Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania

Abstract

BackgroundArtemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization.MethodsOpen-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated.ResultsOf the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2–98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1–99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1–100), 100% in Nagaga (n = 39; 95% CI 91.0–100) and Kyela 2015 (n = 60; 95% CI 94.0–100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4–99.9) and 100% (n = 25; 95% CI 86.3–100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9–100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure.ConclusionAll the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation.Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx

Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea, 2016

“…The results showed high efficacy of ASAQ and AL (microsatellite-corrected D28 efficacies > 99%) to treat uncomplicated malaria, despite their use for more than a decade in Guinea. These results are consistent with the high ACT efficacies observed prior to introduction of ACTs in Guinea and with other studies from Africa [9,[31][32][33][34].…”

Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomised controlled trial

“…The results showed high e cacy of ASAQ and AL (microsatellite-corrected D28 e cacies > 99%) to treat uncomplicated malaria, despite their use for more than a decade in Guinea. These results are consistent with the high ACT e cacies observed prior to introduction of ACT in Guinea and with other studies from Africa [8,11,32,33].…”

“…In line with these recommendations, sub-Saharan African countries have initiated the surveillance of the e cacy and safety of anti-malarial drug treatments to prevent parasite resistance [7][8][9][10]. In Tanzania, a study assessing the e cacy and safety of AL for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of artemisinin resistance molecular markers found high e cacy and safety of AL and no known artemisinin resistance pfk13 mutations [11].…”

Kelch13 and MDR1 Polymorphisms, and Drug Effectiveness at Day 3 after Dihydroartemisinin-Piperaquine Treatment for Plasmodium falciparum Malaria on Bioko Island, Equatorial Guinea: 2014-2017

“…Our results showed that DHA-PIP drugs were efficacious in treating uncomplicated P. falciparum malaria in the region. This high cure rate of DHA-PIP for Bioko P. falciparum supports earlier findings from and across Africa (16-21). This ACT medicine is being increasingly recommended in malaria endemic countries as second-line treatment for falciparum malaria and also used for mass drug administration in special situations (21).…”

“…This high cure rate of DHA-PIP for Bioko P. falciparum supports earlier findings from and across Africa (16-21). This ACT medicine is being increasingly recommended in malaria endemic countries as second-line treatment for falciparum malaria and also used for mass drug administration in special situations (21). However, it was found 5.9% (19/320) patients with D3 positivity, suggesting the possibility that a subset of parasites is becoming less susceptible to ART through mutation in some gene, that some individuals have relatively poor parasite-clearing immune responses, or that some patients were not self-administering their remaining doses of DHA-PIP.…”