Single low-dose primaquine for malaria control in Africa: a systematic review of safety, efficacy and implementation barriers

Abstract

Since 2012, the WHO has recommended a single low dose of primaquine (SLDPQ, 0.25 mg/kg) alongside artemisinin-based combination therapies (ACTs) to block Plasmodium falciparum transmission and combat artemisinin resistance. Despite its proven benefits, SLDPQ adoption in African malaria policies remains limited. We conducted a systematic review of studies published between 2012 and 2023 on the safety, efficacy and implementation of SLDPQ in Africa. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched 7 databases and screened 819 records. Eligible studies focused on SLDPQ co-administered with ACTs for treating uncomplicated P. falciparum malaria in African contexts. Data were extracted and analysed from 41 studies, including 15 randomised controlled trials (RCTs) and 26 non-trial studies. SLDPQ was found to be safe and well-tolerated, including in glucose-6-phosphate dehydrogenase deficiency individuals and children under 5. Eight RCTs confirmed significant reductions in gametocyte carriage, validating SLDPQ’s individual-level efficacy. However, evidence on community-level impact remains limited. Key implementation barriers include persistent misconceptions about primaquine toxicity, absence of paediatric formulations and operational challenges in health systems. Most studies used the WHO-recommended dose (0.25 mg/kg), but higher doses and age-based regimens were also investigated. This review supports SLDPQ as a safe and effective tool for malaria transmission reduction in Africa. Addressing barriers to implementation, through health worker training, community sensitisation and operational research, is essential to accelerate its adoption. The ongoing Implementing Primaquine Single Low Dose in Africa project aims to generate real-world evidence across three countries, with a focus on paediatric use and health system integration. SLDPQ scale-up should be prioritised within malaria elimination strategies across sub-Saharan Africa.

SUMMARY BOX.

• Safety: Strong evidence confirms that single low-dose primaquine (SLDPQ, 0.25 mg/kg) is safe in African settings, including among glucose-6-phosphate dehydrogenase-deficient individuals and children under 5.

• Efficacy: SLDPQ effectively reduces Plasmodium falciparum gametocyte carriage at the individual level but requires further evaluation for community-level impact.

• Implementation barriers: Adoption of SLDPQ in African malaria treatment guidelines is hindered by misconceptions about toxicity, lack of paediatric-friendly formulations and limited real-world data.

• Policy implications: Addressing these barriers is critical to achieving malaria elimination goals in sub-Saharan Africa.

• Future directions: The project (‘Implementing Primaquine Single Low Dose in Africa’) is generating critical data on SLDPQ’s feasibility, safety and acceptability to inform national and global policy updates.

Background

Malaria remains a leading cause of morbidity and mortality, with an estimated 263 million cases and 619 000 deaths reported globally in 2023.¹ Sub-Saharan Africa bears the heaviest burden, accounting for 94% of cases and deaths, with children under 5 years old and pregnant women being the most vulnerable groups.^{1 2} Despite significant progress achieved over the past two decades, largely attributed to interventions such as insecticide-treated bed nets (ITNs), indoor residual spraying and artemisinin-based combination therapies (ACTs), the malaria elimination agenda faces critical challenges.¹,³

One of the most pressing threats is the emergence and spread of artemisinin partial resistance (ART-R), first documented in Southeast Asia³,⁶ and now confirmed in parts of sub-Saharan Africa, including Uganda,^{7 8} Rwanda,^{9 10} Eritrea¹¹ and Tanzania.¹² ART-R increases the likelihood of treatment failure,¹³ jeopardising progress towards the Global Technical Strategy for Malaria 2025 targets¹⁴ and undermining malaria-elimination efforts by increasing residual transmission. Additional threats include logistical challenges in mass drug administration (MDA).

To counter these threats related to ART-R, the WHO introduced new guidelines in 2012 recommending the use of single low-dose primaquine (SLDPQ, 0.25 mg/kg body weight) as an adjunct to ACTs.¹⁵ This gametocytocidal agent targets mature Plasmodium falciparum gametocytes, reducing their potential to infect mosquitoes.¹⁶,²⁰

By 2024, the WHO reaffirmed the central role of SLDPQ in its malaria elimination strategy, highlighting its dual role in blocking transmission and curbing resistance.²¹ However, the adoption of SLDPQ in African malaria treatment guidelines has been slow.¹ We assessed actual implementation of SLD PQ policy in national malaria-control programmes rather than mere guideline recommendations. Concerns about primaquine’s safety, particularly in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), a condition prevalent in many African populations, may have contributed to hesitancy. Limited data on population-level impact, the lack of child-friendly formulations and entrenched misconceptions about primaquine toxicity have also hindered integration into policy and practice.^{15 19}

This systematic review synthesises evidence published between 2012 and 2023 to evaluate the evidence base and policy relevance of SLDPQ in Africa. By identifying key barriers and gaps in knowledge, this work aims to inform evidence-based policymaking and support progress towards malaria elimination in sub-Saharan Africa.

Methodology

Review design and reporting standards

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.^{22 23} The PRISMA 2020 checklist is provided as online supplemental table S1. This review protocol was not registered with PROSPERO. The objective was to synthesise existing evidence on the safety, efficacy and implementation barriers of SLDPQ (0.25 mg/kg) when used as an adjunct to ACTs for the treatment of P. falciparum malaria in sub-Saharan Africa.

Eligibility criteria

Studies were eligible for inclusion if they were published in peer-reviewed journals between January 2012 and December 2023, addressed the use of SLDPQ in combination with ACTs for treating uncomplicated P. falciparum malaria in African settings, and reported on at least one relevant outcome such as safety, tolerability, efficacy or implementation challenges. Both randomised controlled trials (RCTs) and non-trial studies (NTS), such as systematic reviews and narrative reviews, are included to provide the most comprehensive data on the currently available scientific evidence on SLDPQ.

Studies were excluded if they (1) were not written in English or French; (2) were editorials, conference abstracts or full texts that were not available; (3) did not meet the inclusion criteria outlined above (eg, studies focusing on Plasmodium vivax, MDA, general policy analysis, studies not focusing on primaquine or SLDPQ) and (4) were not available (eg, studies still under review or publications not available).

Information sources and search strategy

A comprehensive literature search was performed in seven electronic databases: PubMed, Embase, CENTRAL (Cochrane Library), Medline, Web of Science, Nature Journals and Google Scholar. The search covered the period from January 2012, corresponding to the WHO recommendation of SLDPQ,¹⁵ through December 2023. Search terms included combinations of “single low dose”, “primaquine”, “Plasmodium”, “falciparum” and “Africa”, using both MeSH terms and free-text keywords with Boolean operators and truncation where applicable.

The start of the search period (2012) was chosen for three reasons. First, the WHO introduced its SLDPQ recommendation that year.¹⁵ Second, according to the WHO Evidence Review Group (ERG), studies conducted before 2012 were often limited in quality and based on unpublished or outdated data, with some originating prior to 1950. Third, a notable increase in published evidence on SLDPQ, particularly in Africa, occurred after the 2012 WHO guidance.¹

Study selection

All identified records were imported into a reference management system, and duplicates were removed. References were managed in EndNote V.20, and title-level/abstract-level screening was conducted in Covidence (Veritas Health Innovation, Melbourne, Australia). Screening was performed in two stages. Titles and abstracts were reviewed first to exclude irrelevant articles, followed by full-text screening of potentially eligible studies. Screening was conducted independently by TY and EC; disagreements were resolved through discussion or, when required, adjudicated by DM. The same two reviewers (TY and EC) extracted data independently, and TY verified all risk-of-bias assessments.

Data extraction and synthesis

Data from the included studies were extracted using a standardised template developed in Zotero and organised in Notion. The extracted data included general article information, study design, population characteristics, intervention details and key findings related to SLDPQ safety, efficacy, dosing strategies and implementation barriers. Data extraction was independently reviewed by multiple coauthors to ensure consistency and accuracy. Any discrepancies were resolved through consensus discussion and, when needed, by consulting the original publication.

Risk-of-bias assessment

All RCTs included in this review were assessed using the Revised Cochrane Risk-of-Bias Tool (RoB 2).^{22 23} This tool evaluates key domains such as randomisation process, blinding, adherence to intervention protocols, completeness of outcome data and outcome measurement. The risk of bias for each study was evaluated independently by reviewers, and the findings were synthesised to construct an overall risk profile across the body of evidence.

Results

This review is based on 41 studies selected for their relevance to the evaluation of SLDPQ in malaria control and elimination strategies in African contexts¹⁶,²⁰²⁴ (online supplemental table S2). Of the 819 records initially retrieved, 172 articles underwent full-text assessment. Ultimately, 41 studies met the inclusion criteria, comprising 15 RCTs and 26 non-trial studies (NTS) (figure 1). Studies were geographically distributed across nine African countries: Uganda, Democratic Republic of Congo, Mali, South Africa, Burkina Faso, The Gambia, Senegal, Kenya and Tanzania (figure 2).

Figure 1. The PRISMA flow chart of the selection process. The flow chart summarises the systematic review process, starting with the identification of 819 records through database searches. Duplicates and ineligible records were removed, leaving 172 studies for full-text screening. Further exclusions were made based on predefined eligibility criteria, resulting in the inclusion of 41 studies. These included 15 randomised trials (37%) and 26 non-trial studies (63%). MDA, Mass Drug Administration; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLDPQ, single low-dose primaquine.

Figure 2. Geographical coverage of RCTs on SLDPQ. The figure illustrates the geographical distribution of RCTs evaluating SLDPQ across sub-Saharan Africa. The RCTs covered nine countries: Uganda, the Democratic Republic of Congo, Mali, South Africa, Burkina Faso, The Gambia, Senegal, Kenya and Tanzania. This distribution reflects diverse malaria transmission settings, ranging from high-transmission regions to near-elimination zones, providing a comprehensive perspective on SLDPQ’s safety and efficacy. However, the figure also highlights gaps in representation, particularly in Central and West Africa, where additional studies are necessary to ensure the generalisability of findings. RCTs, randomised controlled trials; SLDPQ, single low-dose primaquine.

Key data extracted from these studies are summarised in online supplemental table S2, which categorises information on safety, efficacy, dosing regimens, paediatric formulations and geographical coverage. The main findings and limitations of the included studies are presented in online supplemental table S3, which highlights the strengths of SLDPQ in reducing P. falciparum transmission and identifies key research gaps, such as its use in individuals with other haemoglobinopathies or comorbidities and its impact on malaria transmission at the community level. A comprehensive risk-of-bias assessment using the Revised Cochrane RoB 2 indicated high methodological quality across all RCTs, ensuring a low risk of bias and supporting the robustness of the findings (see online supplemental table S4).

The included studies addressed three major thematic areas: safety, efficacy and implementation. Safety was examined in 33 studies, including 13 RCTs and 20 non-trial studies (NTS). Among these, 24 studies focused specifically on safety in G6PDd individuals. SLDPQ was generally well tolerated across populations. Of the 13 RCTs assessing safety, 12 reported no serious adverse events (AEs) attributable to SLDPQ.^{1826 28},30 32 34 37 Mild AEs, such as transient haemoglobin reductions, headaches, fever, abdominal pain and reduced appetite, were reported in eight studies.^{26 29 30 34 37 39 42 45} Three studies, conducted in Uganda and the Democratic Republic of Congo, provided specific data on SLDPQ safety in children under 5 years old,^{31 43} confirming its tolerability in this high-risk group. Among the 24 studies focusing on G6PDd populations, 8 RCTs found no significant difference in AE frequency between ACT-only and ACT+SLDPQ groups.^{25 28 30 33 34 38 39 45} One study demonstrated tolerability in both the severe Southeast Asian and common African G6PD variants.⁴⁵

Efficacy outcomes were quantitatively analysed in 17 studies, including 8 RCTs and 9 NTS. All 17 showed ≥90% reductions in P. falciparum gametocyte carriage within 48–72 hours after dosing.^{1820 27},^{30 37 42} The transmission-blocking effect was confirmed across multiple ACTs and settings (South Africa, Mali and The Gambia),^{20 28 30 33 39 42 48} and membrane feeding assays showed loss of infectivity irrespective of G6PD or CYP2D6 status.²⁷,^{3037 42} Beyond these, 16 of the 26 NTS reported qualitative evidence of individual-level efficacy, although outcome reporting was insufficient for inclusion in the quantitative synthesis.^{16 17 20 24 25 27 35 40 43 47} Identified implementation barriers are: (1) absence of paediatric formulation, (2) provider concerns over haemolytic risk, (3) logistical constraints such as supply chain and staff training and (4) inadequate postadministration monitoring.

Optimal dosing and paediatric considerations were addressed in 16 studies. Eight studies confirmed the safety and efficacy of the WHO-recommended 0.25 mg/kg dose^{1820 25 28},^{30 38 45} while others supported higher doses (up to 0.4 mg/kg) as safe and potentially more effective.²⁰²⁶,^{28 45} Three trials have compared the standard 0.25 mg/kg dose with a higher 0.40 mg/kg (or equivalent) and all reported faster parasite or infectivity clearance without extra safety signals. Bastiaens et al (Burkina Faso and The Gambia, asymptomatic adult males, n=82) showed that the median time to gametocyte clearance fell from 4 days with 0.25 mg/kg to 2 days with 0.40 mg/kg, and no grade-3 haemoglobin drops were observed.²⁶ Okebe et al (The Gambia, asymptomatic carriers, n=694) found that the day-7 gametocyte prevalence was 17% at 0.25 mg/kg vs 10% at 0.40 mg/kg (p<0.05), with identical safety profiles.³⁷ Dicko et al (Mali, gametocytaemic males, n=80) showed that mosquito infectivity was already negligible by day 2 with 0.50 mg/kg (≈0.40 mg/kg base) compared with 6% at 0.25 mg/kg, again without any serious haemolysis.²⁸ Age-based regimens were proposed to account for weight and metabolic variability in children.⁴⁵

SLDPQ was evaluated in combination with several ACTs, including dihydroartemisinin-piperaquine (DP),^{28 30 37 42} sulfadoxine-pyrimethamine,²⁹ artesunate-mefloquine,¹⁸ artemether-lumefantrine^{30 33 39 40} and pyronaridine-artesunate.⁴² Evidence showed consistent safety and enhanced transmission-blocking efficacy regardless of the ACT used (online supplemental table S2).

Discussion

This systematic review synthesised evidence from 41 studies, including 15 RCTs and 26 non-trial studies, to evaluate the implementation of the WHO recommendation on SLDPQ for malaria control in sub-Saharan Africa.

Key findings and challenges

Three major themes emerged regarding the implementation of SLDPQ in sub-Saharan Africa: safety, efficacy and paediatric challenges, including dosing and formulation.

A substantial body of evidence supports the safety of SLDPQ, even among vulnerable populations such as G6PDd individuals and children under 5 years of age. In contrast to high, multidose regimens for P. vivax malaria, the SLDPQ strategy involves a single low dose (0.25 mg/kg), which has demonstrated excellent tolerability. Notably, Mwaiswelo et al reported that no deaths attributable to SLDPQ have been documented over 60 years of clinical use.¹⁹ These findings highlight the importance of educational campaigns to combat misconceptions about primaquine toxicity. Studies confirmed that haemoglobin reductions in G6PDd individuals were mild, transient and resolved without medical intervention. In addition, at least twelve NTS concluded that SLDPQ is safe for use without prior G6PDd testing, aligning with WHO recommendations.^{17 19 20 25 31 34 41 48}

SLDPQ’s ability to clear mature P. falciparum gametocytes at the individual level is well documented: eight randomised trials and several meta-analyses report rapid (>90%) reductions in gametocyte carriage within 48–72 hours after dosing.^{1820 27},^{30 37 42} In contrast, evidence for a measurable reduction in onward transmission at population scale is limited and inconsistent; the four cluster or modelling studies available yielded heterogeneous results, largely because ecological heterogeneity, human mobility and vector dynamics dilute the individual benefit.^{20 29 43 46} White et al argued that substantial community-level impact is plausible if coverage exceeds 80% and dosing coincides with peak gametocytaemia, but this hypothesis remains untested.⁴⁷ Robust cluster-randomised or stepped-wedge trials that incorporate adherence checks, vector behaviour and population movement are therefore a research priority.

Children under 5 years old are disproportionately affected by malaria, yet data on SLDPQ’s pharmacokinetics in this demographic remain sparse. The lack of child-friendly formulations and limited paediatric-specific research hinders SLDPQ’s implementation in this vulnerable population.^{1820 28},30 37 38 45 Taylor et al proposed regimens tailored to sub-Saharan African populations to account for differences in weight, haemoglobin levels and metabolic rates.⁴⁵ Further research is needed to define dosing regimens that balance safety and efficacy across diverse age groups. Currently, primaquine tablets (available as 2.5 mg, 7.5 mg and 15 mg strengths) must often be crushed for paediatric use, leading to dose inaccuracies, reduced adherence due to bitterness and risks of drug resistance. Progress has been made under the ‘Developing Paediatric Primaquine’project,⁴⁹ which has developed flavoured, low-strength primaquine tablets for children. Pregnant and breastfeeding women represent an additional high-risk population currently excluded from SLD PQ administration because of the absence of safety data and therefore require targeted investigation.

Barriers to implementation

Despite strong evidence supporting the safety and efficacy of SLDPQ, several barriers hinder its widespread implementation in sub-Saharan Africa. These challenges span educational and perception issues, operational complexities and geographical and infrastructural limitations. Misinformation and negative perceptions about primaquine toxicity represent one of the most significant barriers to SLDPQ implementation.^{2 19 20} Evidence indicates that provider perceptions, rather than patient fears, drive these toxicity concerns. We recommend qualitative studies with healthcare providers to identify misconceptions and codesign educational interventions. Multidose primaquine, used for P. vivax malaria, has been linked to severe haemolytic anaemia in individuals with G6PD deficiency. This well-documented risk has perpetuated fears about primaquine’s safety, and the risk of haemolytic anaemia remains relevant today, particularly for P. vivax radical cure.

Mwaiswelo et al noted that misconceptions about primaquine toxicity are prevalent even in malaria-endemic regions.¹⁹ To ensure the successful adoption of SLDPQ, targeted training programmes for healthcare providers should be developed, emphasising its safety and effectiveness in malaria transmission control. Simultaneously, public health campaigns must address misconceptions about primaquine toxicity and build trust within communities.

The practical implementation of SLDPQ faces numerous operational challenges, including uncertainties around the timing of administration, dosing logistics and integration into existing malaria control programmes.^{17 19 25 43} SLDPQ is typically administered on the first day of ACT treatment to optimise adherence. However, studies suggest that delayed administration (eg, 2–3 days after starting ACTs) may enhance efficacy by aligning with peak gametocyte densities and reducing the risk of haemolysis in afebrile G6PDd individuals.^{16 27 29 40}

The geographic scope of SLDPQ studies remains limited, with most research conducted in a small number of sub-Saharan African countries. Central and West Africa, where malaria transmission is high, is under-represented in the evidence base. The majority of SLDPQ trials have been conducted in countries such as Uganda, the Democratic Republic of Congo, Mali and The Gambia. Regions with differing transmission dynamics, ecological factors and healthcare capacities are often excluded from research, limiting the generalisability of findings. Expanding research on SLDPQ in under-represented regions is essential to capture the diversity of malaria transmission settings.

Need for large-scale population studies

Most of the included studies assess SLDPQ efficacy under controlled clinical conditions, but fewer examine its impact in real-world settings. Longitudinal community-based trials and mathematical modelling studies could provide better insights into the epidemiological benefits of SLDPQ.

Challenges in real-world implementation

Although SLDPQ has been shown to be safe and effective, its adoption in national malaria programmes remains limited due to operational and logistical barriers. A significant challenge is acceptability and adherence, particularly among vulnerable groups such as infants, younger children and individuals with comorbidities requiring polypharmacy, who may fail to initiate or complete the regimen (eg, by not taking the SLDPQ or by not adhering to the dosage or schedule of the medication). Understanding the sociocultural factors that influence adherence will be crucial for its successful implementation. Future research should focus on identifying strategies to integrate SLDPQ into routine malaria treatment protocols. Another challenge lies in the exclusion of pregnant and lactating women from receiving SLDPQ due to potential risks, despite their heightened vulnerability to malaria and their role in community transmission dynamics. Addressing this gap requires robust clinical studies targeting this high-risk group, along with investigation of alternative antimalarial therapies and community-based measures.

Recommendations and future directions

To overcome the identified barriers to implementing SLDPQ and maximise its potential for malaria elimination, several key actions are recommended (table 1). First, addressing gaps in paediatric pharmacokinetics is essential to define safe and effective dosing regimens tailored to children of varying age groups and physiological profiles. This can be achieved through age-stratified clinical studies, including pharmacokinetic and pharmacodynamic assessments in real-world settings. Collaboration with paediatric researchers and regulatory agencies will be key to accelerating this work. Second, the development of child-friendly formulations, such as flavoured and low-strength primaquine tablets, to improve adherence and ensure accurate dosing should be prioritised. These can be pursued through public–private partnerships and product development incentives that encourage pharmaceutical innovation to be tailored to resource-limited settings. Third, the lack of conclusive evidence on SLDPQ’s community-level impact on malaria transmission calls for comprehensive redesign and implementation of innovative, context-sensitive trials. These studies should be codesigned with endemic communities and local health decision-makers to ensure feasibility and uptake. Fourth, understanding how SLDPQ interacts with other malaria interventions is vital. Studies should explore its synergistic potential when combined with established tools like ITNs, vaccines and seasonal malaria chemoprevention. Fifth, effectively addressing persistent misconceptions around primaquine toxicity is critical for fostering acceptance and trust among healthcare providers, policymakers and communities. To achieve this, targeted training programmes should be developed to educate clinicians on the unique safety profile of SLDPQ and its critical role in malaria elimination efforts. Community engagement should involve culturally sensitive campaigns that emphasise the benefits of SLDPQ while dispelling myths related to primaquine toxicity.

Table 1. Recommendations and actions for advancing SLDPQ implementation.

Recommendation	Actionable steps
Address gaps in paediatric pharmacokinetics	Conduct age-stratified pharmacokinetic and pharmacodynamic studies in real-world endemic settings. Collaborate with paediatric research institutions and regulatory bodies to expedite data generation and guideline development.
Develop child-friendly formulations	Prioritise the development of flavoured, dispersible and low-dose primaquine tablets to support accurate dosing and adherence in children. Promote public–private partnerships and incentivise pharmaceutical innovation tailored to low-resource settings.
Develop evidence on community-level impact	Design and implement innovative, context-specific trials to assess SLDPQ’s effect on malaria transmission. Co-create studies with endemic communities and local health decision-makers to ensure feasibility, uptake and policy alignment.
Explore integration with other malaria interventions	Investigate SLDPQ’s combined use with existing tools like ITNs, vaccines and SMC. Conduct operational research to evaluate codelivery strategies and potential synergies.
Address misconceptions about primaquine toxicity	Develop targeted clinician training to clarify SLDPQ’s safety profile and utility. Implement culturally sensitive community engagement campaigns to dispel myths and build trust among health workers and affected communities.

ITNs, insecticide-treated bed nets; SLDPQ, single low-dose primaquine; SMC, seasonal malaria chemoprevention.

Finally, we are aware that potential duplication of primary trial data contained in systematic and narrative reviews may bias our synthesis; we acknowledge this as a study limitation.

Conclusions

This systematic review provides a comprehensive overview of the current evidence on the safety, efficacy, optimal dosing regimens and paediatric formulations of SLDPQ. The findings affirm SLDPQ’s role as a safe and effective tool for blocking malaria transmission and mitigating the spread of ART-R. However, the successful implementation of the WHO recommendations for SLDPQ in Sub-Saharan Africa requires addressing several critical barriers, including operational challenges, data gaps in paediatric pharmacology and persistent misconceptions about primaquine toxicity.

In this context, the IMPRIMA project (‘Implementing Primaquine Single Low Dose in Africa’), funded by the GH EDCTP3 Joint Undertaking, represents a pivotal endeavour.⁵⁰ The project’s studies, conducted across three Sub-Saharan African countries—Madagascar, Burundi and Burkina Faso—cover diverse malaria transmission intensities, ensuring the findings are broadly applicable. By working closely with national malaria programmes, IMPRIMA seeks to translate its findings into policy and routine treatment guidelines, while training local health workers and researchers to ensure sustainable implementation of SLDPQ.

The funders had no involvement in the study design, execution, data interpretation or manuscript preparation.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.