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.).
Highlights
Malaria remains a major public health challenge with an estimated 228 million cases recorded in [1]
As no data were available at that time in Cambodia, we investigated the transmission-blocking efficacy of SLDPQ
Our results show that SLDPQ, given on the first day of the 3-day standard artemisinin-based combination therapies (ACTs) treatment, significantly decreased gametocyte carriage over time, starting on D3 and was least on D7 resulting in a 5.59 fold reduced risk, relative to DP alone, over 28 days in the univariate analysis
Summary
Malaria remains a major public health challenge with an estimated 228 million cases recorded in [1]. While considerable progress has been made since 2010 when the estimated case burden was 251 million, the recent emergence and spread of both artemisinin and piperaquine resistant. Plasmodium falciparum lineage (KEL1/PLA1) in the Eastern Greater Mekong subRegion (GMS), threaten this remarkable global achievement [2,3,4,5,6,7]. Eliminating rapidly multidrug resistant P. falciparum (MDRPf) is, the top priority for countries of the Greater. In 2012, the WHO recommended the addition of single low dose of primaquine (SLDPQ, target dose 0.25mg/kg) to ACTs to interrupt malaria transmission, primarily in low transmission areas of MDRPf like the GMS [13]
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