Longitudinal trial of chloroquine monotherapy and combination therapy for uncomplicated falciparum malaria in children in Blantyre, Malawi Presenter: Patricia Mawindo Clinical Research Coordinator, Blantyre Malaria Project, Ndirande Research Clinic, Malawi.

BACKGROUND Malawi was the first country to stop using chloroquine as the first line treatment of malaria due to high rates of resistance. The decline in the prevalence of genetic marker of Chroloquine-resistance malaria began immediately following the switch to Sulfadoxine-Pyrimethamine in 1993 and was undetectable in In 2005, BMP conducted a study demonstrating 99% effectiveness of Chroloquine in uncomplicated malaria in children

RATIONALE Reintroduction of Chroloquine, whether for routine treatment or targeted prevention with a partner drug would protect against the re-emergence of resistance. Combination therapy is recommended to effectively treat individual infections and to prevent the emergence and spread of resistance. Rather, our hope was to answer the question: for how long does a partner drug need to be active to protect against resistance?

OBJECTIVES Primary: Compare annual incidence of malaria clinical episodes. Secondary: Assess antimalarial drug efficacy at first and subsequent administrations by treatment arm. Measure the effect of each treatment arm on anaemia.

Objectives Measure the prevalence of chloroquine resistance. Assess the safety of each study arm with repeated use.

METHODS Ndirande H/Centre serving a population of 200,000. Targeted children aged 6 months to 5 years (attending the pediatric clinic). Studied Chloroquine: as monotherapy in combination with drugs with different half- lives; Artesunate, azithromycin and atovaquine- proguanil.

STUDY DESIGN & DURATION Ppts identified at the time of first episode of uncomplicated malaria. 640 children randomized to one of the four treatment arms. Treatment outcome assessed through the standard 28-day efficacy study. Subsequently, evaluated every 4wks and encouraged to return when sick.

DESIGN & DURATION Offered same therapy as assigned at enrollment incases of a new episode of uncomplicated malaria. PCR-corrected 28-day efficacy evaluated at each treatment episode. Primary endpoint: annual incidence of malaria. Study duration was 1.5 years.

RESULTS Out of 640 children, 628 included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 ( ),.61 ( ),.63 ( ) and.68 ( ) episodes/person-year. Treatment efficacy for 1 st episodes was 100% for CQ monotherapy, 97% for subsequent episodes. Similar results in combination groups.

RESULTS The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in 2 out of 911 infections. Young children treated with chloroquine- azithromycin had higher hemoglobin concentrations at the studys end than did those in the chloroquine monotherapy.

Conclusions and next steps chloroquine is once again an effective drug for treatment of malaria in Malawi. with its excellent safety profile, low cost and long post-treatment prophylactic effect, an attractive candidate for prevention in vulnerable groups, typically women and infants, in areas where resistance to SP is high.

Conclusions and next steps Clinical efficacy of chloroquine was maintained with repeated use in a clinical trial. Evidence of resistance on a molecular level will be evaluated. PK-PD modeling in susceptible and resistant parasites.

Acknowledgements Study leadership: –Chris Plowe –Miriam Laufer –Terrie Taylor –Fraction Dzinjalamala –Phil Thesing Blantyre Malaria Project staff, led by –Osward Nyirenda –Rhoda Masonga –Joseph Kanyangalika Administrative support –Esther Gondwe, BMP –Nicole Eddington, UMB Data management and biostatistical support EMMES Corp. We are grateful to the children and their parents who participated in this study and continue to welcome us at the research clinic in Ndirande. Funded by NIH: U01AI and K23AI Zithromax (azithromycin) donated by Pfizer Inc.