
  of good-quality primary care, has made a positive
  impact on the health of children in our cohort
• Decrease in prevalence of asymptomatic
  parasitemia from 20 to lt 5
• Decrease in anemia from 9 to 2
• No cases of severe malaria
• No deaths
• Study treatments appear to work well
• Relatively low risk of treatment failure