Safety and benefits of interventions to increase folate status in malaria-endemic areas

Abstract

For decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine-pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria-endemic countries. We conclude that formal cost-benefit analyses are required.

Keywords: folic acid; folic acid antagonists; malaria; neural tube defects; sulfadoxine-pyrimethamine.

Figure 1

Folate metabolism in human cells. Folates, metabolites involved in the methionine cycle and methylated end products are indicated in red, green and yellow, respectively. Methyl donors and methyl receptors are indicated by thick and thin lines, respectively. Reduced tetrahydrofolate, the active form of folate, serves as a cofactor to carry one‐carbon units from donor molecules such as serine to intermediaries in the biosynthesis of a range of compounds. One such compound is thymidine monophosphate (dTMP), a precursor of thymidine that constitutes one of four nucleobases in DNA. In the methionine cycle, a methyl group is transferred from 5‐methyl‐tetrahydrofolate to S‐adenosylmethionine (SAM), which serves as a methyl donor to many acceptor substrates, such as nucleic acids, proteins, lipids and secondary metabolites. Cellular tetrahydrofolate is obtained from plasma mostly in the form of 5‐methyl‐tetrahydrofolate, but it can also be derived from folic acid, which is taken up and converted by the enzyme dihydrofolate reductase via dihydrofolate to tetrahydrofolate. Several metabolic pathways are not shown. For example, tetrahydrofolate can also react with formic acid to form 10‐formyl‐tetrahydrofolate, an essential metabolite in the biosynthesis of purines, whilst homocysteine can also be used for the synthesis of the amino acid cysteine. DHF: dihydrofolate; DHFR: dihydrofolate reductase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate (a deoxynucleotide); (Glu)_n: polyglutamate; MS: methionine synthase; MTHFR: 5, 10‐methylene‐THF reductase; SAH: S‐adenosyl homocysteine; SAM: S‐adenosyl methionine; THF: tetrahydrofolate.

Figure 2

Intestinal absorption of dietary folates, folic acid and 5‐methyl‐tetrahydrofolic acid. Dietary folates and folic acid at low doses is converted in the small intestine to 5‐methyl‐THF. At high oral doses, folic acid enters the circulation through passive diffusion in unmodified form (dotted line). DHF: dihydrofolate; DHFR: dihydrofolate reductase; Glu: glutamate; (Glu)_n: polyglutamate; MTHFR: 5, 10‐methylene‐THF reductase; THF: tetrahydrofolate. Adapted from: Clinical Pharmacokinetics, 49, 2010, 535–548, Pietrzik, K., Bailey, L. & Shane, B. Folic acid and l‐5‐methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. © 2010. With permission of Springer.

Figure 3

Folate metabolism in erythrocytic stages of Plasmodium parasites. Methyl donors and methyl receptors are indicated by thick and thin lines, respectively. In the endogenous pathway, Plasmodium can synthesize dihydrofolate and tetrahydrofolate de novo from dihydropteroate, pABA and glutamate moieties. Antifolate drugs (e.g. sulfadoxine, pyrimethamine) act by competitive binding to enzymes involved in this synthetic pathway. Thus DHPS is competitively inhibited by sulfadoxine and dapsone, whereas DHFR is competitively inhibited by pyrimethamine, proguanil and trimethoprim (red arrows). This antifolate activity results in inhibition of folate synthesis and, ultimately, reduced synthesis of thymidylate and parasite DNA. Ingested folic acid enters the circulation when ingested in high doses (dashed blue line). The parasite can access circulating folic acid and convert it through DHFR to dihydrofolate and tetrahydrofolate. By utilising the exogenous folic acid as a source of folates, the parasite can bypass the inhibition of the endogenous pathway and thus antagonise the activity of antifolate drugs. In theory, 5‐methyl‐THF is a methyl donor in the methionine cycle (lower cycle, with metabolites in green), resulting in the production of tetrahydrofolate and methionine (blue dotted lines). Recent evidence from an in vitro study suggests, however, that this pathway is not effectively utilised in Plasmodium, either because 5‐methyl‐THF monoglutamate from the erythrocytic pool cannot cross the membranes of the parasitophorous vacuole and the parasite (blue dotted line, with question mark) or because the parasite does not need methionine, because it derives this amino acid precursor of S‐adenosylmethionine from haemoglobin degradation or human plasma (Nduati et al, 2008). This evidence suggests that oral 5‐methyl‐THF may act as a source of folates in humans without antagonising the in vitro activity of antifolate drugs against P. falciparum (Nduati et al, 2008; Nzila et al, 2014). DHF: dihydrofolate; DHFR: dihydrofolate reductase; DHPS: dihydropteroate synthase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate (a deoxynucleotide); pABA: para‐aminobenzoic acid: SAM: S‐adenosyl methionine; THF: tetrahydrofolate.