Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso. An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies

Activation and maturation of peripheral blood T cells in HIV-1-infected and HIV-1-uninfected adults in Burkina Faso: a cross-sectional study

Background: We wanted to explore to what extent environmental exposure to immune stimulants, which is expected to be more present in rural than in urban settings, influences T cell activation and maturation in healthy and in HIV-1-infected individuals in Burkina Faso in west Africa. Methods: The proportion of circulating naïve T cells and the expression of the T cell activation markers, CD95 and CD38, were analyzed by immunophenotyping and three-colour flow cytometry in 63 healthy individuals and 137 treatment-naïve HIV-1-infected subjects from Ouagadougou (urban setting) and 26 healthy adults and 61 treatment-naïve patients from Nouna (rural). Results: A slightly higher activation level of CD4+ and CD8+ peripheral blood T cells was seen in healthy adults living in Nouna than in those living in Ouagadougou. The percentages of naïve CD45RAbright CCR7+ T cells were not significantly different between both study sites. Taking into consideration that relatively more HIV-1-infected patients in Nouna were in an advanced disease stage, no relevant differences were seen in T cell activation and maturation between patients at both study sites. As expected, the percentage of CD95+ CD4+ and CD38+ CD8+ T cells and the respective antigen density on these cells was significantly higher in patients than in controls in both settings. The percentage of naïve CD8+ T cells was lower in HIV-1-infected subjects than in healthy controls irrespective of the study site, while a lower proportion of naïve CD4+ T cells in patients compared with controls was seen only in Nouna. Conclusions: Environmentally triggered immune activation may contribute to the increased expression of the activation markers CD95 and CD38 on peripheral blood T cells from healthy adults living in rural versus urban settings in Burkina Faso. T cell activation is further increased in HIV-1-infected individuals due to T cell loss and high plasma viral load levels. The observed variations in T cell activation levels or the proportion of naïve T cells in our study patients, however, are not explained by differences in CD4+ T cell counts or HIV-1 plasma viral load levels alone

Substandard anti-malarial drugs in Burkina Faso

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Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380

Efficacy of amodiaquine in the treatment of uncomplicated falciparum malaria in young children of rural north-western Burkina Faso

BACKGROUND: Combination therapy has become a new paradigm in malaria treatment. Amodiaquine is a common partner drug in different malaria combination therapies used or investigated in sub-Saharan Africa, but data on its efficacy as a single drug are scarce. METHODS: The objective of the study was to determine the efficacy of amodiaquine against falciparum malaria in neighbouring rural and urban areas of north-western Burkina Faso. The study was designed as an uncontrolled trial in children aged 6–59 months with uncomplicated falciparum malaria in the Nouna Health District. RESULTS: During the rainy season 2005, 117 children were enrolled, 62 from the rural and 55 from the urban study area. The crude adequate clinical and parasitological response (ACPR) rate was 103/117 (88%) by day 14 but decreased to 28/117 (24%) by day 28. After PCR correction for reinfections, ACPR rates were 108/117 (92%) and 71/117 (61%) by day 14 and day 28, respectively. There were no significant differences in efficacy between urban and rural areas. The Plasmodium falciparum crt K76T mutation not predict AQ failure, but was selected in parasites re-appearing following treatment. No serious adverse events occurred and only 16 other adverse events were recorded. CONCLUSION: Compared to chloroquine, amodiaquine is more effective against uncomplicated falciparum malaria in Burkina Faso. However, a considerable degree of amodiaquine resistance already exists and it is currently unclear how this resistance will develop when amodiaquine in combination with other drugs is used on a large scale. TRIAL REGISTRATION: Current Controlled Trials ISRCTN73824458

Safety of insecticide-treated mosquito nets for infants and their mothers: randomized controlled community trial in Burkina Faso

Background: Insecticide-treated bed nets (ITNs) are now the main tool for malaria prevention in endemic areas. Synthetic pyrethroids are the only group of insecticides recommended by the World Health Organization for the use on ITNs. There are only few studies which have specifically investigated potential adverse effects of frequent exposure to ITNs in the vulnerable group of young infants and their mothers. Methods: This study was nested into a large randomized controlled ITN effectiveness trial. Ninety newborns and their mothers were selected from the study population for participation. Together with their mothers they were protected with ITNs from birth (group A, n = 45) or from age 6 months (group B, n = 45) and followed up for 18 weeks (daily visits in the first 4 weeks, weekly visits thereafter). Potential side effects related to synthetic pyrethroids (deltamethrin) exposure were systematically investigated by trained field staff. The frequency and duration of respective symptoms was compared between the two study groups. Results: A total of 180 participants (90 mothers and 90 infants) were followed up over the study period without any loss to follow up. There were no significant differences in the frequency and duration of side effects between the two study groups, except that the frequency of headache was significantly higher in group A compared to group B mothers (p = 0.01). Conclusions: The study provides further evidence for ITNs being sufficiently safe in children and even in newborns. The association with headache in mothers could be explained by them handling the ITNs more intensely or it could be a chance finding

Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial

With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso.An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days.The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline.MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies.(ClinicalTrials.gov) NCT00354380