In-Vivo Efficacy of Chloroquine to Clear Asymptomatic Infections in Mozambican Adults: A Randomized, Placebo-controlled Trial with Implications for Elimination Strategies

Abstract

Recent reports regarding the re-emergence of parasite sensitivity to chloroquine call for a new consideration of this drug as an interesting complementary tool in malaria elimination efforts, given its good safety profile and long half-life. A randomized (2:1), single-blind, placebo-controlled trial was conducted in Manhiça, Mozambique, to assess the in-vivo efficacy of chloroquine to clear plasmodium falciparum (Pf) asymptomatic infections. Primary study endpoint was the rate of adequate and parasitological response (ACPR) to therapy on day 28 (PCR-corrected). Day 0 isolates were analyzed to assess the presence of the PfCRT-76T CQ resistance marker. A total of 52 and 27 male adults were included in the CQ and Placebo group respectively. PCR-corrected ACPR was significantly higher in the CQ arm 89.4% (95%CI 80-98%) compared to the placebo (p < 0.001). CQ cleared 49/50 infections within the first 72 h while placebo cleared 12/26 (LRT p < 0.001). The PfCRT-76T mutation was present only in one out of 108 (0.9%) samples at baseline, well below the 84% prevalence found in 1999 in the same area. This study presents preliminary evidence of a return of chloroquine sensitivity in Mozambican Pf isolates, and calls for its further evaluation in community-based malaria elimination efforts, in combination with other effective anti-malarials.

Trial registration: www.clinicalTrials.gov NCT02698748.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1

Consort flow diagram of study participants.

Figure 2

PCR uncorrected (2A) and PCR-corrected (2B) Kaplan Meier curves showing the treatment success cumulative proportion for each study arm until day 28 in the ATP population. Cumulative risks of failure were computed for day 28 and Log-Rank tests used to compare the number of events that occurred in each arm. PCR-corrected curves censored participants who experienced a reinfection on the day it was detected.

Figure 3

Linear regressions fitted to the log-transformed parasite densities during the first 72 hours after first-dose administration.

Figure 4

Prevalence of PfCRT K76 mutated, wildtype and mixed parasites from samples collected in 1999 and 2015. Samples were genotyped using restriction fragment length polymorphism in 1999 and bi-directional DNA sequencing in 2015.