| 1. |
- Mwaiswelo, Richard, et al.
(author)
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Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania : a randomized, single-blinded clinical trial
- 2016
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In: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 15
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Journal article (peer-reviewed)abstract
- Background: The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged >= 1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection. Results: Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection. Conclusion: The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania.
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| 2. |
- Mwaiswelo, Richard Owden, et al.
(author)
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A single low dose of primaquine is safe and sufficient to reduce transmission of Plasmodium falciparum gametocytes regardless of cytochrome P450 2D6 enzyme activity in Bagamoyo district, Tanzania
- 2022
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In: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
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Journal article (peer-reviewed)abstract
- Background: Primaquine is a pro-drug and its active metabolite is potent against mature Plasmodium falciparum gametocytes. Primaquine is metabolized by a highly polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Mutations in the gene encoding this enzyme may lead to impaired primaquine activity. This study assessed if 0.25 mg/kg single-dose primaquine is safe and sufficient to reduce transmission of gametocytes in individuals with no, reduced, or increased CYP2D6 enzyme activity.Methods: Between June 2019 and January 2020 children aged 1-10 years, attending at Yombo dispensary, Bagamoyo district, with confirmed microcopy-determined uncomplicated P. falciparum malaria were enrolled in the study. The enrolled patients were treated with a standard artemether-lumefantrine regimen plus 0.25 mg/kg single-dose primaquine and followed up for 28 days for clinical and laboratory assessment. Primaquine was administered with the first dose of artemether-lumefantrine. Safety assessment involved direct questioning and recording of the nature and incidence of clinical signs and symptoms, and measurement of haemoglobin (Hb) concentration. Blood samples collected from 100 patients were used for assessment of post-treatment infectiousness on day 7 using mosquito membrane feeding assays. Molecular methods were used to determine CYP2D6 and glucose-6-phosphate dehydrogenase (G6PD) status. The primary outcome was the safety of 0.25 mg/kg single-dose primaquine based on CYP2D6 status.Results: In total, 157 children [median age 6.4 (Interquartile range 4.0-8.2) years] were recruited, of whom 21.0% (33/157) and 12.7% (20/157) had reduced CYP2D6 and deficient G6PD activity, respectively. Day 3 mean absolute Hb concentration reduction was 1.50 g/dL [95% confidence interval (CI) 1.10-1.90] and 1.51 g/dL (95% CI 1.31-1.71) in reduced and normal CYP2D6 patients, respectively (t = 0.012, p = 0.990). The day 3 mean absolute Hb concentration reduction in G6PD deficient, G6PD normal and heterozygous female was 1.82 g/dL (95% CI 1.32-2.32), 1.48 g/dL (95% CI 1.30-1.67) and 1.47 g/dL (95% CI 0.76-2.18), respectively (F = 0.838, p = 0.435). Sixteen percent (16/98) of the patients each infected at least one mosquito on day 7, and of these, 10.0% (2/20) and 17.9% (14/78) had reduced and normal CYP2D6 enzyme activity, respectively (x(2) = 0.736, p = 0.513).Conclusion: Single-dose 0.25 mg/kg primaquine was safe and sufficient for reducing transmission of P. falciparum gametocytes regardless of CYP2D6 or G6PD status. Trial registration Study registration number: NCT03352843.
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| 3. |
- Mwaiswelo, Richard, et al.
(author)
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Prevalence of and Risk Factors Associated with Polymerase Chain Reaction-Determined Plasmodium falciparum Positivity on Day 3 after Initiation of Artemether-Lumefantrine Treatment for Uncomplicated Malaria in Bagamoyo District, Tanzania
- 2019
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In: American Journal of Tropical Medicine and Hygiene. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 100:5, s. 1179-1186
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Journal article (peer-reviewed)abstract
- Prevalence of and risk factors associated with polymerase chain reaction (PCR)-determined Plasmodium falciparum positivity were assessed on day 3 after initiation of treatment, pre-implementation and up to 8 years post-deployment of artemether-lumefantrine as first-line treatment for uncomplicated malaria in Bagamoyo district, Tanzania. Samples originated from previously reported trials conducted between 2006 and 2014. Cytochrome b-nested PCR was used to detect malaria parasites from blood samples collected on a filter paper on day 3. Chi-square and McNemar chi-squared tests, logistic regression models, and analysis of variance were used as appropriate. Primary outcome was based on the proportion of patients with day 3 PCR-determined P. falciparum positivity. Overall, 256/584 (43.8%) of screened patients had day 3 PCR-determined positivity, whereas only 2/584 (0.3%) had microscopy-determined asexual parasitemia. Day 3 PCR-determined positivity increased from 28.0% (14/50) in 2006 to 74.2% (132/178) in 2007-2008 and declined, thereafter, to 36.0% (50/139) in 2012-2013 and 27.6% (60/217) in 2014. When data were pooled, pretreatment microscopy-determined asexual parasitemia ≥ 100,000/µL, hemoglobin < 10 g/dL, age < 5 years, temperature ≥ 37.5°C, and year of study 2007-2008 and 2012-2013 were significantly associated with PCR-determined positivity on day 3. Significant increases in P. falciparum multidrug resistance gene 1 N86 and P. falciparum chloroquine resistant transporter K76 across years were not associated with PCR-determined positivity on day 3. No statistically significant association was observed between day 3 PCR-determined positivity and PCR-adjusted recrudescence. Day 3 PCR-determined P. falciparum positivity remained common in patients treated before and after implementation of artemether-lumefantrine in Bagamoyo district, Tanzania. However, its presence was associated with pretreatment characteristics. Trials registration numbers: NCT00336375, ISRCTN69189899, NCT01998295, and NCT02090036.
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| 4. |
- Mwaiswelo, Richard, et al.
(author)
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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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In: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 15
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Journal article (peer-reviewed)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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| 5. |
- Mwaiswelo, Richard, et al.
(author)
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Sustained High Cure Rate of Artemether-Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania
- 2017
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In: American Journal of Tropical Medicine and Hygiene. - : AMER SOC TROP MED & HYGIENE. - 0002-9637 .- 1476-1645. ; 97:2, s. 526-532
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Journal article (peer-reviewed)abstract
- We assessed the temporal trend of artemether-lumefantrine (AL) cure rate after 8 years of its wide-scale use for treatment of uncomplicated Plasmodium falciparum malaria from 2006 to 2014 in Bagamoyo district, Tanzania. Trend analysis was performed for four studies conducted in 2006, 2007-2008, 2012-2013, and 2014. Patients with acute uncomplicated P. falciparum malaria were enrolled, treated with standard AL regimen and followed-up for 3 (2006), 28 (2014), 42 (2012-2013), or 56 (2007-2008) days for clinical and laboratory evaluation. Primary outcome was day 28 polymerase chain reaction (PCR)-adjusted cure rate across years from 2007 to 2014. Parasite clearance was slower for the 2006 and 2007-2008 cohorts with less than 50% of patients cleared of parasitemia on day 1, but was rapid for the 2012-2013 and 2014 cohorts. Day 28 PCR-adjusted cure rate was 168/170 (98.8%) (95% confidence interval [CI], 97.2-100), 122/127 (96.1%) (95% CI, 92.6-99.5), and 206/207 (99.5%) (95% CI, 98.6-100) in 2007-2008, 2012-2013, and 2014, respectively. There was no significant change in the trend of cure rate between 2007 and 2014 (chi(2)(trend) test = 0.06, P = 0.90). Pretreatment P. falciparum multidrug-resistant gene 1 (Pfmdr1) N86 prevalence increased significantly across years from 13/48 (27.1%) in 2006 to 183/213 (85.9%) in 2014 (P < 0.001), and P. falciparum chloroquine resistance transporter gene (Pfcrt) K76 prevalence increased significantly from 24/47 (51.1%) in 2006 to 198/205 (96.6%) in 2014 (P < 0.001). The AL cure rate remained high after 8 years of its wide-scale use in Bagamoyo district for the treatment of uncomplicated P. falciparum malaria despite an increase in prevalence of pretreatment Pfmdr1 N86 and Pfcrt K76 between 2006 and 2014.
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| 6. |
- Ngasala, Billy, et al.
(author)
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Anemia among Schoolchildren with Malaria and Soil-Transmitted Helminth Coinfections after Repeated Rounds of Mass Drug Administration in Muheza District, Tanzania
- 2019
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In: American Journal of Tropical Medicine and Hygiene. - : The American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 101:5, s. 1148-1155
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Journal article (peer-reviewed)abstract
- Coinfections with malaria and soil-transmitted helminths (STHs) has been common among school-aged children in Tanzania. However, after a countrywide scaling up of interventions for malaria and STHs, there are limited data on the prevalence of malaria-STH coinfections and its effect on anemia in schoolchildren in Tanzania. We assessed the distribution and risk factors for malaria, STHs, and malaria-STH coinfections, and its relation to anemia among 445 primary schoolchildren in Muheza district. A semi-structured questionnaire was used to collect demographic characteristics of the children. Malaria rapid diagnostic test (mRDT) was used to diagnose malaria infection. Soil-transmitted helminths were diagnosed using the Kato-Katz technique. Primary outcome was anemia, defined as hemoglobin concentration < 11 g/dL. Chi-square (chi(2)) or Fisher's exact tests, Kruskal-Wallis or t-test, and logistic models were used as appropriate. Overall, the prevalence of malaria, STHs, malaria-STH coinfection, and anemia were 18.4%, 6.1%, 1.6%, and 19.8%, respectively. Anemic children were more likely to have malaria (adjusted odds ratio [aOR] = 4.538, 95% CI: 2.189-9.409), whereas frequent use of bed nets was associated with reduced risk of malaria (aOR = 0.234, 95% CI: 0.130-0.42). On the other hand, not always using latrines and eating raw uncooked food increased the risk of STH infection. The prevalence of anemia was high and was associated with both malaria and malaria-STH infections, therefore calling for more integrated malaria-STH control approaches to target school-aged children.
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| 7. |
- Ngasala, Billy, et al.
(author)
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Diagnostic Performance of Malaria Rapid Diagnostic Test and Microscopy Compared with PCR for Detection of Plasmodium falciparum Infections among Primary Schoolchildren in Kibiti District, Eastern Tanzania : An Area with Moderate Malaria Transmission
- 2019
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In: American Journal of Tropical Medicine and Hygiene. - : AMER SOC TROP MED & HYGIENE. - 0002-9637 .- 1476-1645. ; 101:4, s. 809-811
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Journal article (peer-reviewed)abstract
- A substantial decline of malaria transmission intensity has been observed in sub-Saharan Africa over the past two decades and may affect the diagnostic performance of malaria rapid diagnostic test (mRDT) and microscopy. Diagnostic performance of histidine-rich protein II (HRP-II)/pan-lactate dehydrogenase (pLDH)-based mRDT and microscopy was evaluated against polymerase chain reaction (PCR) for the diagnosis of Plasmodium falciparum infection among 316 primary schoolchildren in Kibiti district, in 2016. Polymerase chain reaction detected more cases of P. falciparum infection than mRDT or microscopy. Using PCR as reference, the sensitivity and specificity of mRDT were 75.9% (95% CI = 62.8-86.1) and 96.9% (95% CI = 94.0-98.7), respectively, whereas that of microscopy were 63.8% (95% CI = 50.1-76.0) and 95.7% (95% CI = 92.5-97.9), respectively. Polymerase chain reaction and other molecular methods should be considered for use in schools and other epidemiological surveys as supplement to mRDT or microscopy.
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| 8. |
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| 9. |
- Ngasala, Billy, et al.
(author)
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The usefulness of indirect diagnostic tests for Schistosoma haematobium infection after repeated rounds of mass treatment with praziquantel in Mpwapwa and Chakechake districts in Tanzania
- 2019
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In: International Journal of Infectious Diseases. - : Elsevier BV. - 1201-9712 .- 1878-3511. ; 90, s. 132-137
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Journal article (peer-reviewed)abstract
- Background Indirect diagnostic tests are used to assess the disease burden and to monitor the impact of different interventions in areas endemic for urinary schistosomiasis. This study was performed to assess their accuracy in the diagnosis of urinary schistosomiasis among primary school children in low and moderate transmission areas in the districts of Mpwapwa and Chakechake, respectively.Methods School children were interviewed regarding their history of haematuria and participation in treatment campaigns. Urine samples were collected and inspected for macro-haematuria (visual haematuria) and tested for micro-haematuria using urine reagent strips and Schistosoma haematobium eggs by urine filtration method.Results The prevalence of S. haematobium was 6.8% in Mtera Dam area and 38.7% in Uwandani Shehia. In Mtera Dam area, a history of haematuria and visual haematuria had low sensitivity (<60%) with high specificity (>90%). The urine reagent strips had high sensitivity and specificity (≥75%). In Uwandani Shehia, a history of haematuria had high sensitivity and specificity (>60%). Visual haematuria had low sensitivity (<50%) but high specificity (>80%). The urine reagent strips maintained high performance in all parameters assessed.Conclusions The study findings suggest that urine reagent strips will continue to serve as a very useful adjunct test for monitoring the prevalence of urinary schistosomiasis in endemic areas.
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| 10. |
- Stepniewska, Kasia, et al.
(author)
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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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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:7, s. 1215-1226
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Journal article (peer-reviewed)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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