Improving Plasmodium vivax malaria treatment: a little more chloroquine
Authors: Georges Snounou
Journal: The Lancet Infectious Diseases (2018)

The efficacy of first-line malaria treatment underpins the success of malaria control programmes. Left untreated, malaria infections will generally recur over many months. These recurrences increase malaria morbidity and enhance transmission. Crucially, suboptimal parasite clearance promotes the emergence of drug resistance. Thus, treatment should aim at total parasite elimination. Defining optimal dose, and monitoring for efficacy, rely on findings from clinical trials done in endemic areas. Patients, although monitored over 4 weeks or longer (depending on the drugs' pharmacokinetics), are usually discharged within days as symptoms wane and parasites become undetectable microscopically. Drug efficacy, or indeed indication of resistance, are deduced from the occurrence, timing, and frequency of recurrent episodes during follow-up. For malaria caused by Plasmodium vivax, the species with the broadest global distribution, now and historically, the path to successful treatment has been long. Early last century, Yorke1Yorke W Further observations on malaria made during treatment of general paralysis.Trans R Soc Trop Med Hyg. 1925; 19: 108-130Summary Full Text PDF Scopus (15) Google Scholar showed that whereas recurrences occurred in only 2% of quinine-treated P vivax cases inoculated with infected blood, recurrences were noted in 57% of those similarly treated but infected by mosquito bite. The biological basis of this conundrum was only discovered in the early 1980s:2Krotoski WA Collins WE Bray RS et al.Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection.Am J Trop Med Hyg. 1982; 31: 1291-1293Crossref PubMed Scopus (154) Google Scholar sporozoites inoculated by the mosquito invade hepatocytes where they develop within 1–2 weeks to release merozoites, which invade red blood cells, but for P vivax a subset of the liver forms remain dormant as hypnozoites, activating at various intervals over the following months to cause further episodes (ie, relapses). Following on from the pioneering work of Werner Schulemann and colleagues at IG Farben in Eberfield, Germany, in the 1920s, US workers 30 years later produced primaquine,3Edgcomb JH Arnold JD Yount Jr, EH Alving AS Eichelberger L Primaquine, SN 13272, a new curative agent in vivax malaria: a preliminary report.J Natl Malar Soc. 1950; 9: 285-292PubMed Google Scholar an 8-aminoquinoline that remains the only licensed compound able to eliminate hypnozoites to achieve radical cure. The recent drive to rid the world of malaria has brought P vivax to the fore, with the recognition that relapses pose a serious obstacle to its eradication, and with a recommendation that chloroquine and primaquine should be combined as a first-line treatment. However, primaquine, which can precipitate severe haemolysis in people with glucose-6-phosphate deficiency, is consequently often omitted or underdosed. Thus, in practice P vivax infections are frequently treated with chloroquine alone. Within this context, Robert Commons and colleauges4Commons RJ Simpson JA Thriemer K et al.The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis.Lancet Infect Dis. 2018; (published online July 19.)http://dx.doi.org/10.1016/S1473-3099(18)30348-7Summary Full Text Full Text PDF PubMed Scopus (66) Google Scholar sought to establish whether variations in chloroquine dose could have an effect on outcome. They selected a subset of 37 recent trials (from 2000 onwards) encompassing 5240 patients from a painstakingly gathered database of all therapeutic clinical trials done against P vivax.5Commons RJ Thriemer K Humphreys GS et al.The Vivax Surveyor: online mapping database for Plasmodium vivax clinical trials.Int J Parasitol Drugs Drug Resist. 2017; 7: 181-190Crossref PubMed Scopus (18) Google Scholar Two salient findings from this unique pooled analysis are as simple as they are compelling. First, slight increases in chloroquine target dose (5 mg/kg) led to a significant decrease in the risk of having a recurrent episode over 7–42 days after chloroquine administration (adjusted hazard ratio 0·82, 95% CI 0·69–0·97; p=0·021), an effect that was magnified in children younger than 5 years for an increase from 25 mg/kg to 30 mg/kg (0·59, 0·41–0·86; p=0·0058). This finding is of particular importance given that parasite rates for P vivax peak at 2–6 years of age.6Howes RE Battle KE Mendis KN et al.Global epidemiology of Plasmodium vivax.Am J Trop Med Hyg. 2016; 95: 15-34Crossref PubMed Scopus (237) Google Scholar The second finding is arguably the more important: concurrent administration of primaquine reduced the number of recurrent episodes by a massive 90% compared with chloroquine alone (adjusted hazard ratio 0·10, 0·05–0·17; p<0·0001), thereby also minimising the selection of chloroquine-resistant lines.7Chu CS Phyo AP Lwin KM et al.Comparison of the cumulative efficacy and safety of chloroquine, artesunate, and chloroquine-primaquine in Plasmodium vivax malaria.Clin Infect Dis. 2018; (published online June 8.)DOI:10.1093/cid/ciy319Crossref Scopus (43) Google Scholar The overarching conclusion, that the recommended chloroquine treatment of P vivax malaria has been suboptimal for decades, could not have been reached without the broad collaborative participation under the aegis of the WorldWide Antimalarial Resistance Network (WWARN). Given the potential positive impact on global P vivax morbidity, medical practitioners and public health administrators should give serious consideration to implementation of a modest increase to the long-standing WHO recommendations of a total chloroquine dose of 25 mg/kg.8WHOGuidelines for the treatment of malaria.3rd edition. World Health Organization, Geneva2015Google Scholar The minimal costs incurred will surely be outweighed by the resulting health and socioeconomic benefits. Nonetheless, the fact that chloroquine monotherapy continues to be the treatment most frequently administered in many P vivax-endemic areas is concerning, and this meta-analysis should not be taken as advocating this regimen. Also, the treatment of P vivax must include a hypnozoicidal component. Tafenoquine, another 8-aminoquinoline, which offers elimination of hypnozoites with a single dose, is nearing US Food and Drug Administration approval and shares primaquine's haemolytic potential. However, neither compounds are at present suitable for administration without the availability of cheap and reliable point-of-care testing for glucose-6-phosphate deficiency. With P vivax malaria now firmly in the sight of the malaria control community, and in view of the rising number of endemic areas where chloroquine resistance is recorded,9Price RN Von Seidlein L Valecha N Nosten F Baird JK White NJ Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis.Lancet Infect Dis. 2014; 14: 982-991Summary Full Text Full Text PDF PubMed Scopus (258) Google Scholar the malaria community needs to prioritise research leading to the universal implementation of efficacious combination therapies for P vivax that incorporate an anti-hypnozoicidal partner. The threat of P vivax endemicity is unlikely to disappear until radical cure becomes the usual treatment outcome. I declare no competing interests. The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysisChloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Full-Text PDF Open Access