Features of recrudescent chloroquine-resistant Plasmodium falciparum infections confer a survival advantage on parasites and have implications for disease control

Abstract
This paper reports on the features of recrudescent infections of chloroquine-resistant Plasmodium falciparum (CQRPf) malaria from a study in vivo of patients from a malaria endemic (n = 527) and non-endemic (n = 129) region of Sri Lanka where the incidence of RI resistance was 30% and 55%, respectively. In both groups of patients, the recrudescent infections which emerged after treatment of the primary infection with chloroquine (CQ) and primaquine had significantly lower peripheral parasitaemia (0.036% and 0.108% in endemic and non-endemic patients, respectively) compared to their primary infections (mean parasitaemia 0.13% and 0.49%; P = 0.021 and 0.002, respectively). The recrudescences of CQ resistant infections also gave rise to clinical disease of markedly reduced severity (average clinical scores of 10.1 and 8.2) compared to their primary infections (average clinical scores of 12.4 and 12.3; P = 0.003 and 0.001, respectively, in endemic and non-endemic patients). CQ resistant recrudescent infections therefore had a lower probability of being diagnosed and treated. In endemic patients, a higher proportion of CQRPf infections (57%) had gametocytaemia compared to the chloroquine sensitive ones (29%) (P = 0.014, chi 2 = 5.96) and were significantly more infective to mosquitoes (P = 0.047). these findings imply that, in areas where CQ resistance is prevalent, the continued use of the drug may confer a survival and propagation advantage on resistant parasites and favour the rapid expansion of their reservoir. In support of this, we also present epidemiological evidence showing that, in endemic areas, the proportion of P. falciparum patients carrying gametocytes has increased significantly since the emergence of chloroquine resistance. These findings are relevant to the management of drug resistance and malaria control in countries where P.falciparum is only partially resistant to CQ.

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