Dihydroartemisinin-piperaquine versus chloroquine for the treatment of uncomplicated Plasmodium vivax malaria with concurrent or delayed high-dose primaquine in Brazil (Curavivax): an open-label, single-centre, randomised clinical trial.

Abstract

We aimed to evaluate the efficacy and tolerability of dihydroartemisinin-piperaquine as an alternative schizontocide to chloroquine for the treatment of Plasmodium vivax malaria in Brazil, where early recurrences despite chloroquine therapy and operational challenges with primaquine adherence highlight the need to assess alternative treatment regimens. Curavivax was an open-label, single-centre, parallel-group, randomised trial done in a public reference centre for infectious diseases in Manaus (Brazilian Amazon). Patients older than 6 months with microscopically confirmed P vivax malaria, weighing up to 100 kg, with glucose-6-phosphate dehydrogenase activity greater than 30% of normal, were randomly assigned (1:1:1:1), based on a computer-generated list of blocks of five participants, to dihydroartemisinin-piperaquine or chloroquine plus primaquine initiated on day 0 or delayed until day 42. Dihydroartemisinin-piperaquine (40/320 mg or 20/160 mg oral tablets) and chloroquine (150 mg oral tablets) were administered once daily for 3 days. Primaquine (15 mg oral tablets) was administered once daily for 14 days. All medicines were dosed by bodyweight and dispensed open-label. The primary outcome was the recurrence rate at day 42 in the per-protocol population. Safety was assessed in all participants who received at least one dose of study medication. This trial was registered with ClinicalTrials.gov, NCT03208907, and is completed. Between July 5, 2018, and Jan 13, 2021, 1649 patients were screened for eligibility, 419 of whom were randomly assigned to chloroquine plus primaquine (n=114), dihydroartemisinin-piperaquine plus primaquine (n=112), chloroquine plus delayed primaquine (n=98), and dihydroartemisinin-piperaquine plus delayed primaquine (n=95). One patient in the chloroquine plus primaquine group was excluded owing to a severe protocol deviation. 287 (69%) of 418 patients were male and 131 (31%) were female. Day 42 recurrence rate in the per-protocol population was similar for chloroquine plus primaquine (2·0% [95% CI 0·2-7·0]) and dihydroartemisinin-piperaquine plus primaquine (1·0% [0·0-5·3]; hazard ratio [HR] 0·48 [95% CI 0·00-40 209·06; p=0·44); whereas dihydroartemisinin-piperaquine alone (delayed primaquine; 2·4% [0·3-8·5]) was superiorto chloroquine alone (delayed primaquine; 27·3% [18·3-37·8]; HR 0·08 [95% CI 0·00-0·22]; p<0·0001). All treatments were well tolerated. The high therapeutic efficacy and early recurrence prevention with dihydroartemisinin-piperaquine with primaquine started on day 0 or delayed to day 42 supports the use of this schizontocide for P vivax treatment in Latin America. Ministry of Health of Brazil and the National Council for Scientific and Technological Development.