Efficacy of primaquine-chloroquine combination on Plasmodium vivax transmission and parasite clearance in Ethiopia: a randomized controlled trial

Primaquine (PQ) targets the hypnozoite stage of <i>Plasmodium vivax</i> and prevents transmission by targeting mature gametocytes. However, limited information exists on how quickly adding PQ reduces parasite transmission and clears parasites. We aimed to assess whether adding PQ can reduce <i>P. vivax</i> transmission and improve parasite clearance compared to using CQ alone. We conducted an open-label, randomized controlled trial. Patients aged 15 or older diagnosed with <i>P. vivax</i> mono-infection by microscopy were recruited from a health facility. One group received PQ at a dosage of 0.25 mg/kg daily for 14 days, in addition to CQ, in accordance with national treatment guidelines. A membrane feeding assay was performed using the colony <i>Anopheles arabiensis</i> before and after treatment. Mosquito midgut dissections were conducted on day 8 to observe oocyst development and on day 12 to detect circumsporozoite protein (CSP). We followed the patients for 28 days. We used a zero-inflated Poisson regression model to analyze how predictor variables influenced oocyst count and binary logistic regression with generalized estimating equations to predict the proportion of sporozoite-positive mosquitoes. Fifty-six patients completed the three-day mosquito feeding experiments, and forty-nine completed the 28-day follow-up. Before treatment, 57% (16/28) of patients in the CQ group and 82% (23/28) in the CQ-PQ group were infectious to mosquitoes (<i>P</i> = 0.08). After one day of treatment, the percentage of reduction was significantly higher in the CQ-PQ group than in the CQ alone group (<i>P</i> < 0.0001). When considering the oocyst number, the decline was significantly more pronounced in the CQ-PQ group (<i>P</i> < 0.001). The rate of CSP reduction was higher in the CQ-PQ group (<i>P</i> = 0.002). One day after treatment, the number of patients with gametocytes was lower in the CQ-PQ group compared to the CQ-alone group (<i>P</i> = 0.02). There was no significant difference in the asexual parasite clearance rate between the two groups three days post-treatment (<i>P</i> = 0.42). The results indicate that adding PQ reduced parasite transmission to mosquitoes; however, some patients remained infectious up to 24 h post-treatment. This trial was registered on the Pan African Clinical Trial Registry: PACTR202408837266041.