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Meta-Analysis
. 2018 Feb 2;2(2):CD008152.
doi: 10.1002/14651858.CD008152.pub5.

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Patricia M Graves  1 , Leslie Choi, Hellen Gelband, Paul Garner
Affiliations
Meta-Analysis

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Patricia M Graves et al. Cochrane Database Syst Rev. .

Abstract

Background: The 8-aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear.

Objectives: To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using 'malaria*', 'falciparum', 'primaquine', '8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017.

Selection criteria: Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria.

Data collection and analysis: Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups.

Main results: We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing.No cluster trials evaluating community effects on malaria transmission met the inclusion criteria.With artemisinin treatmentLow dose PQInfectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence).Moderate dose PQInfectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups.High dose PQInfectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis.With non-artemisinin treatmentTrials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis.Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants).

Authors' conclusions: A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce malaria transmission at community level.

PubMed Disclaimer

Conflict of interest statement

We have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (for example, employment, consultancy, stock ownership, honoraria, or expert testimony).

This review and the salary of PG is supported by a DFID grant aimed at ensuring the best possible systematic reviews, particularly Cochrane Reviews, are completed on topics relevant to the poor in low‐ and middle‐income countries. DFID does not participate in the selection of topics, in the conduct of the review or in the interpretation of findings. PG is a member of the WHO Guidelines for the Treatment of Malaria Group that made the recommendation for PQ to reduce P. falciparum malaria transmission.

PMG was a member from 2012 to 2016 of the WHO Malaria Policy Advisory Committee, which provides independent strategic advice in forming WHO policies in malaria.

HG and LC have no known conflicts of interest.

None of the review authors are investigators on any of the included trials.

Figures

1
1
Review logic framework: the potential points in the Plasmodium parasite life cycle that could be impacted by PQ and the outcomes used to measure impact. Abbreviations: AUC: area under the curve. EIR: entomological inoculation rate; PQ: primaquine.
2
2
‘Risk of bias' summary: review authors' judgements about each risk of bias item for each included trial.
3
3
‘Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
4
4
Study flow diagram
1.1
1.1. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 3 or 4, by dose.
1.2
1.2. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (PCR), day 3 or 4, by dose.
1.3
1.3. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants with gametocytes (microscopy), day 3 or 4, by dose.
1.4
1.4. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants infectious, day 8, by dose.
1.5
1.5. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Participants with gametocytes (PCR), day 8, by dose.
1.6
1.6. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Participants with gametocytes (microscopy), day 8, by dose.
1.7
1.7. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 7 Gametocyte clearance time (PCR), by dose.
1.8
1.8. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 8 Area under curve of gametocytes (PCR), days 1 to 15, by dose.
1.9
1.9. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 9 Participants with severe haemolysis, by dose.
1.10
1.10. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 10 Mean max change in haemoglobin concentration, by dose.
1.11
1.11. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 11 Percent change in haemoglobin, day 8, by dose.
1.12
1.12. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 12 Max percent change in haemoglobin, by dose.
1.13
1.13. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 13 Haemoglobinuria/dark urine.
1.14
1.14. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 14 Other adverse effects (CNS symptoms).
1.15
1.15. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 15 Other adverse effects (systemic).
1.16
1.16. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 16 Other adverse effects (respiratory symptoms).
1.17
1.17. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 17 Other adverse effects (gastrointestinal symptoms).
1.18
1.18. Analysis
Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 18 Other adverse effects (Miscellaneous).
2.1
2.1. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 1 Participants infectious, day 3 to 4.
2.2
2.2. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 2 Participants with gametocytes (PCR), day 3 to 4.
2.3
2.3. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 3 Participants with gametocytes (microscopy), day 3 to 4.
2.4
2.4. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 4 Participants infectious, day 8.
2.5
2.5. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 5 Participants with gametocytes (PCR), day 8.
2.6
2.6. Analysis
Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 6 Participants with gametocytes (microscopy), day 8.
3.1
3.1. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 5, by dose.
3.2
3.2. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (microscopy), day 4 to 5, by dose.
3.3
3.3. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants infectious, day 8, by dose.
3.4
3.4. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants with gametocytes (microscopy), day 8, by dose.
3.5
3.5. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Gametocyte clearance time.
3.6
3.6. Analysis
Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Adverse effects.
4.1
4.1. Analysis
Comparison 4 PQ versus other 8AQ, Outcome 1 Participants with gametocytes (microscopy), day 8.
See this image and copyright information in PMC

Update of

References

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Huang 2001 {published data only}
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Kyaw 1994 {published data only}
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Li 2007 {published data only}
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Lin 2004 {published data only}
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Mackerras 1949 {published data only}
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References to studies awaiting assessment

Chen 1993b {published data only}
    1. Chen L. Efficacy of artemether/primaquine against drug resistant P. falciparum [Chinese]. Journal of Applied Medicine 1993;1(1):31‐3.
Ishii 2009 {unpublished data only}
    1. Ishii A, Ohta N, Owhashi M, Kawabata M, Chung D, Bobogare A, et al. Trials of transmission blocking of P. falciparum with single dose primaquine in villages of Solomon Islands. MIM conference October 2009 MIM 16723361.
Li 2006 {published data only}
    1. Li J, et al. Artemether combined with primaquine for treatment of 50 Pf cases [Chinese]. Journal of Applied Medicine 2006;22(19):2299‐300.

References to ongoing studies

ISRCTN11594437 {unpublished data only}
    1. ISRCTN11594437. Primaquine in African Children (PAC study) [Assessing the tolerability and safety of single low dose primaquine in African children with acute uncomplicated falciparum malaria and glucose 6 phosphate dehydrogenase deficiency in Africa.]. isrctn.com/ISRCTN11594437 (first received 09/05/2017).
NCT01906788 {unpublished data only}
    1. NCT01906788. The optimal timing of primaquine to prevent malaria transmission after artemisinin‐combination therapy. clinicaltrials.gov/ct2/show/NCT01906788 (first posted 24 July 2013).
NCT02259426 {unpublished data only}
    1. NCT02259426. Dihydroartemisinin‐piperaquine with low dose primaquine to reduce malaria transmission (DAPPI). clinicaltrials.gov/ct2/show/NCT02259426 (first posted 8 October 2014).
NCT02431650 {unpublished data only}
    1. NCT02431650. Effectiveness of OZ439 as a gametocytocidal and transmission blocking agent (OZGAM) [A proof‐of‐concept study to assess the effectiveness of OZ439 as a gametocytocidal and transmission blocking agent in experimental P. falciparum infection]. clinicaltrials.gov/ct2/show/NCT02431650 (first posted 1 May 2015).
NCT02434952 {unpublished data only}
    1. NCT02434952. Safety and tolerability of low dose primaquine. clinicaltrials.gov/ct2/show/NCT02434952 (first posted 6 May 2015).
NCT02831023 {unpublished data only}
    1. NCT02831023. Phase 2 efficacy study of primaquine and methylene blue. clinicaltrials.gov/ct2/show/NCT02831023 (first posted 13 July 2016).
NCT02851108 {unpublished data only}
    1. NCT02851108. Methylene blue against falciparum malaria in Burkina Faso (BlueACTn) [Safety of artesunate‐amodiaquine combined with methylene blue or primaquine for falciparum malaria treatment in African children: a randomised controlled trial]. clinicaltrials.gov/ct2/show/NCT02851108 (first posted 1 August 2016).
PACTR201611001859416 {unpublished data only}
    1. PACTR201611001859416. Addition of low dose primaquine to artemether‐lumefantrine for the treatment of uncomplicated malaria [A randomised controlled trial to investigate the efficacy, safety and tolerability of adding a single low primaquine dose to artemether‐lumefantrine for the treatment of symptomatic uncomplicated Plasmodium falciparum malaria]. www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR20... (date of registration 11 November 2016).

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References to other published versions of this review

Graves 2012
    1. Graves PM, Gelband H, Garner P. Primaquine for reducing Plasmodium falciparum transmission. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD008152.pub2] - DOI - PubMed
Graves 2014
    1. Graves PM, Gelband H, Garner P. Primaquine or other 8‐aminoquinoline for reducing P. falciparum transmission. Cochrane Database of Systematic Reviews 2014, Issue 6. [DOI: 10.1002/14651858.CD008152.pub3] - DOI - PMC - PubMed
Graves 2015
    1. Graves PM, Gelband H, Garner P. Primaquine or other 8‐aminoquinoline for reducing Plasmodium falciparum transmission. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD008152.pub4] - DOI - PMC - PubMed

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