[Effect of low-dose primaquine treatment on Plasmodium vivax recurrence and transmission-blocking activity in southwest Ethiopia: a longitudinal cohort study

Abstract

Background: Existing malaria control strategies for Plasmodium vivax are challenging due to its dormant and relapsing liver stages, as well as the early onset of gametocytogenesis. Primaquine (PQ) effectively eliminates dormant stages and can kill gametocytes; however, it necessitates repeated dosing. In this study, the effectiveness of chloroquine (CQ) plus low-dose of PQ on recurrence and its transmission-blocking activity was evaluated.

Methods: Between September 2019 and July 2022, a prospective cohort study was conducted in the Jimma-Arjo and Dabo-Hanna districts of the Oromia region in Ethiopia. A total of 214 uncomplicated cases of P. vivax malaria were enrolled in the study. Participants were treated with either CQ alone (106) or CQ + PQ (108), based on whether their district was targeted for P. vivax elimination by the national malaria programme or not. After enrolment, participants were followed for clinical illness and parasitaemia on days 28, 42, and monthly for one year. To assess the effect of different treatment regimens on transmission-blocking activity, Anopheles arabiensis mosquitoes were used in direct membrane-feeding assays (DMFA) at baseline (pre-treatment) and on day 42 (post-treatment). Based on polymerase chain reaction (PCR) positivity, the time to the first recurrence was estimated using Kaplan-Meier survival analysis. Cox regression models were employed to assess risk factors for recurrence.

Results: Of 3,590 individuals screened for malaria, 323 tested positive for P. vivax, and 214 were enrolled. Of these, 98.6% (211/214) completed the day 28 follow-up, and 67.3% (144/214) completed the one-year follow-up. Between days 28 and 42, 24% (95% CI 15.8-32.2%) of those individuals receiving CQ alone were PCR positive, and 10.3% (95% CI 4.5-16.0%) in those receiving CQ plus PQ. This represented a 57.3% reduction P. vivax recurrence in the CQ + PQ treatment group compared to CQ alone (risk ratio = 0.427, 95% CI 0.222-0.824, p = 0.008). During the year of follow-up at least one recurrence occurred in 70% (95% CI 59.1-80.2%) of the CQ alone and 46% (95% CI 35.5-58.1%) in the CQ + PQ treatment group (p < 0.001). Treatment regimen, high baseline parasitaemia and presence of gametocytaemia were risk factors for P. vivax recurrence. Compared to baseline DMFA at day 42, individuals showed an inhibition intensity of 39.0% in the CQ alone versus 77.8% in the CQ + PQ treatment group (p = 0.016), while inhibition prevalence was 35.2% in the CQ alone and 70.1% in the CQ + PQ treatment group (p = 0.021).

Conclusions: This study demonstrate that with limited supervision of CQ + PQ treatment significantly lowers the risk of P. vivax recurrence in health clinics of southwest Ethiopia compared to CQ alone. Adding PQ to CQ also reduced P. vivax transmission to mosquito vectors relative to CQ alone but did not result in a complete transmission-blocking effect by day 42 post-treatment. Therefore, improved health education on treatment adherence and bed net use could enhance the effectiveness of PQ plus CQ. Higher doses of PQ for a shorter duration may be necessary to enhance treatment adherence, reduce recurrence rates, and decrease the risk of transmission.

Keywords: Plasmodium vivax; Chloroquine; Primaquine; Recurrent; Transmission-blocking activity.

Fig. 1

Flow chart of Plasmodium vivax patient screening and recruitment for CQ alone and CQ + PQ treatment groups, in Arjo-Didessa sugar development site and its surrounding, southwest Ethiopia

Fig. 2

The overall Kaplan–Meier Survival estimate between CQ alone and CQ + PQ treatment groups for complete-cases

Fig. 3

The mean asexual parasitaemia (A and B) and mean gametocytaemia (C and D) at baseline and day 42 of CQ alone and CQ + PQ treatment group, respectively. The small star or asterisks (*) indicate significant difference in mean asexual parasitaemia and mean gametocytaemia at day 42 against the baseline. Error bars indicate standard error of mean. Key: ns: not significant; * p < 0.05; ** p < 0.001; **** p < 0.0001 significant level

Fig. 4

A The proportion of individual’s infectiousness to mosquitoes at the baseline and day 42 post treatment of CQ alone and CQ + PQ treatment group. B Mean oocyst/mosquito midgut at the baseline and day 42 of CQ alone and CQ + PQ treatment group. C the inhibition intensity between CQ alone and CQ + PQ treatment group by day 42. D the inhibition prevalence between CQ alone and CQ + PQ treatment group by day 42. Violin plot showing the blue horizontal dot lines indicate median, the black horizontal dot line indicates interquartile range; and spikes indicate upper and lower adjacent values. Asterisks (*) indicate the significant difference against the antimalarial treatment group