Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial

Simple item page
dc.contributor.authorRaman, Jaishree
dc.contributor.authorAllen, Elizabeth
dc.contributor.authorWorkman, Lesley
dc.contributor.authorMabuza, Aaron
dc.contributor.authorSwanepoel, Hendrik
dc.contributor.authorMalatje, Gillian
dc.contributor.authorFrean, John
dc.contributor.authorWiesner, Lubbe
dc.contributor.authorBarnes, Karen I
dc.date.accessioned2019-12-10T09:03:05Z
dc.date.available2019-12-10T09:03:05Z
dc.date.issued2019-06-24
dc.date.updated2019-06-30T03:25:38Z
dc.description.abstractAbstract Background To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. Methods This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. Results Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. Conclusions Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859
dc.identifier.apacitationRaman, J., Allen, E., Workman, L., Mabuza, A., Swanepoel, H., Malatje, G., ... Barnes, K. I. (2019). Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial. http://hdl.handle.net/11427/30677en_ZA
dc.identifier.chicagocitationRaman, Jaishree, Elizabeth Allen, Lesley Workman, Aaron Mabuza, Hendrik Swanepoel, Gillian Malatje, John Frean, Lubbe Wiesner, and Karen I Barnes "Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial." (2019) http://hdl.handle.net/11427/30677en_ZA
dc.identifier.citationMalaria Journal. 2019 Jun 24;18(1):209
dc.identifier.ris TY - Journal Article AU - Raman, Jaishree AU - Allen, Elizabeth AU - Workman, Lesley AU - Mabuza, Aaron AU - Swanepoel, Hendrik AU - Malatje, Gillian AU - Frean, John AU - Wiesner, Lubbe AU - Barnes, Karen I AB - Abstract Background To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. Methods This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. Results Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. Conclusions Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859 DA - 2019-06-24 DB - OpenUCT DP - University of Cape Town KW - Primaquine KW - Artemether–lumefantrine KW - Efficacy KW - Safety KW - Tolerability KW - Gametocyte carriage KW - South Africa KW - Plasmodium falciparum LK - https://open.uct.ac.za PY - 2019 T1 - Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial TI - Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial UR - http://hdl.handle.net/11427/30677 ER - en_ZA
dc.identifier.urihttps://doi.org/10.1186/s12936-019-2841-8
dc.identifier.urihttp://hdl.handle.net/11427/30677
dc.identifier.vancouvercitationRaman J, Allen E, Workman L, Mabuza A, Swanepoel H, Malatje G, et al. Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial. 2019; http://hdl.handle.net/11427/30677.en_ZA
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.subjectPrimaquine
dc.subjectArtemether–lumefantrine
dc.subjectEfficacy
dc.subjectSafety
dc.subjectTolerability
dc.subjectGametocyte carriage
dc.subjectSouth Africa
dc.subjectPlasmodium falciparum
dc.titleSafety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial
dc.typeJournal Article
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
12936_2019_Article_2841.pdf
Size:
974.71 KB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
0 B
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Journal Articles