| 1. |
- Kloprogge, F., et al.
(författare)
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Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis
- 2018
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials. gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing < 15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.
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| 2. |
- Stepniewska, Kasia, et al.
(författare)
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Efficacy of single dose primaquine with artemisinin combination therapy on P. falciparum gametocytes and transmission : A WWARN individual patient meta-analysis.
- 2020
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:7, s. 1215-1226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy.METHODS: An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected.RESULTS: In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08-0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.CONCLUSION: Primaquine's transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
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| 3. |
- Connelly, Sean, V, et al.
(författare)
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Strong isolation by distance and evidence of population microstructure reflect ongoing Plasmodium falciparum transmission in Zanzibar
- 2024
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission. Methods: To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018. Results: Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes. Conclusions: Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
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| 4. |
- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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| 5. |
- Mansoor, Rashid, et al.
(författare)
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Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
- 2022
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPlasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.MethodsIndividual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7.ResultsA total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).ConclusionsIn patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
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| 6. |
- Ngasala, Billy E., et al.
(författare)
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Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania : an open label prospective study
- 2011
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 10, s. 64-
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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. Methods: 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. Results: 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). Conclusions: 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.
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| 7. |
- Ngasala, Billy E., et al.
(författare)
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Efficacy and Effectiveness of Artemether-Lumefantrine after Initial and Repeated Treatment in Children < 5 Years of Age with Acute Uncomplicated Plasmodium falciparum Malaria in Rural Tanzania : A Randomized Trial
- 2011
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 52:7, s. 873-882
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Tidskriftsartikel (refereegranskat)abstract
- Background. We assessed the efficacy, effectiveness and safety of artemether-lumefantrine, which is the most widely used artemisinin-based combination therapy in Africa, against Plasmodium falciparum malaria during an extended follow-up period after initial and repeated treatment. Methods. We performed an open-label randomized trial of artemether-lumefantrine with supervised (n 5 180) and unsupervised intake (n = 179) in children <5 years of age with uncomplicated falciparum malaria in rural Tanzania. Recurrent infections between day 14 and day 56 were retreated within the same study arm. Main end points were polymerase chain reaction (PCR)-corrected cure rates by day 56 and day 42 after initial and repeated treatment, respectively, as estimated by survival analysis. Results. The PCR-corrected cure rate after initial treatment was 98.1% (95% confidence interval [CI], 94.2%-99.4%) after supervised and 95.1% (95% CI, 90.7%-98.1%) after unsupervised intake (P = .29). After retreatment of recurrent infections, the cure rates were 92.9% (95% CI, 81.8%-97.3%) and 97.6% (95% CI, 89.3%-98.8%), respectively (P = .58). Reinfections occurred in 46.9% (82 of 175) versus 50.9 % of the patients (relative risk [RR], 0.92 [95% CI, 0.74-1.14]; P 5.46) after initial therapy and 32.4% (24 of 74) versus 39.0% (32 of 82) (RR, 0.83 [95% CI, 0.54-1.27]; P 5.39) after retreatment. Median blood lumefantrine concentrations in supervised and unsupervised patients on day 7 were 304 versus 194 ng/ mL (P <.001) after initial treatment and 253 versus 164 ng/ mL (P 5.001) after retreatment. Vomiting was the most commonly reported drug-related adverse event (in 1% of patients) after both initial and repeated treatment. Conclusions. Artemether-lumefantrine was highly efficacious even after unsupervised administration, despite significantly lower lumefantrine concentrations, compared with concentration achieved with supervised intake, and was well-tolerated and safe after initial and repeated treatment.
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| 8. |
- Aydin-Schmidt, Berit, et al.
(författare)
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Usefulness of Plasmodium falciparum-specific rapid diagnostic tests for assessment of parasite clearance and detection of recurrent infections after artemisinin-based combination therapy.
- 2013
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Ingår i: Malaria journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Rapid diagnostic test (RDT) is an important tool for parasite-based malaria diagnosis. High specificity of RDTs to distinguish an active Plasmodium falciparum infection from residual antigens from a previous infection is crucial in endemic areas where residents are repeatedly exposed to malaria. The efficiency of two RDTs based on histidine-rich protein 2 (HRP2) and lactate dehydrogenase (LDH) antigens were studied and compared with two microscopy techniques (Giemsa and acridine orange-stained blood smears) and real-time polymerase chain reaction (PCR) for assessment of initial clearance and detection of recurrent P. falciparum infections after artemisinin-based combination therapy (ACT) in a moderately high endemic area of rural Tanzania.
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| 9. |
- Carlsson, Anja M, et al.
(författare)
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Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment in Tanzanian children with acute uncomplicated malaria
- 2011
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 10, s. 380-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:This study aimed to explore Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment with artemisinin-based combination therapy in children with clinical malaria in a high transmission area in Africa.METHODS:A total of 50 children aged 1-10 years with acute uncomplicated P. falciparum malaria in Bagamoyo District, Tanzania, were enrolled. Participants were hospitalized and received supervised standard treatment with artemether-lumefantrine according to body weight in six doses over 3 days. Blood samples were collected 11 times, i.e. at time of diagnosis (-2 h) and 0, 2, 4, 8, 16, 24, 36, 48, 60 and 72 h after initiation of treatment. Parasite population dynamics were assessed using nested polymerase chain reaction (PCR)-genotyping of merozoite surface protein (msp) 1 and 2.RESULTS:PCR-analyses from nine sequential blood samples collected after initiation of treatment identified 20 and 21 additional genotypes in 15/50 (30%) and 14/50 (28%) children with msp1 and msp2, respectively, non-detectable in the pre-treatment samples (-2 and 0 h combined). Some 15/20 (75%) and 14/21 (67%) of these genotypes were identified within 24 h, whereas 17/20 (85%) and 19/21 (90%) within 48 h for msp1 and msp2, respectively. The genotype profile was diverse, and varied considerably over time both within and between patients, molecular markers and their respective families.CONCLUSION:PCR analyses from multiple blood samples collected during the early treatment phase revealed a complex picture of parasite sub-populations. This underlines the importance of interpreting PCR-outcomes with caution and suggests that the present use of PCR-adjustment from paired blood samples in anti-malarial drug trials may overestimate assessment of drug efficacy in high transmission areas in Africa.The study is registered at http://www.clinicaltrials.gov with identifier NCT00336375.
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| 10. |
- Dahal, Prabin, et al.
(författare)
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Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis
- 2022
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Ingår i: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with <= 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
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| 11. |
- Holmström, Oscar, et al.
(författare)
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A novel deep learning-based point-of-care diagnostic method for detecting Plasmodium falciparum with fluorescence digital microscopy.
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Malaria remains a major global health problem with a need for improved field-usable diagnostic tests. We have developed a portable, low-cost digital microscope scanner, capable of both brightfield and fluorescence imaging. Here, we used the instrument to digitize blood smears, and applied deep learning (DL) algorithms to detect Plasmodium falciparum parasites.METHODS: Thin blood smears (n = 125) were collected from patients with microscopy-confirmed P. falciparum infections in rural Tanzania, prior to and after initiation of artemisinin-based combination therapy. The samples were stained using the 4',6-diamidino-2-phenylindole fluorogen and digitized using the prototype microscope scanner. Two DL algorithms were trained to detect malaria parasites in the samples, and results compared to the visual assessment of both the digitized samples, and the Giemsa-stained thick smears.RESULTS: Detection of P. falciparum parasites in the digitized thin blood smears was possible both by visual assessment and by DL-based analysis with a strong correlation in results (r = 0.99, p < 0.01). A moderately strong correlation was observed between the DL-based thin smear analysis and the visual thick smear-analysis (r = 0.74, p < 0.01). Low levels of parasites were detected by DL-based analysis on day three following treatment initiation, but a small number of fluorescent signals were detected also in microscopy-negative samples.CONCLUSION: Quantification of P. falciparum parasites in DAPI-stained thin smears is feasible using DL-supported, point-of-care digital microscopy, with a high correlation to visual assessment of samples. Fluorescent signals from artefacts in samples with low infection levels represented the main challenge for the digital analysis, thus highlighting the importance of minimizing sample contaminations. The proposed method could support malaria diagnostics and monitoring of treatment response through automated quantification of parasitaemia and is likely to be applicable also for diagnostics of other Plasmodium species and other infectious diseases.
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| 12. |
- Malmberg, Maja, et al.
(författare)
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Temporal trends of molecular markers associated with artemether-lumefantrine tolerance/resistance in Bagamoyo district, Tanzania.
- 2013
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Ingår i: Malaria journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 13. |
- Mhamilawa, Lwidiko E, et al.
(författare)
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Detection of Plasmodium falciparum by Light Microscopy, Loop-Mediated Isothermal Amplification, and Polymerase Chain Reaction on Day 3 after Initiation of Artemether-Lumefantrine Treatment for Uncomplicated Malaria in Bagamoyo District, Tanzania : A Comparative Trial
- 2019
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Ingår i: American Journal of Tropical Medicine and Hygiene. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 101:5, s. 1144-1147
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Tidskriftsartikel (refereegranskat)abstract
- Microscopy-determined Plasmodium falciparum positivity rates exceeding 10% on day 3 after initiation of artemisinin-based combination therapy (ACT) is an important indicator of artemisinin resistance. However, microscopy does not detect low-density parasitemia, contrary to molecular tools such as loop-mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR). We compared microscopy, LAMP, and PCR for detection of P. falciparum on day 3 after ACT in 256 patients with uncomplicated malaria in Bagamoyo District, Tanzania. Day 3 positivity rates were 0%, 84.8%, and 84.4% for each method, respectively. The sensitivity and specificity of LAMP against PCR was 100% (95% CI, 96.1-100) and 77.4% (95% CI, 58.9-90.4) when quantitative PCR-determined parasite densities were ≥ two parasites/µL. Loop-mediated isothermal amplification had comparable diagnostic accuracy to PCR and could potentially represent a field-friendly tool for determining day 3 positivity rates. However, what day 3 P. falciparum positivity determined using molecular methods represents needs to be further elucidated.
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| 14. |
- Mhamilawa, Lwidiko E, 1988-, et al.
(författare)
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Electrocardiographic safety evaluation of a prolonged artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 15. |
- Mhamilawa, Lwidiko E, et al.
(författare)
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Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania
- 2020
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 16. |
- Mhamilawa, Lwidiko E, 1988-
(författare)
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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
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 17. |
- Mhamilawa, Lwidiko E, 1988-, et al.
(författare)
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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.
- 2020
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 19:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 18. |
- Morgan, Andrew P., et al.
(författare)
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Falciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelago
- 2020
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tanzania's Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination. Despite consistent implementation of effective tools since 2002, elimination has not been achieved. Importation of parasites from outside of the archipelago is thought to be an important cause of malaria's persistence, but this paradigm has not been studied using modern genetic tools.Methods: Whole-genome sequencing (WGS) was used to investigate the impact of importation, employing population genetic analyses of Plasmodium falciparum isolates from both the archipelago and mainland Tanzania. Ancestry, levels of genetic diversity and differentiation, patterns of relatedness, and patterns of selection between these two populations were assessed by leveraging recent advances in deconvolution of genomes from polyclonal malaria infections.Results: Significant decreases in the effective population sizes were inferred in both populations that coincide with a period of decreasing malaria transmission in Tanzania. Identity by descent analysis showed that parasites in the two populations shared long segments of their genomes, on the order of 5 cM, suggesting shared ancestry within the last 10 generations. Even with limited sampling, two of isolates between the mainland and Zanzibar were identified that are related at the expected level of half-siblings, consistent with recent importation.Conclusions: These findings suggest that importation plays an important role for malaria incidence on Zanzibar and demonstrate the value of genomic approaches for identifying corridors of parasite movement to the island.
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| 19. |
- Mwaiswelo, Richard, et al.
(författare)
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Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania
- 2016
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: Men and non-pregnant, non-lactating women aged >= 1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart (TM)) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm. Results: Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [ 6.8, 95 % confidence interval (CI) 4.67-8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of >= 25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention. Conclusion: The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania.
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| 20. |
- Ngasala, Billy E., et al.
(författare)
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Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019
- 2024
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Ingår i: MALARIA JOURNAL. - 1475-2875. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania.Methods This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy.Results A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported.Conclusion This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).
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| 21. |
- Sendor, Rachel, et al.
(författare)
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Similar Prevalence of Plasmodium falciparum and Non-P. falciparum Malaria Infections among Schoolchildren, Tanzania
- 2023
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Ingår i: Emerging Infectious Diseases. - : CENTERS DISEASE CONTROL & PREVENTION. - 1080-6040 .- 1080-6059. ; 29:6, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- Achieving malaria elimination requires considering both Plasmodium falciparum and non-P. falciparum infections. We determined prevalence and geographic distribution of 4 Plasmodium spp. by performing PCR on dried blood spots collected within 8 regions of Tan-zania during 2017. Among 3,456 schoolchildren, 22% had P. falciparum, 24% had P. ovale spp., 4% had P. malariae, and 0.3% had P. vivax infections. Most (91%) schoolchildren with P. ovale infections had low parasite densities; 64% of P. ovale infections were single -spe-cies infections, and 35% of those were detected in low malaria endemic regions. P. malariae infections were predominantly (73%) co-infections with P. falciparum. P. vivax was detected mostly in northern and east-ern regions. Co-infections with >1 non-P. falciparum species occurred in 43% of P. falciparum infections. A high prevalence of P. ovale infections exists among schoolchildren in Tanzania, underscoring the need for detection and treatment strategies that target non-P. falciparum species.
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| 22. |
- Silva, M, et al.
(författare)
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Plasmodium falciparum K13 expression associated with parasite clearance during artemisinin-based combination therapy
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 74:7, s. 1890-1893
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Delayed parasite clearance and, consequently, reduced efficacy of artemisinin-based combination therapies have been linked with Plasmodium falciparum K13 gene SNPs in Southeast Asia. In Africa, significantly prolonged clearance has not yet been observed and the presently restricted variation in parasite clearance cannot be explained by K13 polymorphisms.OBJECTIVES: Our aim was to study the in vivo pfK13 transcriptional response in patients treated with artemether-lumefantrine and explore whether the pfk13 transcripts can explain the patients' parasite clearance outcomes.PATIENTS AND METHODS: A total of 47 Tanzanian children with microscopically confirmed uncomplicated P. falciparum malaria were hospitalized and received artemether-lumefantrine treatment (clinical trial ID: NCT00336375). RNA was extracted from venous blood samples collected before treatment initiation and at five more timepoints after treatment. cDNA was synthesized and pfk13 transcripts measured by real-time PCR.RESULTS: A wide range of pfk13 transcript variation was observed throughout all timepoints after artemether-lumefantrine treatment. Taking parasite clearance data together with the pfk13 transcripts profile, we observed a negative correlation inferring that pfk13 down-regulation is associated with longer parasite clearance time.CONCLUSIONS: The findings suggest that a reduced PfK13 transcriptional response may represent a first step towards artemisinin tolerance/resistance.
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| 23. |
- Stepniewska, Kasia, et al.
(författare)
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Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide : a systematic review and meta-analysis of individual patient data
- 2022
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Forskningsöversikt (refereegranskat)abstract
- BackgroundIn 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.MethodsA systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.ResultsData comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms.ConclusionsOur results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients.
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| 24. |
- Venkatesan, Meera, et al.
(författare)
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Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes : parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
- 2014
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 91:4, s. 833-43
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Tidskriftsartikel (refereegranskat)abstract
- Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
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