In vivo parasitological measures of artemisinin susceptibility

Abstract

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

Figure 1

Cumulative risk of recrudescence for patients with a negative (circles) or positive (squares) parasite count on day 1 (A), day 2, (B), and day 3 (C). SMRU, Shoklo Malaria Research Unit.

Figure 2

Relationship between enrollment parasite density and the proportion of patients with parasitemia on day 3 after the start of treatment with artemisinin derivatives, estimated using logistic regression with random effects for study site. The outer dashed and continuous lines represent 95% and 99% confidence intervals.

Figure 3

Relationship between sample size and the upper limit of the number of patients with a positive parasite count on day 3 for which the null hypothesis of a true positivity rate of 2% (circles), 3% (triangles), or 4% (squares) cannot be rejected, based on Wilson 95% confidence intervals.