Results show that the PQ short treatment unsupervised presented an increased risk of recurrence compared to the supervised group. The shorter PQ regimen (7 days of 0.5 mg/kg/day) is used in Brazil to improve adherence since the middle 1990s, and the 14-day (0.25 mg/kg/day) course actually does not seem to be superior in preventing relapses (14). However, data on compliance to the 7-day regimen is still scarce and has to deal with the methodological issues of randomizing a non-supervision group to serve as a comparator, in which the mere commitment to the study may increase drug intake, not reflecting therefore, the real life situation. In order not to cause any distortion of reality, possibly influencing adherence, an unsupervised treatment group was used in our study, taking advantage of the Zelen's design, where some patients were not randomized to consent and have their treatment supervised, and therefore, no intervention or contact with the participant happened throughout the study duration. ERB allowed for a waiver of consent in this group, understanding that any consent process would bias the results. All participants randomized to the supervised group had home visits from D1 to D7, for drug administration.
In Thailand and Papua New Guinea, a recurrence rate for P. vivax after treatment with CQ and PQ can reach up to 65% over 30 to 180 days of follow-up (15). In the current study, we demonstrated that relapses occurred between 42 to 180 days, possibly the group of unsupervised participants who had the highest number of relapses was due to non-adherence. Many studies have shown that there are problems in the treatment of P. vivax malaria, one of which is the precariousness of the dispensing system and inadequate storage conditions. Several other factors can contribute to the increase in recurrence rates in the Amazon region, including genetic factors, e.g., abnormal CYP2D6 activity (16).
The number of patients who experienced recurrence due to P. vivax in this study raises the hypothesis that recurrence in vivax cases was higher due to improper treatment of these cases (17), considering that participants in each group were randomized. In the Amazon region, treatment is not supervised and there are few studies that discuss the importance of adherence and the often-precarious conditions of dispensing and storing medications can contribute negatively (18). In Pará, Brazil, the relative risk of parasitic resurgence was 3.04 times higher in non-adherent patients (19). Other study reported that adherence frequency was 86.4% (81.7%-90.1%) (20).
Non-adherence to treatment affects the health of patients and is one of the main factors of therapeutic failure that directly impacts the control of the disease and places a socioeconomic burden on health systems. Information on non-adherence to the current antimalarial treatment is essential for interventions aimed at reducing therapeutic failure and further recurrences. However, with the possibility of introducing tafenoquine, the 8-aminoquinoline given as a single dose, with similar efficacy to 14-day PQ regimen (21), there is a concern that the high levels of efficacy observed in clinical trials may not be repeated in the real life (22).
The major limitations of the study are: the small sample size, which should be increased as to include other endemic areas in Brazil, and increase national representativeness; no compliance could be estimated in those under 18 years of age; there is also an underestimation of asymptomatic relapses, as no active microscopic surveillance was performed.
These preliminary data, from a municipality in the Brazilian Amazon, might be used as a first reliable reference, based on real life data, of to which extent the lack of compliance to the 7-day PQ regimen in the treatment of vivax malaria affects recurrences until day 180. Non-supervision more than doubles such risk, which might be a bottleneck if any program pursues malaria elimination.