Evaluation of the efficacy and safety of three 2-drug combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Senegal: artesunate-amodiaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine

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

Section: Discussionsupporting

confidence: 91%

“…This study gave reassurance that this ACT medicine is highly efficacious for the treatment of uncomplicated falciparum malaria. Similar high cure rate has been reported from other African countries [ 7 , 9 , 12 , 14 , 15 , 24 , 25 ].…”

Section: Discussionsupporting

confidence: 89%

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

Kakolwa

Mahende

Ishengoma

et al. 2018

“…All the patients in this study, who were treated by artemether–lumefantrine–doxycycline after artesunate, artesunate–doxycycline or artemether–doxycycline, were successfully cured. The artemether–lumefantrine combination was highly effective with an adequate clinical and parasitological response of 99.2% at day 42 in suburbs of Dakar in 2010–2011 and 100% in 2012–2013 [17, 22]. …”

Section: Discussionmentioning

confidence: 99%

“…The piperaquine in vitro susceptibility was not associated with the pfcrt K76T mutation involved in chloroquine resistance [23]. The dihydroartemisinin–piperaquine combination was highly effective, with an adequate clinical and parasitological response of 99.1% at day 42 in the suburbs of Dakar in 2010–2011 and 100% in 2012–2013 [17, 22]. …”

Section: Discussionmentioning

confidence: 99%

Confirmation of Plasmodium falciparum in vitro resistance to monodesethylamodiaquine and chloroquine in Dakar, Senegal, in 2015

Diawara

Madamet

Kounta

et al. 2017

BackgroundIn response to increasing resistance to anti-malarial drugs, Senegal adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria in 2006. However, resistance of Plasmodium falciparum parasites to artemisinin derivatives, characterized by delayed parasite clearance after treatment with ACT or artesunate monotherapy, has recently emerged and rapidly spread in Southeast Asia. After 10 years of stability with rates ranging from 5.6 to 11.8%, the prevalence of parasites with reduced susceptibility in vitro to monodesethylamodiaquine, the active metabolite of an ACT partner drug, increased to 30.6% in 2014 in Dakar. Additionally, after a decrease of the in vitro chloroquine resistance in Dakar in 2009–2011, the prevalence of parasites that showed in vitro chloroquine resistance increased again to approximately 50% in Dakar since 2013. The aim of this study was to follow the evolution of the susceptibility to ACT partners and other anti-malarial drugs in 2015 in Dakar. An in vitro test is the only method currently available to provide an early indication of resistance to ACT partners.ResultsThirty-two P. falciparum isolates collected in 2015 in Dakar were analysed using a standard ex vivo assay based on an HRP2 ELISA. The prevalence of P. falciparum parasites with reduced susceptibility in vitro to monodesethylamodiaquine, chloroquine, mefloquine, doxycycline and quinine was 28.1, 46.9, 45.2, 31.2 and 9.7%, respectively. None of the parasites were resistant to lumefantrine, piperaquine, pyronaridine, dihydroartemisinin and artesunate. These results confirm an increase in the reduced susceptibility to monodesethylamodiaquine observed in 2014 in Dakar and the chloroquine resistance observed in 2013. The in vitro resistance seems to be established in Dakar. Additionally, the prevalence of parasites with reduced susceptibility to doxycycline has increased two-fold compared to 2014.ConclusionsThe establishment of a reduced susceptibility to monodesethylamodiaquine as well as chloroquine resistance, and the emergence of a reduced susceptibility to doxycycline are disturbing. The in vitro and in vivo surveillance of anti-malarial drugs must be implemented in Senegal.

“…At the end of the screening process, 76 articles were included in the original analysis; K = 13 treatments were involved. The quinine arm was removed from a 3-arm study [ 30 ], and two studies published in French were included [ 31 , 32 ]. The list of the interventions was artesunate–amodiaquine (ASAQ), artesunate–sulfadoxine–pyrimethamine (ASSP), artesunate–sulfamethoxypyrazine–pyrimethamine (ASSMP), artemether–lumefantrine (AL), dihydroartemisinin–piperaquine (DHAP), dihydroartemisinin–piperaquine–trimethoprim (DHAPT), artesunate–chlorproguanil–dapsone (ASCD), ASMQ, artesunate–atovaquone–proguanil (ASATPG), artemisinin–naphtoquine (ASNAPH), artesunate–amodiaquine–chlorpheniramine (ASAQCPH), artesunate–pyronaridine (ASPY) and, the non-ACT combination amodiaquine–sulfadoxine–pyrimethamine (AQSP).…”

Section: Methodsmentioning

confidence: 99%

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

Youdom

Tahar

Basco

2017

Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. Methods:A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in subSaharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. Results:In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.