Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study
Background<br/> Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females are mosaics who, because of X-chromosome inactivation (Lyo...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
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Public Library of Science
2017
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| _version_ | 1826284519673561088 |
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| author | Chu, C Bancone, G Moore, K Win, H Thitipanawan, N Po, C Chowwiwat, N Raksapraidee, R Wilairisak, P Phyo, A Keereecharoen, L Proux, S Charunwatthana, P Nosten, F White, N |
| author_facet | Chu, C Bancone, G Moore, K Win, H Thitipanawan, N Po, C Chowwiwat, N Raksapraidee, R Wilairisak, P Phyo, A Keereecharoen, L Proux, S Charunwatthana, P Nosten, F White, N |
| author_sort | Chu, C |
| collection | OXFORD |
| description | Background<br/> Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females are mosaics who, because of X-chromosome inactivation (Lyonisation), may have low G6PD activity in the majority of their erythrocytes, yet they usually are reported as G6PD “normal” by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. <br/><br/> Methods and Findings<br/> \in a cohort study nested within a randomised clinical trial which compared different treatment regimens of Plasmodium vivax malaria, patients with a normal standard NADPH fluorescent spot test result (~>30-40% of normal G6PD activity) were randomised to receive 3 days of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5mg base/kg/day for 14 days or a higher dose of 1mg base/kg/day for 7 days. Patterns of haemolysis were compared between G6PD wild type and G6PD heterozygous females. Between 21 February 2012 and 04 July 2014, 241 female patients were enrolled of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis 24 was substantially greater and a larger proportion of patients reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 day) primaquine dose, 9/17 (53%) compared with G6PD heterozygotes taking the standard high (14 day) dose, 2/16 (13%); p=0.022. In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7 day regimen): -20.4% (95% CI -26.0 to -14.8) (nadir on day 5) compared with the standard high (14 day) dose: -13.1% (95% CI -17.6 to -8.6) (nadir day 6). Two heterozygotes taking the higher (7 day) primaquine dose required blood transfusion. In wild type patients mean haematocrit reductions were clinically insignificant and similar with both doses; -5.8 (95% CI -7.2 to -4.4) (nadir day 3) compared with -5.5% (95% CI - 7.4 to -3.7) (nadir day 4) respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype, and that the heterozygote groups were small. <br/><br/>Conclusion<br/> Higher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests. |
| first_indexed | 2024-03-07T01:15:04Z |
| format | Journal article |
| id | oxford-uuid:8e60b411-d750-4261-8565-9141628e78e6 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T01:15:04Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:8e60b411-d750-4261-8565-9141628e78e62022-03-26T22:57:17ZPrimaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort studyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8e60b411-d750-4261-8565-9141628e78e6Symplectic Elements at OxfordPublic Library of Science2017Chu, CBancone, GMoore, KWin, HThitipanawan, NPo, CChowwiwat, NRaksapraidee, RWilairisak, PPhyo, AKeereecharoen, LProux, SCharunwatthana, PNosten, FWhite, NBackground<br/> Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females are mosaics who, because of X-chromosome inactivation (Lyonisation), may have low G6PD activity in the majority of their erythrocytes, yet they usually are reported as G6PD “normal” by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. <br/><br/> Methods and Findings<br/> \in a cohort study nested within a randomised clinical trial which compared different treatment regimens of Plasmodium vivax malaria, patients with a normal standard NADPH fluorescent spot test result (~>30-40% of normal G6PD activity) were randomised to receive 3 days of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5mg base/kg/day for 14 days or a higher dose of 1mg base/kg/day for 7 days. Patterns of haemolysis were compared between G6PD wild type and G6PD heterozygous females. Between 21 February 2012 and 04 July 2014, 241 female patients were enrolled of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis 24 was substantially greater and a larger proportion of patients reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 day) primaquine dose, 9/17 (53%) compared with G6PD heterozygotes taking the standard high (14 day) dose, 2/16 (13%); p=0.022. In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7 day regimen): -20.4% (95% CI -26.0 to -14.8) (nadir on day 5) compared with the standard high (14 day) dose: -13.1% (95% CI -17.6 to -8.6) (nadir day 6). Two heterozygotes taking the higher (7 day) primaquine dose required blood transfusion. In wild type patients mean haematocrit reductions were clinically insignificant and similar with both doses; -5.8 (95% CI -7.2 to -4.4) (nadir day 3) compared with -5.5% (95% CI - 7.4 to -3.7) (nadir day 4) respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype, and that the heterozygote groups were small. <br/><br/>Conclusion<br/> Higher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests. |
| spellingShingle | Chu, C Bancone, G Moore, K Win, H Thitipanawan, N Po, C Chowwiwat, N Raksapraidee, R Wilairisak, P Phyo, A Keereecharoen, L Proux, S Charunwatthana, P Nosten, F White, N Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title | Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title_full | Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title_fullStr | Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title_full_unstemmed | Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title_short | Primaquine induced haemolysis in G6PD heterozygous females treated for the radical cure of Plasmodium vivax malaria: a nested cohort study |
| title_sort | primaquine induced haemolysis in g6pd heterozygous females treated for the radical cure of plasmodium vivax malaria a nested cohort study |
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