Primaquine radical cure of Plasmodium vivax: a critical review of the literature

Abstract

BackgroundPrimaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax.MethodsPublished studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up.ResultsData could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4–6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001).ConclusionsLow dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.

Primaquina y recurrencias de malaria por Plasmodium vivax. Metanálisis de estudios clínicos controlados

“…In Cochrane Infectious Diseases Group, we found the same as in Cochrane Library. In PubMed we found review articles and meta-analysis ones; in both cases, many references were obtained 5,6,[13][14][15] . The search in Scholar Google yielded 94 results; the titles in the writings were compared to the ones obtained in all other sources, but it resulted in no new reference which would meet the inclusion criteria.…”

“…Because, regarding the review by Cochrane, we found 23 studies instead of 9; we analyzed 5 treatment schemes instead of 3 (0: zero mg of PQ; 75-5: 75 mg of PQ distributed into 5 days; 210-14: 210 mg of PQ distributed into 14 days); we worked with 6,350 patients instead of 3,423. In relation to the meta-analysis made by John et al 15 , it included segments of < 30 days (that measure the response of the acute attack); it included 7 studies without schizonticide, the TD categories used include one which contains the standard TD used in the standard procedure (14 days) or in 7 days, along with higher TD such as 315-14 (315 mg of PQ distributed into 14 days), 420-14 (420 mg of PQ distributed into 14 days), etc, and it does not discriminate the results among these values; because it includes Prospective and Retrospective studies; because it includes many studies without control group, it is to say Descriptive and solo CCT studies, without differentiating the recurrences in relation to the kind of study.…”

“…The clinical and parasitary cure, which include avoiding recurrences of the infection by P. cynomolgi and P. vivax is the role of the TD of the 8-AQ 9,10 . There are several recent reviews on the use of PQ to avoid the recurrences 3,11,12 , as well as meta-analysis on the theme 5,6,[13][14][15] . The 2 meta-analysis of Cochrane 6,13 assessed random and semi-random controlled clinical trials (CCT) in humans who compared treatments with chloroquine only against chloroquine added with PQ, given as 210-14, and other PQ schemes.…”

“…The 2 meta-analysis of Cochrane 6,13 assessed random and semi-random controlled clinical trials (CCT) in humans who compared treatments with chloroquine only against chloroquine added with PQ, given as 210-14, and other PQ schemes. The meta-analysis by John et al 15 included 87 studies published since 1950 under regimens of PQ anti-reccurences and they were based on what was found in Medline and Cochrane Central Register of Controlled Trials. The meta-analysis by Carmona-Fonseca 5 was based exclusively on descriptive studies.…”

High Efficacy of Primaquine Treatment for Plasmodium vivax in Western Thailand

“…19 In addition, our data also indicate that untreated, asymptomatic P. vivax infections can be of very short duration (2-4 weeks). Together these observations highlight that anti-hypnozoite treatment efficacy studies need long-term follow-up with intensive and active monitoring for asymptomatic infections (ideally by PCR given the low densities) 20 ; otherwise such studies may overestimate the efficacy of primaquine and novel anti-liverstage drugs such as tafenoquine.…”