Objectives: Combination therapy using existing anti-malarials together with artesunate (AS) has been advocated as a method to slow the spread of drug resistance. We assessed the effect on Plasmodium falciparum transmissibility of the addition of AS to chloroquine (CQ) in an area of The Gambia where resistance to CQ is increasing.
Methods: Gambian children with acute uncomplicated P. falciparum malaria were treated with either CQ monotherapy (n=120) or the combination of CQ plus three doses of AS (CQ/AS; n=352). Post-treatment sexual-stage parasitaemia was assessed during a 4-week follow-up period. Experimental infections of Anopheles gambiae s.s. mosquitoes were performed with blood from patients who were carrying gametocytes 7 days after starting treatment (n=69).
Results: The addition of AS significantly reduced post-treatment prevalence and mean density of gametocytes in the first 14 days (day 7: 43.7% vs. 12.4%, 62.4/microl vs. 6.2/microl; day 14: 32.9% vs. 3.7%; 21.9/microl vs. 5.2/microl; CQ vs. CQ/AS), although by day 28 the benefits of the combination were substantially less marked (40.5% vs. 21.8%; 23.0/microl vs. 63.1/microl; CQ vs. CQ/AS). The duration of gametocyte carriage over the study period was significantly lower in the CQ/AS group (5.2 days vs. 1.5 days; CQ vs. CQ/AS). The estimated infectious proportion of children at day 7 was also lower in the combination group (19.2% vs. 3.4%; CQ vs. CQ/AS), as were the proportion of mosquitoes infected and mean oocyst density (11.5% vs. 0.9%; 0.3 vs. 0.01; CQ vs. CQ/AS). Treatment failure was associated with threefold and twofold higher gametocyte carriage rates during follow-up in CQ and CQ/AS groups, respectively (P<0.001 in both cases), and 26-fold and 2.3-fold higher intensity of infection at day 7 among CQ- and CQ/AS-treated children, respectively (P=0.002 and 0.30, respectively).
Conclusion: The benefits of adding AS to CQ monotherapy in lowering gametocyte prevalence and density were transient, suggesting that the addition of AS delayed, but did not prevent, the emergence of gametocytes. This is consistent with our finding that treatment failure, and thus the presence of CQ-resistant parasites, was significantly associated with a higher gametocyte carriage rate in both treatment groups. At day 7, CQ monotherapy significantly favoured transmission of resistant infections, which showed an 11-fold greater intensity of transmission compared with infections that were successfully treated. In contrast, the combination of CQ/AS did not significantly favour resistant infections at day 7. We conclude that significant transmission-reduction is achieved by the combination but is not maintained because of the recrudescence of CQ-resistant parasites.