Dataset Information

Adherence to and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania.

ABSTRACT:

Background

Controlled clinical trials have shown that a six-dose regimen of artemether-lumefantrine (AL) therapy for uncomplicated Plasmodium falciparum malaria results in cure rates >95% with good tolerability.

Materials and methods

A prospective study was carried out to document the adherence to and acceptability of AL administration. This was undertaken in the context of the ALIVE study, a prospective, community-based, observational study in a rural, malaria-endemic area of Tanzania. Following microscopic confirmation of P. falciparum infection, the first AL dose was taken under supervision, with the subsequent five doses taken unsupervised at home. Patients were randomized to receive a home-based assessment close to the scheduled time for one of the unsupervised doses, but were blinded to which follow-up visit they had been allocated. A structured questionnaire was administered by trained staff and AL consumption was confirmed by inspection of blister packs.

Results

A total of 552 patients were recruited of whom 352 (63.8%) were <13 years old. The randomization process allocated 112, 109, 110, 100 and 111 patients to a follow-up visit after doses 2, 3, 4, 5 and 6, respectively. For dose 2, 92.0% of patients (103/112) correctly took AL at 8 +/- 1 hours after dose 1. The remaining doses were taken within four hours of the correct time in 87-95% of cases. Nine patients (1.7%) missed one dose. Blister packs were available for inspection in 548 of cases (99.3%) and confirmed patient-reported data that the previous dose had been administered. Nearly all patients took AL with water (549/552 [99.5%]). Two patients (0.4%) took the drug with food. The dosing pictogram and clustering of tablets within the blister packs was considered helpful by 91.8% and 100.0% of patients, respectively. Overall, 87.1% of patients (481/552) found AL easier to take/administer than sulphadoxine-pyrimethamine (SP) and 87.7% (484/552) believed that AL was more effective than SP.

Discussion

Factors contributing to adherence were likely to be helpful packaging, pictorial dosing instructions and patients' conviction that AL is effective.

Conclusion

Adherence to the dosing regimen and timing of AL administration was very good.

SUBMITTER: Kabanywanyi AM

PROVIDER: S-EPMC2833168 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Adherence to and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania.

Kabanywanyi Abdunoor M AM Lengeler Christian C Kasim Prudensiana P King'eng'ena Said S Schlienger Raymond R Mulure Nathan N Genton Blaise B

Malaria journal 20100211

<h4>Background</h4>Controlled clinical trials have shown that a six-dose regimen of artemether-lumefantrine (AL) therapy for uncomplicated Plasmodium falciparum malaria results in cure rates >95% with good tolerability.<h4>Materials and methods</h4>A prospective study was carried out to document the adherence to and acceptability of AL administration. This was undertaken in the context of the ALIVE study, a prospective, community-based, observational study in a rural, malaria-endemic area of Tan ...[more]

PMID: 20149235

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Project description:Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home.An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961.A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p ? 0.046).Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

Project description:Development and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) constitutes a major threat to recent global malaria control achievements. Surveillance of molecular markers could act as an early warning system of ACT-resistance before clinical treatment failures are apparent. The aim of this study was to analyse temporal trends of established genotypes associated with artemether-lumefantrine tolerance/resistance before and after its deployment as first-line treatment for uncomplicated malaria in Tanzania 2006.Single nucleotide polymorphisms in the P. falciparum multidrug resistance gene 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine transporter gene (pfcrt) K76T were analysed from dried blood spots collected during six consecutive studies from children with uncomplicated P. falciparum malaria in Fukayosi village, Bagamoyo District, Tanzania, between 2004-2011.There was a statistically significant yearly increase of pfmdr1 N86, 184F, D1246 and pfcrt K76 between 2006-2011 from 14% to 61% (yearly OR = 1.38 [95% CI 1.25-1.52] p < 0.0001), 14% to 35% (OR = 1.17 [95% CI 1.07-1.30] p = 0.001), 54% to 85% (OR = 1.21 [95% CI 1.03-1.42] p = 0.016) and 49% to 85% (OR = 1.33 [95% CI 1.17-1.51] p < 0.0001), respectively. Unlike for the pfmdr1 SNP, a significant increase of pfcrt K76 was observed already between 2004-2006, from 26% to 49% (OR = 1.68 [95% CI 1.17-2.40] p = 0.005). From 2006 to 2011 the pfmdr1 NFD haplotype increased from 10% to 37% (OR = 1.25 [95% CI 1.12-1.39] p < 0.0001), whereas the YYY haplotype decreased from 31% to 6% (OR = 0.73 [95% CI 0.56-0.98] p = 0.018). All 390 successfully analysed samples had one copy of the pfmdr1 gene.The temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy in Tanzania and emphasizes the importance of molecular surveillance as a complement to standard in vivo trials.

Project description:BACKGROUND:Dissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets. METHODS:The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products. RESULTS:A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25-100 μg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality. CONCLUSIONS:The developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

Project description:BackgroundExtended 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 anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern.MethodsMale 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 h 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 (ΔQTc) > 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.ResultsA 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 ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p = 0.010) and 13.4 ms (95% CI 5.3-21.5, p = 0.001), for QTcB and QTcF, respectively.ConclusionThe 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. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901.

Project description:BackgroundArtemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).MethodsA single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes.ResultsA total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouvé and 98.6% (92.4-100) in Anié, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed.ConclusionThe results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention.Trial registrationACTRN12623000344695.

Dataset Information

Adherence to and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania.

Background

Materials and methods

Results

Discussion

Conclusion

Publications

Adherence to and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania.

Similar Datasets

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