A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria.

Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection's country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs > 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria.

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. METHODS: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Symptomatic identification of malaria in the home and in the primary health care clinic.

In endemic areas in the absence of microscopy, the WHO case definition of malaria is the presence or a history of fever without other obvious cause. Yet there is little empirical evidence on the accuracy, predictability and reliability of clinical signs and symptoms for diagnosing malaria within different endemic settings. Studying patients in endemic communities in the Philippines, we found that fever alone did not discriminate well for malaria. In contrast, a sequential occurrence of fever, chills and/or sweating, or a combination of all three symptoms was a good general predictor of the disease. However, the place of diagnosis and observation (home or clinic), age, and season affected the positive predictive values obtained. Specificities and positive predictive values were greatest (over 80%) for those at most risk--children under 9 years of age in highly endemic communities--and were most reliable when the diagnosis was made at home. Predictive values were also greatest during the season when childhood acute lower respiratory infections in the study area increase. The good predictability of clinical signs and symptoms for high-risk groups suggests that simple protocols can be developed for the management of malaria in endemic areas of the Philippines.

PIP: Over the past 30 years, the mountainous area of Kalinga Apayao Province on Luzon Island in the Philippines was extensively deforested due to slash and burn farming. The malaria risk is reduced, but malaria is still endemic. During 1990-1992, morbidity surveys identified 614 malaria cases. Researchers wanted to determine the accuracy, predictability, and reliability of clinical signs and symptoms for diagnosing malaria. Most individuals (89%) claimed to have had fever, yet just 35.4% had a body temperature greater than 37.6 degrees Celsius. Only 51.8% of fever cases had parasitemia, indicating that the World Health Organization's recommended case definition of malaria (i.e., presence or history of fever) did not adequately identify malaria. Further, prior to this study, about 50% of the area's children were usually infected, but just 11.3% of children younger than 6 in this study had fever. A good general predictor of malaria included a sequential occurrence of fever, chills and/or sweating, or a combination of all 3 symptoms. The positive predictive values were: at-home observation and diagnosis (74-76% vs. 69-72% at the rural health clinic), age younger than 9 years (80-84% vs. 65-69% for = or 10 year olds), and presentation during November-January (94-100% vs. 74% for February-October). November-January was the season when the prevalence of acute lower respiratory infections was highest. These results demonstrate that health workers can develop simple algorithms with good predictability of clinical signs and symptoms for high-risk groups to manage malaria in endemic areas of the Philippines.