Dataset Information

Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

ABSTRACT:

Background

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, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD "normal" by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized.

Methods and findings

In a cohort study nested within a randomised clinical trial that compared different treatment regimens for P. vivax malaria, patients with a normal standard NADPH fluorescent spot test result (?30%-40% of normal G6PD activity) were randomised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants. Between 21 February 2012 and 04 July 2014, 241 female participants were enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 d) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 d) dose (2/16 [13%]; p = 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-d regimen): -20.4% (95% CI -26.0% to -14.8%) (nadir on day 5) compared with the standard high (14 d) dose: -13.1% (95% CI -17.6% to -8.6%) (nadir day 6). Two heterozygotes taking the higher (7 d) primaquine dose required blood transfusion. In wild-type participants, 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.

Conclusion

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.

Trial registration

ClinicalTrials.gov NCT01640574.

SUBMITTER: Chu CS

PROVIDER: S-EPMC5295665 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

Chu Cindy S CS Bancone Germana G Moore Kerryn A KA Win Htun Htun HH Thitipanawan Niramon N Po Christina C Chowwiwat Nongnud N Raksapraidee Rattanaporn R Wilairisak Pornpimon P Phyo Aung Pyae AP Keereecharoen Lily L Proux Stéphane S Charunwatthana Prakaykaew P Nosten François F White Nicholas J NJ

PLoS medicine 20170207 2

<h4>Background</h4>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, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD "normal" by current phenotypic screening tests. The ...[more]

PMID: 28170391

Similar Datasets

Project description:BackgroundThe incidence of malaria in the Americas has decreased markedly in recent years. Honduras and the other countries of Mesoamerica and the island of Hispaniola have set the goal of eliminating native malaria by the year 2020. To achieve this goal, Honduras has recently approved national regulations to expand the possibilities of a shortened double dose primaquine (PQ) treatment for vivax malaria. Considering this new shortened anti-malarial treatment, the high frequency of G6PDd genotypes in Honduras, and the lack of routinely assessment of the G6PD deficiency status, this study aimed at investigating the potential association between the intake of PQ and haemolysis in malaria-infected G6PDd subjects.MethodsThis was a prospective cohort and open-label study. Participants with malaria were recruited. Plasmodium vivax infection was treated with 0.25 mg/kg of PQ daily for 14 days. Safety and signs of haemolysis were evaluated by clinical criteria and laboratory values before and during the 3rd and 7th day of PQ treatment. G6PD status was assessed by a rapid test (CareStart™) and two molecular approaches.ResultsOverall 55 participants were enrolled. The frequency of G6PD deficient genotypes was 7/55 (12.7%), where 5/7 (71.4%) were hemizygous A-?males and 2/7 (28.6%) heterozygous A-?females. Haemoglobin concentrations were compared between G6PD wild type (B) and G6PDd A-?subjects, showing a significant difference between the means of both groups in the 3rd and 7th days. Furthermore, a statistically significant difference was evident in the change in haemoglobin concentration between the 3rd day and the 1st day for both genotypes, but there was no statistical difference for the change in haemoglobin concentration between the 7th day and the 1st day. Besides these changes in the haemoglobin concentrations, none of the patients showed signs or symptoms associated with severe haemolysis, and none needed to be admitted to a hospital for further medical attention.ConclusionsThe findings support that the intake of PQ during 14 days of treatment against vivax malaria is safe in patients with a class III variant of G6PDd. In view of the new national regulations in the shortened treatment of vivax malaria for 7 days, it is advisable to be alert of potential cases of severe haemolysis that could occur among G6PD deficient hemizygous males with a class II mutation such as the Santamaria variant, previously reported in the country.

Project description:Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75 mg/kg (adult dose 45 mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25 mg/kg (adult dose 15 mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%.The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic.The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria.ClinicalTrials.gov NCT01872702.

Project description:BackgroundAcute Plasmodium vivax malaria is associated with haemolysis, bone marrow suppression, reticulocytopenia, and post-treatment reticulocytosis leading to haemoglobin recovery. Little is known how malaria affects glucose-6-phosphate dehydrogenase (G6PD) activity and whether changes in activity when patients present may lead qualitative tests, like the fluorescent spot test (FST), to misdiagnose G6PD deficient (G6PDd) patients as G6PD normal (G6PDn). Giving primaquine or tafenoquine to such patients could result in severe haemolysis.MethodsWe investigated the G6PD genotype, G6PD enzyme activity over time and the baseline FST phenotype in Cambodians with acute P. vivax malaria treated with 3-day dihydroartemisinin piperaquine and weekly primaquine, 0·75 mg/kg x8 doses.ResultsOf 75 recruited patients (males 63), aged 5-63 years (median 24), 15 were G6PDd males (14 Viangchan, 1 Canton), 3 were G6PD Viangchan heterozygous females, and 57 were G6PDn; 6 patients had α/β-thalassaemia and 26 had HbE. Median (range) Day0 G6PD activities were 0·85 U/g Hb (0·10-1·36) and 11·4 U/g Hb (6·67-16·78) in G6PDd and G6PDn patients, respectively, rising significantly to 1·45 (0·36-5·54, p<0.01) and 12·0 (8·1-17·4, p = 0.04) U/g Hb on Day7, then falling to ~Day0 values by Day56. Day0 G6PD activity did not correlate (p = 0.28) with the Day0 reticulocyte counts but both correlated over time. The FST diagnosed correctly 17/18 G6PDd patients, misclassifying one heterozygous female as G6PDn.ConclusionsIn Cambodia, acute P. vivax malaria did not elevate G6PD activities in our small sample of G6PDd patients to levels that would result in a false normal qualitative test. Low G6PDd enzyme activity at disease presentation increases upon parasite clearance, parallel to reticulocytosis. More work is needed in G6PDd heterozygous females to ascertain the effect of P. vivax on their G6PD activities.Trial registrationThe trial was registered (ACTRN12613000003774) with the Australia New Zealand Clinical trials (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363399&isReview=true).

Project description: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.

Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection.Methods and findingsWe conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies.ConclusionsThe A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait.

Project description:Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients.This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events.This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir.ClinicalTrials.gov Identifier: NCT01814683 . Registered March 18, 2013.

Dataset Information

Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

Background

Methods and findings

Conclusion

Trial registration

Publications

Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets