Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

Abstract

Background: Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasites, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), were previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, we examined the persistence of ring-stage parasitemia following ACT and non-ACT treatment. Methods: We used samples from naturally infected Malian gametocyte carriers who received dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP-AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results: At baseline, 89% (64/73) of participants had measurable ring-stage parasites. Following treatment, the proportion of ring-stage parasite-positive individuals and ring-stage parasite densities declined for all four treatment groups. Participants who received DP had 81% lower post-treatment ring-stage parasite density compared to participants who received SP-AQ (p<0.001). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite densities on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14=0.011 and pday 28=0.068). We observed no association of ring-stage persistence with gametocyte carriage. Conclusions: Our findings of lower ring-stage persistence after ACT treatment without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker and argues against preferential persistence of low densities of rings following ACT treatment. The implications of our findings for monitoring drug sensitivity require further study.