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Review 4: "Evidence of Artemisinin Partial Resistance in North-Western Tanzania: Clinical and Drug Resistance Markers Study"

Overall, reviewers highlight that this study has important findings and significantly contributes to molecular surveillance efforts in Africa. However, they expressed concern about the study’s analytical methodology and the overall conclusions drawn from the data.

Published onMar 28, 2024
Review 4: "Evidence of Artemisinin Partial Resistance in North-Western Tanzania: Clinical and Drug Resistance Markers Study"
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key-enterThis Pub is a Review of
Evidence of artemisinin partial resistance in North-western Tanzania: clinical and drug resistance markers study
Evidence of artemisinin partial resistance in North-western Tanzania: clinical and drug resistance markers study

Abstract Background Artemisinin-based combination therapies (ACTs) are the recommended antimalarial drugs for the treatment of uncomplicated malaria. The recent emergence of artemisinin partial resistance (ART-R) in Rwanda, Uganda and Eritrea is of great concern. In Tanzania, a nationwide molecular malaria surveillance in 2021 showed a high prevalence of the Kelch13 (K13) 561H mutation in Plasmodium falciparum from the north-western region, close to the border with Rwanda and Uganda. This study was conducted in 2022 to evaluate the efficacy of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) for the treatment of uncomplicated falciparum malaria and to confirm the presence of ART-R in Tanzania.Methods This single-arm study evaluated the efficacy of AL and ASAQ in eligible children aged six months to 10 years at Bukangara Dispensary in Karagwe District, Kagera Region. Clinical and parasitological responses were monitored for 28 days according to standard WHO protocol. Mutations in K13 gene and extended haplotypes with these mutations were analysed using Sanger and whole genome sequencing data, respectively.Findings 176 children (88 in each AL and ASAQ group) were enrolled and all achieved the defined outcomes. PCR-corrected adequate clinical and parasitological response (ACPR) was 98.3% (95% CI: 90.8-100) and 100.0% (95% CI: 95.8-100) for AL and ASAQ, respectively. Parasitaemia on day 3 was observed in 11/88 (12.5%) and 17/88 (19.3%) in the AL and ASAQ groups, respectively. The half-life of parasitaemia was significantly higher (>6.5 hrs) in patients with parasitaemia on day 3 and/or mutations in K13 gene at enrolment. Most patients with parasitaemia on day 3 (8/11 = 72.7% in the AL group and 10/17 = 58.8% in the ASAQ group) had 561H mutation at enrolment. The parasites with K13 mutations were not similar to those from south-east Asia and Rwanda, but had the same core haplotype of a new 561H haplotype reported in Kagera in 2021.Interpretation These findings confirm the presence of ART-R in Tanzania. A context-specific strategy to respond to artemisinin partial resistance is urgently needed. Although both AL and ASAQ showed high efficacy, increased vigilance for reduced efficacy of these ACTs and detection of ART-R in other parts of the country is critical.Funding Bill and Melinda Gates Foundation to the World Health Organization (WHO, OPP 1209843) and the National Institute for Medical Research (NIMR, Inv. No. 002202), and US National Institute for Health (R01AI156267 to JAB, DSI and JJJ, and K24AI134990 to JJJ).Research in context Evidence before this study Artemisinin partial resistance (ART-R) is defined as delayed clearance after treatment with an artemisinin combination therapy (ACT) or artesunate monotherapy of a parasite strain carrying a validated marker of ART-R. At present, 13 different Kelch13 (K13) mutations have been validated as markers of ART-R. ART-R is confirmed in an area if a quality-controlled study using an ACT or artesunate monotherapy, finds more than 5% of patients have parasites with validated K13 mutations and delayed clearance as evidenced by either persistent parasitemia detected by microscopy on day 3 or a parasite clearance half-life of ≥5 hours. ART-R was first reported from Cambodia in 2008 and later from several countries in Southeast Asia. Published articles up to December 2023 were searched in PubMed with the terms; “artemisini n”, “artemisinin partial resistance”, “artemisinin-based combination therapies”, “Kelch 13” in combination with “Africa” or “Tanzania”. The publications confirmed the emergence of ART-R associated with mutations in K13: 561H in Rwanda, A675V and C469Y in Uganda and R622I in Eritrea. All these studies showed a high cure rate of the tested ACTs. The R622I mutant was not reported from Southeast Asia but is circulating in the Horn of Africa (Eritrea, Ethiopia, Sudan and Somalia). In Tanzania, a nationwide malaria molecular surveilla nce launched in January 2021 showed a high prevalence of 561H mutation in the north-western region of Kagera, close to the border with Rwanda and Uganda.Added value of this study The study documented delayed parasite clearance associated with pre-treatment validated K13 561H mutation. It confirms and provides evidence for the first-time of ART-R in Kagera region, north-western Tanzania, an area close to the border with Rwanda and Uganda. This makes Tanzania the fourth country in Africa with confirmed ART-R. The study documents presence of K13 mutation associated with ART-R suggesting that partial resistance to artemisinins is rapidly evolving and can still be found in more areas of Africa. Parasites with K13 mutations were not similar to those from south-east Asia and Rwanda, but had the same core haplotype of a new 561H haplotype reported in Kagera in 2021.The findings of this study furthermore show that both AL and ASAQ are highly effective.Implications of all the available evidence The emergence of confirmed ART-R in Africa, so far in four countries (Rwanda, Uganda, Eritrea and Tanzania), poses a serious threat to malaria control in Africa, which accounts for more than 95% of the global malaria burden. The current evidence of ART-R in Kagera region calls for an urgent response, including the development of a context-specific strategy based on the recently launched WHO strategy to respond to antimalarial drug resistance in Africa. The fact that ART-R has been confirmed in Kagera region, an area bordering Rwanda and Uganda, where resistance also has been reported, also calls for cross-border collaboration to harmonize strategies to combat this threat in the Great Lakes region of Africa. Nationwide studies on molecular markers in Tanzania, which revealed a high prevalence of K13 validated mutatio ns in the Kagera region, guided where to conduct the current study. This suggests that molecular marker surveillance could play an important role in conducting targeted antimalarial drug efficacy studies and confirming ART-R in other parts of Tanzania and beyond.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.


Review: The overall findings in this study confirm evidence on the emergence of Artemisinin partial resistance(APR) in Africa and specifically in East Africa where historically resistance of Chloroquine and Sulfadoxine-Pyrimethamine have been reported before.

The main conclusion and recommendations are carefully interpreted to reflect the findings of the study which was conducted as per recommended design by World Health Organization(WHO), choice of population and sample size estimation which is powered enough to answer the key outcomes. The study procedures such as; screening, enrollment, treatment and drug administration and diagnostic approach (blood slides reading) followed WHO guideline and Good Clinical Practise(GCP) compliance. 

However, investigators need to consider the current recommendation on parasites genotyping analysis using microsatellite technique over glurp from WHO. In the future the investigator should consider using this technique i.e., microsatellite to add stronger scientific evidence on the reported findings.

Per the findings and reports of APR in Rwanda, Uganda and Eritrea, cross-border APR surveillance activities involving countries in the East African Community (EAC) regional block should be initiated to monitor the efficacy of anti-malaria drugs, and further preventive measures to control spread of resistance need to follow harmonized protocols as recommended by WHO guideline on Strategy to respond to Anti-malarial drug Resistance in Africa (STAR).

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