Malaria Journal - Latest Articles

A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Cote d'Ivoire

Offianan Toure — 2009-07-03T00:00:00Z

Background: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast. Methods: 122 participants aged six months or more, with uncomplicated falciparum malaria, were enrolled in the study. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. Results: Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance Conclusions: These data suggest that AN could prove to be suitable for use as combination anti-malarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.

2La chromosomal inversion enhances thermal tolerance of Anopheles gambiae larvae

Kyle Rocca — 2009-07-02T00:00:00Z

Background: The mosquito Anopheles gambiae is broadly distributed throughout sub-Saharan Africa and this contributes to making it the most efficient vector of malaria on the continent. The pervasiveness of this species is hypothesized to originate in local adaptations facilitated by inversion polymorphisms. One inversion, named 2La, is strongly associated with aridity clines in West and Central Africa: while 2La is fixed in arid savannas, the 2L+a arrangement is predominantly found in the rainforest. Ability to survive high temperature exposure is an essential component of aridity tolerance, particularly in immature stages that are restricted to shallow puddles. Toward deciphering the role of the 2La inversion in local adaptation, the present investigation focused on variation in larval and pupal thermo-tolerance in two populations dissimilar solely in 2La arrangement. Methods: A laboratory colony of A. gambiae that is polymorphic for 2La but standard for all other known inversions was used to create 2 homokaryotypic populations (2L+a and 2La). The survival of 4th instar larvae and pupae from both populations was then tested following exposure to thermal stress with and without prior heat hardening. Results: Larvae responded identically to a 40oC heat stress, with about 50% of larvae dying after 1.5-2 h and few larvae surviving a 3 h stress. When heat hardened prior to the thermal stress, thermo-tolerance of both larval populations increased, with 2La 24 h survival significantly exceeding that of 2L+a. Pupae were generally more thermo-tolerant than larvae, although 2La pupae were less so than 2L+a. Heat hardening had no positive effect on pupal thermo-tolerance. Conclusions: The increased thermo-tolerance observed in 2La larvae following heat hardening suggests higher responsiveness (i.e., thermal sensitivity) of the inverted karyotype. By responding more drastically to the heat shock, 2La larvae are better equipped to resist the potentially lethal temperatures that occur in arid habitats. The lower survival of 2La pupae compared with 2L+a may reflect the cost of this sensitivity, whereby the thermal resistance mechanisms prevent successful completion of metamorphosis. The costs and benefits of thermal resistance are discussed in light of the climates characterizing either end of the 2La frequency cline.

Correction: Monitoring and evaluation of malaria in pregnancy - developing a rational basis for control

Bernard Brabin — 2009-07-01T00:00:00Z

I have noted since publication of our paper [Brabin BJ, et al. Monitoring and evaluation of malaria in pregnancy - developing a rational basis for control. Malar J. 2008, 7(Suppl 1):S6] that my surname is incorrect. My surname has been spelt incorrectly as Wasame as it is actually spelt Warsame.

Predictors of anti-convulsant treatment failure in children presenting with malaria and prolonged seizures in Kampala, Uganda

Arthur Mpimbaza — 2009-06-29T00:00:00Z

Background: In endemic areas, falciparum malaria remains the leading cause of seizures in children presenting to emergency departments. In addition, seizures in malaria have been shown to increase morbidity and mortality in these patients. The management of seizures in malaria is sometimes complicated by the refractory nature of these seizures to readily available anti-convulsants. The objective of this study was to determine predictors of anti-convulsant treatment failure and seizure recurrence after initial control among children with malaria. Methods: In a previous study, the efficacy and safety of buccal midazolam was compared to that of rectal diazepam in the treatment of prolonged seizures in children aged three months to 12 years in Kampala, Uganda. For this study, predictive models were used to determine risk factors for anti-convulsant treatment failure and seizure recurrence among the 221 of these children with malaria.ResultUsing predictive models, focal seizures (OR 3.21; 95% CI 1.42-7.25, p=0.005), cerebral malaria (OR 2.43; 95% CI 1.20-4.91, p=0.01) and a blood sugar >200 mg/dl at presentation (OR 2.84; 95% CI 1.11-7.20, p=0.02) were independent predictors of treatment failure (seizure persistence beyond 10 minutes or recurrence within one hour of treatment). Predictors of seizure recurrence included: 1) cerebral malaria (HR 3.32; 95% CI 1.94-5.66, p <0.001), 2) presenting with multiple seizures (HR 2.45; 95% CI 1.42-4.23, p=0.001), 3) focal seizures (HR 2.86; 95% CI 1.49-5.49, p=0.002), 4) recent use of diazepam (HR 2.43; 95% CI 1.19-4.95, p=0.01) and 5) initial control of the seizure with diazepam (HR 1.96; 95% CI 1.16-3.33, p=0.01). Conclusion: Specific predictors, including cerebral malaria, can identify patients with malaria at risk of anti-convulsant treatment failure and seizure recurrence.

Socio-cultural factors explaining timely and appropriate use of health facilities for degedege in south-eastern Tanzania

Angel Dillip — 2009-06-29T00:00:00Z

Background: Convulsions is one of the key signs of severe malaria among children under five years of age, potentially leading to serious complications or death. Several studies of care-seeking behaviour have revealed that local illness concepts linked to convulsions (referred to as degedege in Tanzanian Kiswahili) called for traditional treatment practices while modern treatment was preferred for common fevers. However, recent studies found that even children with convulsions were first brought to health facilities. This study integrated ethnographic and public health approaches in order to investigate this seemingly contradictory evidence. Carefully drawn random samples were used to maximize the representativity of the results. Methods: The study used a cultural epidemiology approach and applied a locally adapted version of the Explanatory Model Interview Catalogue (EMIC), which ensures a comprehensive investigation of disease perception and treatment patterns. The tool was applied in three studies; i) the 2004 random sample cross-sectional community fever survey (N=80), ii) the 2004-2006 longitudinal degedege study (N=129), and iii) the 2005 cohort study on fever during the main farming season (N=29). Results: 71.1% of all convulsion cases were brought to a health facility in time, i.e. within 24 hours after onset of first symptoms. This compares very favourably with a figure of 45.6% for mild fever cases in children. The patterns of distress associated with less timely health facility use and receipt of anti-malarials among children with degedege were generalized symptoms, rather than the typical symptoms of convulsions. Traditional and moral causes were associated with less timely health facility use and receipt of anti-malarials. However, the high rate of appropriate action indicates that these ideas were not so influential any more as in the past. Reasons given by caretakers who administered anti-malarials to children without attending a health facility were either that facilities were out of stock, that they lacked money to pay for treatment, or that facilities did not provide diagnosis. Conclusion: The findings from this representative sample from a highly malaria-endemic area give support to the more recent studies showing that children with convulsions are more likely to use health facilities than traditional practices. This study has identified health system and livelihood factors, rather than local understandings of symptoms and causes relating to degedege as limiting health-seeking behaviours. Improvements on the supply side and the demand side are necessary to ensure people's timely and appropriate treatment: Quality of care at health facilities needs to be improved by making diagnosis and provider compliance with treatment guidelines more accurate and therapies including drugs more available and affordable to communities. Treatment seeking needs to be facilitated by strengthening livelihoods including economic capabilities.

Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris

Marion Avril — 2009-06-29T00:00:00Z

Background: VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. Methods: VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. Results: From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. Conclusions: These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.

The spatial and temporal patterns of falciparum and vivax malaria in Peru: 1994-2006

Gerardo Chowell — 2009-06-27T00:00:00Z

Background: Malaria is the direct cause of approximately one million deaths worldwide each year, though it is both preventable and curable. Increasing the understanding of the transmission dynamics of falciparum and vivax malaria and their relationship could suggest improvements for malaria control efforts. Here the weekly number of malaria cases due to Plasmodium falciparum (1994-2006) and Plasmodium vivax (1999-2006) in Peru at different spatial scales in conjunction with associated demographic, geographic and climatological data are analysed. Methods: Malaria periodicity patterns were analysed through wavelet spectral analysis, studied patterns of persistence as a function of community size and assessed spatial heterogeneity via the Lorenz curve and the summary Gini index. Results: Wavelet time series analyses identified annual cycles in the incidence of both malaria species as the dominant pattern. However, significant spatial heterogeneity was observed across jungle, mountain and coastal regions with slightly higher levels of spatial heterogeneity for P. vivax than P. falciparum. While the incidence of P. falciparum has been declining in recent years across geographic regions, P. vivax incidence has remained relatively steady in jungle and mountain regions with a slight decline in coastal regions. Factors that may be contributing to this decline are discussed. The time series of both malaria species were significantly synchronized in coastal (rho=0.9, P<0.0001) and jungle regions (rho=0.76, P<0.0001) but not in mountain regions. Community size was significantly associated with malaria persistence due to both species in jungle regions, but not in coastal and mountain regions. Conclusions: Overall, findings highlight the importance of highly refined spatial and temporal data on malaria incidence together with demographic and geographic information in improving the understanding of malaria persistence associated with multiple malaria species in human populations, impact of interventions, detection of heterogeneity and generation of hypotheses.

Efficacy of sulphadoxine-pyrimethamine with or without artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in southern Mozambique: a randomized controlled trial

Elizabeth Allen — 2009-06-26T00:00:00Z

Background: An artemisinin-based combination therapy, artesunate (AS) plus sulphadoxine-pyrimethamine (SP), was compared to SP monotherapy to provide evidence of further treatment options in southern Mozambique. Methods: Between 2003 and 2005, 411 patients over one year and 10kg with uncomplicated Plasmodium falciparum malaria were randomly allocated SP (25/1.25mg per kg day 0) or AS/SP (as above plus 4mg/kg artesunate days 0, 1 and 2). Allocation was concealed, but treatment was open-label except to microscopists. The primary objective was the relative risk of treatment failure, which was assessed using World Health Organization response definitions modified to a 42-day follow-up. Results: Of the 411 subjects enrolled, 359 (87.3%) completed the follow up period (SP n= 175, AS/SP n=184). A survival analysis including 408 subjects showed that the polymerase chain reaction-adjusted cure rates were 90.4% (95% confidence interval [CI] 84.9%-93.9%) and 98.0% (95% CI 94.8%-99.3%) for SP and AS/SP respectively. Multivariable analysis showed that treatment with AS/SP decreased the relative hazard of treatment failure by 80% compared to SP (hazard ratio [HR] 0.2; 95% CI 0.1-0.6) and age over seven years decreased the relative hazard of failure by 70% (HR 0.3; 95% CI 0.1-0.9), when compared to younger age. However, having a quintuple dhfr/dhps mutation increased the relative hazard of failure compared to fewer mutations (HR 3.2; 95% CI 1.3-7.5) and baseline axillary temperature increased the relative hazard of failure by 50% for each degreesC increase (HR 1.5; 95% CI 1.1-2.2). Conclusions: While both treatments were efficacious, AS plus SP significantly decreased the relative hazard of treatment failure compared to SP monotherapy Artesunate plus sulphadoxine-pyrimethamine, but not sulphadoxine-pyrimethamine monotherapy, met the current WHO criteria of >95% efficacy for policy implementation.Trial registrationNCT00203736 and NCT00203814

Characterization of the repertoire diversity of the Plasmodium falciparum stevor multigene family in laboratory and field isolates

Jane Blythe — 2009-06-26T00:00:00Z

Background: The evasion of host immune response by the human malaria parasite Plasmodium falciparum has been linked to expression of a range of variable antigens on the infected erythrocyte surface. Several genes are potentially involved in this process with the var, rif and stevor multigene families being the most likely candidates and coding for rapidly evolving proteins. The high sequence diversity of proteins encoded by these gene families may have evolved as an immune evasion strategy that enables the parasite to establish long lasting chronic infections. Previous findings have shown that the hypervariable region (HVR) of STEVOR has significant sequence diversity both within as well as across different P. falciparum lines. However, these studies did not address whether or not there are ancestral stevor that can be found in different parasites. Methods: DNA and RNA sequences analysis as well as phylogenetic approaches were used to analyse the stevor sequence repertoire and diversity in laboratory lines and Kilifi (Kenya) fresh isolates. Results: Conserved stevor genes were identified in different P. falciparum isolates from different global locations. Consistent with previous studies, the HVR of the stevor gene family was found to be highly divergent both within and between isolates. Importantly phylogenetic analysis shows some clustering of stevor sequences both within a single parasite clone as well as across different parasite isolates. Conclusion: This indicates that the ancestral P. falciparum parasite genome already contained multiple stevor genes that have subsequently diversified further within the different P. falciparum populations. It also confirms that STEVOR is under strong selection pressure.

Antimalarial activity of a cis-terpenone

DC Ghislaine Mayer — 2009-06-25T00:00:00Z

Background: Malaria is the third most prevalent cause of infectious disease in the world. Resistance of the parasite to classical drugs makes the discovery of new and effective drugs more urgent. The oxidized derivative of hydroxy-cis terpenone (OHCT) is a synthetic molecule that is not toxic to cultured human liver cells at concentrations as high as 60 uM and inhibits activity of cytochrome P450s that metabolize many drugs. Methods: OHCT activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum, and a P. falciparum clone that is partially resistant to artemisinin was assayed in vitro. Results: OHCT at nanomolar concentrations was effective against all intraerythrocytic stages of P. falciparum and exhibited activity in vitro against both chloroquine-sensitive and -resistant strains of P. falciparum as well as a P. falciparum clone that is partially resistant to artemisinin. Moreover, OHCT exhibited potent activity against gametocytes, the form that is transmitted by mosquitoes and essential for the spread of malaria. Conclusions: OHCT displays strong growth inhibitory activity against all stages of P. falciparum and no evidence of toxicity to human cells in culture. It is easily synthesized and has the potential for inhibiting metabolism of drugs used in combination therapies.