Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria

Amélie Vantaux, Saorin Kim, Eakpor Piv, Sophy Chy, Laura Berne, Nimol Khim, Dysoley Lek, Sovannaroth Siv, Mavuto Mukaka, Walter R Taylor, Didier Ménard, Amélie Vantaux, Saorin Kim, Eakpor Piv, Sophy Chy, Laura Berne, Nimol Khim, Dysoley Lek, Sovannaroth Siv, Mavuto Mukaka, Walter R Taylor, Didier Ménard

Abstract

Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.).

Keywords: direct membrane feeding assays; malaria; primaquine; transmission blocking.

Copyright © 2020 Vantaux et al.

Figures

FIG 1
FIG 1
Gametocyte prevalence by TaqMan RT-PCR by follow-up day and treatment group. Data show the proportion ± 95% confidence intervals. DP, dihydroartemisinin-piperaquine.
FIG 2
FIG 2
Gametocyte prevalence by TaqMan RT-PCR by follow-up day and presence of gametocyte prior to treatment on day 0 (D0), detected by TaqMan RT-PCR. Data show the proportion ± 95% confidence intervals.

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