In the Amazon, an artemisinin combination outperforms chloroquine for vivax malaria

Chloroquine has been the first-line treatment for Plasmodium vivax malaria for decades. A randomised trial from the Brazilian Amazon now shows how poorly it holds up when it is used on its own — and how well an artemisinin-based alternative does in its place.

The Curavivax trial, published in The Lancet Infectious Diseases, was run at a public reference centre for infectious diseases in Manaus, in the Brazilian Amazon [s1]. Between 5 July 2018 and 13 January 2021 it screened 1,649 patients and randomly assigned 419 with microscopically confirmed P. vivax malaria to one of four regimens [s1]. Two combined a blood-stage drug — either chloroquine or dihydroartemisinin-piperaquine — with primaquine started on day 0; the other two gave the same blood-stage drugs but delayed primaquine until day 42, isolating what each schizontocide does on its own [s1]. Of 418 analysed patients, 287 (69%) were male and 131 (31%) female [s1].

The gap that opens without primaquine

The primary outcome was the recurrence rate at day 42 [s1]. With primaquine started immediately, both drugs performed well: recurrence was 2.0% with chloroquine plus primaquine and 1.0% with dihydroartemisinin-piperaquine plus primaquine, a difference that was not statistically distinguishable [s1].

The separation appears when primaquine is delayed. Chloroquine on its own let 27.3% of patients recur by day 42 [s1]. Dihydroartemisinin-piperaquine on its own held recurrence to 2.4% — superior to chloroquine, with a hazard ratio of 0.08 (95% CI 0.00–0.22) [s1]. In other words, the artemisinin combination suppressed early vivax recurrences that chloroquine could not, even before the radical-cure drug was added.

That matters because primaquine is exactly the part of vivax treatment that most often goes wrong in practice. Primaquine clears the dormant liver stages that cause relapse, but it must be taken for 14 days and requires testing for glucose-6-phosphate dehydrogenase deficiency before use — in this trial, enrolment was limited to patients with G6PD activity above 30% of normal, and primaquine was given at 15 mg once daily for 14 days [s1]. The blood-stage drugs, by contrast, were three-day courses: dihydroartemisinin-piperaquine and chloroquine were each dosed once daily for three days, by bodyweight [s1]. Patients older than six months and weighing up to 100 kg were eligible, and the trial — registered as NCT03208907 — assigned them in blocks of five to the four arms [s1]. The authors frame the Brazilian problem plainly: early recurrences despite chloroquine, together with the operational difficulty of getting patients to complete primaquine, are what prompted the search for an alternative blood-stage drug [s1]. Their conclusion is that dihydroartemisinin-piperaquine, whether primaquine is given on day 0 or delayed to day 42, supports its use as a schizontocide for P. vivax in Latin America [s1].

Why vivax is the harder half of malaria

P. vivax is the malaria parasite that most stubbornly resists elimination, because its liver stages can reactivate weeks or months after the first infection and seed new transmission without a fresh mosquito bite. A blood-stage drug that also prevents early recurrence therefore does double duty — treating the illness in front of the clinician and reducing the chances that the same patient becomes infectious again soon after.

The trial's design cannot answer every question. It was single-centre, open-label, and its confidence intervals for the primaquine-containing arms were wide, reflecting how few recurrences occurred when the radical-cure drug was given on time [s1]. All medicines were dispensed open-label and dosed by bodyweight, and safety was assessed in every patient who received at least one dose [s1]. The work was funded by Brazil's Ministry of Health and the country's National Council for Scientific and Technological Development [s1]. What the trial does show cleanly is the size of the hole that chloroquine leaves when its companion drug is missing or delayed — a scenario that, in routine care, is common rather than hypothetical.

The wider burden

Malaria remains one of the largest infectious-disease killers. Globally in 2024 there were an estimated 282 million malaria cases and 610,000 malaria deaths across 80 countries, according to WHO [s2]. The WHO African Region carried 95% of cases — 265 million — and 95% of deaths, 579,000, with children under five accounting for about 75% of deaths in that region [s2].

Those figures are dominated by P. falciparum in Africa, not by vivax in the Americas. But the Curavivax result speaks to a different front in the same war: the parasite that keeps coming back, in regions where the standard cure depends on a drug regimen that patients frequently fail to finish. A schizontocide that prevents early recurrence on its own gives programmes a margin they do not currently have — and, the authors argue, an option worth taking up in Latin America [s1].

Sources

• Dihydroartemisinin–piperaquine versus chloroquine for uncomplicated Plasmodium vivax malaria (Curavivax) — The Lancet Infectious Diseases, September 2026
• Malaria (fact sheet) — World Health Organization, 4 December 2025