Estimated impact of tafenoquine for Plasmodium vivax control and elimination in Brazil: A modelling study

Abstract

Background Despite recent intensification of control measures, Plasmodium vivax poses a major challenge for malaria elimination efforts. Liver-stage hypnozoite parasites that cause relapsing infections can be cleared with primaquine; however, poor treatment adherence undermines drug effectiveness. Tafenoquine, a new single-dose treatment, offers an alternative option for preventing relapses and reducing transmission. In 2018, over 237,000 cases of malaria were reported to the Brazilian health system, of which 91.5% were due to P. vivax. Methods and findings We evaluated the impact of introducing tafenoquine into case management practices on population-level transmission dynamics using a mathematical model of P. vivax transmission. The model was calibrated to reflect the transmission dynamics of P. vivax endemic settings in Brazil in 2018, informed by nationwide malaria case reporting data. Parameters for treatment pathways with chloroquine, primaquine, and tafenoquine with glucose-6-phosphate dehydrogenase deficiency (G6PDd) testing were informed by clinical trial data and the literature. We assumed 71.3% efficacy for primaquine and tafenoquine, a 66.7% adherence rate to the 7-day primaquine regimen, a mean 5.5% G6PDd prevalence, and 8.1% low metaboliser prevalence. The introduction of tafenoquine is predicted to improve effective hypnozoite clearance among P. vivax cases and reduce population-level transmission over time, with heterogeneous levels of impact across different transmission settings. According to the model, while achieving elimination in only few settings in Brazil, tafenoquine rollout in 2021 is estimated to improve the mean effective radical cure rate from 42% (95% uncertainty interval [UI] 41%–44%) to 62% (95% UI 54%–68%) among clinical cases, leading to a predicted 38% (95% UI 7%–99%) reduction in transmission and over 214,000 cumulative averted cases between 2021 and 2025. Higher impact is predicted in settings with low transmission, low pre-existing primaquine adherence, and a high proportion of cases in working-aged males. High-transmission settings with a high proportion of cases in children would benefit from a safe high-efficacy tafenoquine dose for children. Our methodological limitations include not accounting for the role of imported cases from outside the transmission setting, relying on reported clinical cases as a measurement of community-level transmission, and implementing treatment efficacy as a binary condition. Conclusions In our modelling study, we predicted that, provided there is concurrent rollout of G6PDd diagnostics, tafenoquine has the potential to reduce P. vivax transmission by improving effective radical cure through increased adherence and increased protection from new infections. While tafenoquine alone may not be sufficient for P. vivax elimination, its introduction will improve case management, prevent a substantial number of cases, and bring countries closer to achieving malaria elimination goals.

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

“…To simulate P. vivax transmission, this study used a stochastic, individual-based model developed by White et al [ 11 ] and Nekkab et al [ 20 ]. This model extends the Ross-MacDonald framework of Plasmodium falciparum transmission to incorporate relapses [ 27 ], a characteristic feature of P. vivax transmission [ 28 ].…”

“…Calibrated to epidemiological surveys conducted in Papua New Guinea, the Solomon Islands and Brazil, the model by White et al . [ 11 ] and Nekkab et al [ 20 ] reproduces P. vivax transmission dynamics across a range of epidemiological settings.…”

“…[ 11 ] and Nekkab et al [ 20 ] considers three types of blood-stage infections: (1) sub-microscopic infections detectable by PCR; (2) sub-clinical infections detectable by LM and PCR; and, (3) clinical infections detectable by LM and PCR. Following White et al [ 11 ] and Nekkab et al [ 20 ], it was assumed that each clinical infection was characterized by a fever exceeding 38 °C within the past 48 h and a parasite density greater than 500/µL. Individuals with clinical P. vivax infections then seek treatment with anti-malarial drugs according to a probability of treatment-seeking behaviour.…”

“…For further description of the model and its assumptions, please refer to the Supplement and the documentation provided in White et al . [ 11 ] and Nekkab et al [ 20 ].…”

“…Here, an existing and validated individual-based model of P. vivax transmission [ 11 , 20 ] is extended to simulate clinical trials for radical cure. Individual-based models have been used to design and evaluate clinical trials, both for malaria [ 21 , 22 ] and other infectious diseases [ 23 – 26 ].…”