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Electrocardiographic safety evaluation of a prolonged artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili University of Health and Allied Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili University of Health and Allied Sciences.ORCID iD: 0000-0001-9300-7719
Tanga Centre, National Institute for Medical Research, Tanga, Tanzania..
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 Background:

Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among antimalarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern.

 

Method:

Male and non-pregnant females aged 1–65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4–5 hours after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett’s (QTcB) and Fridericia’s (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation >500, change in QTc interval (DQTc) >60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively.

 

Results:

A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals >500 ms on day 5 by both formulae. Patients with DQTc >60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) in the intervention and control arms, respectively. For QTcB was 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in DQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms 50 (p= 0.010) and 13.4 ms (p= 0.001), for QTcB and QTcF respectively.

 

Conclusion:

The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment.

Keywords [en]
Malaria, Plasmodium falciparum, cardiotoxicity, artemether–lumefantrine, Tanzania, prolonged treatment, artemisinin resistance, ECG
National Category
Clinical Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-407932OAI: oai:DiVA.org:uu-407932DiVA, id: diva2:1420822
Funder
Swedish Research Council, 2016-0577Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2020-04-01
In thesis
1. New strategies and tools for Plasmodium falciparum case management and surveillance in the era of imminent resistance to artemisinin-based combination therapy in Tanzania.
Open this publication in new window or tab >>New strategies and tools for Plasmodium falciparum case management and surveillance in the era of imminent resistance to artemisinin-based combination therapy in Tanzania.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Artemether-lumefantrine has been an efficacious first line treatment for uncomplicated Plasmodium falciparum malaria in Tanzania since its introduction in 2006. Interest has developed in understanding the observation of high residual PCR determined positivity rates on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015 in Bagamoyo district, Tanzania. Deep sequencing has recently been used to study these Bagamoyo parasites with delayed clearance, and the clearance times by PCR of some P. falciparum sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, albeit lacking the described mutations in the Kelch13 propeller gene associated with artemisinin resistance. Moreover, molecular epidemiological studies from Bagamoyo, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers (pfmdr1 - N86, 184F, D1246 and pfcrt - K76) in the parasite population following wide scale use of artemether-lumefantrine but without signs of compromised treatment efficacy. On the other hand, traditional epidemiological studies have reported that imported malaria cases in Zanzibar from Tanzania mainland contribute to regressing the malaria elimination efforts in this pre-elimination part of the country.

This PhD project explored efficacy and safety of extending the artemether-lumefantrine regimen from standard 3 days to 6 days and adding single low dose primaquine (0.25mg/kg) as a new strategy that can be used in order to protect the therapeutic lifespan of artemether-lumefantrine. Also, whole-genome sequencing was used to study genomic epidemiology of P. falciparum population between Tanzania mainland and Zanzibar.

The results revealed that extended artemether-lumefantrine treatment did not have superior efficacy in the current context of artemether-lumefantrine sensitive P. falciparum parasites. However, the safety profile was excellent and similar to standard 3 days treatment. Parasite detection by molecular methods was 84% on day 3 after artemether-lumefantrine treatment. Meanwhile, significant decreases in the effective population sizes were inferred in both Tanzania mainland and Zanzibar parasite populations, that coincide with a period of decreasing malaria transmission in Tanzania. The parasite population from Tanzania mainland and Zanzibar were found to be connected, implying importation of cases from high transmission mainland to pre elimination regions of Zanzibar.

Utility of these results is during exploring options of alternative artemisinin-based combination therapy regimens to protect their therapeutic efficacy in an era of imminent artemisinin resistance in sub Saharan Africa. Moreover, the genomic epidemiological findings in this project may be of interest for malaria elimination programs, in the incorporation of molecular tools in future malaria elimination strategies and resistance surveillance, in the context of understanding importation of malaria from high to low transmission regions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 100
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1661
Keywords
Malaria, Plasmodium falciparum, artemether-lumefantrine, drug resistance, Tanzania
National Category
Infectious Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-407806 (URN)978-91-513-0929-3 (ISBN)
Public defence
2020-05-25, Rudbecksalen, Rudbeck entreplan, C11, Uppsala, 10:00 (English)
Opponent
Supervisors
Funder
Sida - Swedish International Development Cooperation Agency, 16/9875007059Swedish Research Council, 2016-0577
Available from: 2020-04-29 Created: 2020-04-01 Last updated: 2020-05-19

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Mhamilawa, Lwidiko ENgasala, BillyMårtensson, Andreas

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