Pyronaridine–artesunate or dihydroartemisinin–piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial

Abstract

Background Pyronaridine-artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine-artesunate and dihydroartemisinin-piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes. MethodsWe conducted a four-arm, single-blind, phase 2/3, randomised trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako (Bamako, Mali). Participants were aged 5-50 years, with asymptomatic P falciparum malaria mono-infection and gametocyte carriage on microscopy, haemoglobin density of 9•5 g/dL or higher, bodyweight less than 80 kg, and no use of antimalarial drugs over the past week. Participants were randomly assigned (1:1:1:1) to one of four treatment groups: pyronaridine-artesunate, pyronaridine-artesunate plus primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus primaquine. Treatment allocation was concealed to all study staff other than the trial pharmacist and treating physician. Dihydroartemisinin-piperaquine and pyronaridine-artesunate were administered as per manufacturer guidelines over 3 days; primaquine was administered as a single dose in oral solution according to bodyweight (0•25 mg/kg; in 1 kg bands). The primary endpoint was percentage reduction in mosquito infection rate (percentage of mosquitoes surviving to dissection that were infected with P falciparum) at 48 h after treatment compared with baseline (before treatment) in all treatment groups. Data were analysed per protocol. This trial is now complete, and is registered with ClinicalTrials.gov, NCT04049916. Findings Between Sept 10 and Nov 19, 2019, 1044 patients were assessed for eligibility and 100 were enrolled and randomly assigned to one of the four treatment groups (n=25 per group). Before treatment, 66 (66%) of 100 participants were infectious to mosquitoes, with a median of 15•8% (IQR 5•4-31•9) of mosquitoes becoming infected. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 48 h after treatment was 100•0% (IQR 100•0 to 100•0) for individuals treated with pyronaridineartesunate plus primaquine (n=18; p<0•0001) and dihydroartemisinin-piperaquine plus primaquine (n=15; p=0•0001), compared with -8•7% (-54•8 to 93•2) with pyronaridine-artesunate (n=17; p=0•88) and 50•4% (13•8 to 70•9) with dihydroartemisinin-piperaquine (n=16; p=0•13). There were no serious adverse events, and there were no significant differences between treatment groups at any point in the frequency of any adverse events (Fisher's exact test p=0•96) or adverse events related to study drugs (p=0•64). The most common adverse events were headaches (40 events in 32 [32%...

Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial

“… 5 Comparing the current findings with previous trials on the transmission-blocking effects of primaquine, wherein primaquine blocked transmission by day 2 post-treatment, 9 , 11 gametocyte clearance appears to be slower after tafenoquine, corroborating findings from a clinical trial in patients with P vivax in which tafenoquine had a longer time to gametocyte and parasite clearance compared with chloroquine plus primaquine. 17 Contrary to observations with primaquine, 9 , 18 we also observed no evidence for an early sterilising effect of tafenoquine. Only by day 7 did we observe lower per-gametocyte infectivity in the tafenoquine treatment groups that we interpret as an indication that some gametocytes lose viability before their clearance; studies with more observations before day 7 are required to examine this further.…”

Plasmodium falciparum sexual conversion rates can be affected by artemisinin-based treatment in naturally infected malaria patients

“…97 The combination of ACTs with a gametocidal drug would counteract any enhancement of sexual conversion associated with ART-based treatment. 98 , 99 Otherwise, ART-induced changes in sexual conversion rates may in some cases attenuate the reduction in transmission potential associated with ART-based parasite killing.…”

Effectiveness of pyronaridine-artesunate against Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections: a post-hoc analysis of the CANTAM-Pyramax trial

“…The effect of antimalarial treatment regimens with and without 8-aminoquinolines on P falciparum gametocytes have been described previously, and a 2022 publication has detailed the specific clinical effects of pyronaridine–artesunate on the sexual stages of this species. 23 However, the effects of antimalarials on the sexual stages of Plasmodium malariae and Plasmodium ovale spp, and the characteristics of those stages, have not been described conclusively so far. 12 , 24 Therefore, we cannot rule out that these submicroscopic parasitaemias were due to sexual stages of said non-falciparum parasite species that, to date, cannot be reliably distinguished from asexual stages with the available molecular methods.…”