An assessment of the supply, programmatic use, and regulatory issues of single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa

Abstract

BackgroundGlobal ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required.MethodsChallenges to the rollout of SLD primaquine in sub-Saharan Africa were established through semi-structured qualitative interviews with three primaquine manufacturers, 43 key informants from Ethiopia, Senegal, Swaziland, Zambia, and Tanzania, and 16 malaria research experts.ResultsSanofi and Remedica are the only two sources of SRA-approved primaquine suitable for procurement by international donors. Neither manufacturer produces primaquine tablet strengths suitable for the transmission blocking indication.In-country key informants revealed that the WHO weight-based recommendation to use SLD primaquine is challenging to implement in actual field settings. Malaria programmes expressed safety concerns of SLD primaquine use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as potential interactions between primaquine and co-morbidities, and drug-drug interactions with HIV and/or tuberculosis treatments. Regulatory processes are a major barrier to the rollout of SLD primaquine, requiring multiple steps at both the country and global level. Despite these barriers, demand for SLD primaquine is growing, and malaria researchers are interested in primaquine deployment through mass screen and treat and/or mass drug administration campaigns.ConclusionDemand for primaquine as a transmission blocking agent is growing rapidly yet multiple barriers to SLD primaquine use exist. Research is needed to define the therapeutic dose range, which will guide dosing regimens in the field, inform the development of new, lower strength primaquine tablets and/or formulation(s), and allay programmatic safety concerns in individuals with G6PD deficiency. Potential interactions between primaquine and co-morbidities and treatments should be explored. To minimize regulatory delays, countries need to prepare for product registration at an early stage, WHO prequalification for suitable primaquine tablet strengths and/or new formulations should be sought, and in the meanwhile only Stringent Regulatory Authority (SRA)-approved primaquine should be used.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0714-3) contains supplementary material, which is available to authorized users.

Plasmodium falciparum genotype and gametocyte prevalence in children with uncomplicated malaria in coastal Ghana

“…As Ghana targets to move beyond the malaria control phase into the pre elimination phase, there is a possibility of implementing PQ with first-line anti-malarial ACT to reduce gametocyte prevalence in Ghana as is on-going in some countries in the elimination and pre elimination phase [45]. The prevalence and extent of g6pd deficiency is a major concern for malaria eradication programmes, where they plan to use PQ as a gametocidal agent as although a single low dose of PQ has been suggested to be well tolerated in G6PD deficient malaria patients, PQ has been found at certain concentrations and in certain instances to cause RBC lysis in g6pd deficient individuals [48–50]. The 4.7% incidence of g6pd deficiency identified in this study was similar to another study conducted in 2015 in two different communities along the coast of Ghana where G6PD deficiency was 5.9% in hemizygous males and homozygous females [31].…”

A high susceptibility to redox imbalance of the transmissible stages of Plasmodium falciparum revealed with a luciferase‐based mature gametocyte assay

“…At present the only exception is primaquine (Smithuis et al ., 2010), an approved 8-aminoquinoline recommended by WHO as a gametocytocidal adjunct to first-line artemisinin-based combination therapies (ACT). Primaquine, however, has toxicity issues and can cause hemolysis in individuals harboring certain forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency (Butterworth et al ., 2013; Chen et al ., 2015). …”

Prevalence and genetic variants of G6PD deficiency among two Malagasy populations living in Plasmodium vivax-endemic areas

“…Although the 14 day primaquine regimen is recommended for the radical cure of P. vivax by Madagascar’s National Strategic Plan (2013–2017) [38], as in most malaria-endemic regions [12], primaquine is not prescribed. Its numerous limitations as a drug [39] contribute to this, but the potential risk of inducing haemolytic anaemia in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd) enzyme activity levels is the primary limitation.…”

“…Madagascar was notable in that analysis for being one of the countries with the highest uncertainty surrounding its predicted G6PDd prevalence, emphasizing the need for additional surveys to inform the sparse evidence from the Malagasy population. Setting this result in its geographic context, with the aim of identifying neighbouring areas with potentially similar G6PDd epidemiology, could help to guide programmatic roll-out of single-dose primaquine in Madagascar, a country where no evaluation of this intervention have yet been carried out [12]. The observed G6PDd prevalence in Madagascar was generally consistent with modelled estimates across continental Africa where 15 countries had estimated population-weighted G6PD d allele frequencies ≥15%, and prevalence in 19 countries was <10% [16].…”