In vivo efficacy of anti-malarial drugs against clinical Plasmodium vivax malaria in Ethiopia: a systematic review and meta-analysis
Authors: Ketema Tsige , Bacha Ketema , Getahun Kefelegn , Bassat Quique 
Published: December 2021

Abstract
Background
Ethiopia is one of the few countries in Africa where Plasmodium vivax commonly co-exists with Plasmodium falciparum, and which accounts for ~ 40% of the total number of malaria infections in the country. Regardless of the growing evidence over many decades of decreasing sensitivity of this parasite to different anti-malarial drugs, there has been no comprehensive attempt made to systematically review and meta-analyse the efficacy of different anti-malarial drugs against P. vivax in the country. However, outlining the efficacy of available anti-malarial drugs against this parasite is essential to guide recommendations for the optimal therapeutic strategy to use in clinical practice. The aim of this study was to synthesize evidence on the efficacy of anti-malarial drugs against clinical P. vivax malaria in Ethiopia.

Methods
All potentially relevant, peer-reviewed articles accessible in PubMed, Scopus, Web of Science, and Clinical Trial.gov electronic databases were retrieved using a search strategy combining keywords and related database-specific subject terms. Randomized controlled trials (RCTs) and non-randomized trials aiming to investigate the efficacy of anti-malarial drugs against P. vivax were included in the review. Data were analysed using Review Manager Software. Cochrane Q (χ2) and the I2 tests were used to assess heterogeneity. The funnel plot and Egger’s test were used to examine risk of publication bias.

Results
Out of 1294 identified citations, 14 articles that presented data on 29 treatment options were included in the analysis. These studies enrolled 2144 clinical vivax malaria patients. The pooled estimate of in vivo efficacy of anti-malarial drugs against vivax malaria in Ethiopia was 97.91% (95% CI: 97.29–98.52%), with significant heterogeneity (I2 = 86%, p < 0.0001) and publication bias (Egger’s test = -12.86, p < 0.001). Different anti-malarial drugs showed varied efficacies against vivax malaria. The duration of follow-up significantly affected the calculated efficacy of any given anti-malarial drug, with longer duration of the follow-up (42 days) associated with significantly lower efficacy than efficacy reported on day 28. Also, pooled PCR-corrected efficacy and efficacy estimated from altitudinally lower transmission settings were significantly higher than PCR-uncorrected efficacy that estimated for moderate transmission settings, respectively.

Conclusion
The overall efficacy of anti-malarial drugs evaluated for the treatment of vivax malaria in Ethiopia was generally high, although there was wide-ranging degree of efficacy, which was affected by the treatment options, duration of follow-up, transmission intensity, and the confirmation procedures for recurrent parasitaemia. Regardless of evidence of sporadic efficacy reduction reported in the country, chloroquine (CQ), the first-line regimen in Ethiopia, remained highly efficacious, supporting its continuous utilization for confirmed P. vivax mono-infections. The addition of primaquine (PQ) to CQ is recommended, as this is the only approved way to provide radical cure, and thus ensure sustained efficacy and longer protection against P. vivax. Continuous surveillance of the efficacy of anti-malarial drugs and clinical trials to allow robust conclusions remains necessary to proactively act against possible emergence and spread of drug-resistant P. vivax in Ethiopia.