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<p>Abstract</p> <p>Background</p> <p>A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data.</p> <p>Methods</p> <p>Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan <it>Plasmodium falciparum </it>transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]_day3) and day 7 (C [lum]_day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]_day7and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa.</p> <p>Results</p> <p>C [lum]_day3and C [lum]_day7distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]_day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]_day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]_day7below 400 ng/mL (p < 0.001).</p> <p>Conclusion</p> <p>Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.</p>