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.

Keywords: Artemisinin partial resistance; Kagera; Kelch 13; Plasmodium falciparum; Tanzania; artemisinin-based combination therapy; falciparum malaria.

Figure 1:

Map showing the location of Bukangara Dispensary in Karagwe district of Kagera region, North-western Tanzania.

Figure 2.. Extended flanking haplotype plot around K13 among single strain 561H mutants.

The core haplotype described in Kagera in 2021 [haplotype two (TZ2)] is shown in the pink spanning approximately 9kb, while grey regions represent loci where a call could not be made. Sample nomenclature: TES 2022 (T09521D14, T0939BDO, T0938ADO, T0906BDO), 2021 Kagera (MSMTE12, MSMTD11, MSMTC1, MSMTB12, MSMTB1, MSMTB2, MSMTD10, MSMTD4), Rwanda 2014–2015 (ERR42833089, ERR42833099, ERR4283102, ERR4283111), and Southeast Asia (RC09812, RC09828, RC09832, RC09845, RC09935, RC03319).