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Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania– a randomized controlled trial.
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, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili University of Health and Allied sciences.ORCID iD: 0000-0001-9300-7719
Karolinska Institutet.
Food and drugs administration, Office of clinical pharmacology, Division of Pharmacometrics, Silver Spring, Maryland, USA..
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:

Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa.

Methods: 

Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence. Results. A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p=0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p=0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p=0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p=0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and hematological safety was high and similar in both arms.

Conclusion:

Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections, but importantly equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa.

Keywords [en]
Malaria, Plasmodium falciparum, artemether-lumefantrine, drug resistance, Tanzania
National Category
Medical and Health Sciences
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-407921OAI: oai:DiVA.org:uu-407921DiVA, id: diva2:1420771
Funder
Sida - Swedish International Development Cooperation Agency, Bil-Tz 16/9875007059Available 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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