Artesunate combinations for treatment of malaria: meta-analysis
Adjuik M., Agnamey P., Babiker A., Baptista J., Borrmann S., Brasseur P., Carnevale P., Cisse M., Collins R., D'Alessandro U., Day N., de Boom W., Doherty T., Dorsey G., Garner P., Gikunda S., Gil V., Greenwood B., Guthmann JP., Henry MC., Kamya MR., Kremsner PG., Konate E., Krishna S., Lalloo D., Lange P., Loolpapit M., Malenga G., Marquino W., Marsh K., Milligan P., Molyneux M., Mugittu K., Niangue J., Nosten F., Ntoumi F., Obonyo C., Ochieng F., Olliaro P., Oloo AJ., Osorio L., Pinoges L., Priotto G., Rosenthal PJ., Ruebush T., Simpson J., Sirima S., Some E., Taylor W., ter Kuile F., Tiono A., von Seidlein L., Watkins B., White N., Grp IAS.
BACKGROUND: Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials. METHODS: We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods. FINDINGS: For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, n=4504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, n=2908; including re-infections, 0.30, 0.26-0.35, n=4332). Parasite clearance was significantly faster (rate ratio 1.98, 95% CI 1.85-2.12, n=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09-0.15, n=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48-0.77, n=1980) and day 28 (adjusted to exclude new infections 0.68, 0.53-0.89, n=1205; unadjusted including reinfections 0.77, 0.63-0.95, n=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0.11, 0.09-0.15, n=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo. INTERPRETATION: The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.