• Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis.

      Zwang, Julien; Ashley, Elizabeth A; Karema, Corine; D'Alessandro, Umberto; Smithuis, Frank; Dorsey, Grant; Janssens, Bart; Mayxay, Mayfong; Newton, Paul; Singhasivanon, Pratap; et al. (2009-07-15)
      BACKGROUND: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. METHODS AND FINDINGS: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). CONCLUSIONS: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.
    • Seasonal Malaria Chemoprevention with Sulphadoxine-Pyrimethamine and Amodiaquine Selects Pfdhfr-dhps Quintuple Mutant Genotype in Mali

      Maiga, H; Lasry, E; Diarra, M; Sagara, I; Bamadio, A; Traore, A; Coumare, S; Bahonan, S; Sangare, B; Dicko, Y; et al. (Public Library of Science, 2016-09-23)
      Seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine (SP) plus amodiaquine (AQ) is being scaled up in Sahelian countries of West Africa. However, the potential development of Plasmodium falciparum resistance to the respective component drugs is a major concern.
    • Seasonal Malaria Chemoprevention: successes and missed opportunities

      Coldiron, ME; Von Seidlein, L; Grais, RF (BioMed Central, 2017-11-28)
      Seasonal malaria chemoprevention (SMC) was recommended in 2012 for young children in the Sahel during the peak malaria transmission season. Children are given a single dose of sulfadoxine/pyrimethamine combined with a 3-day course of amodiaquine, once a month for up to 4 months. Roll-out and scale-up of SMC has been impressive, with 12 million children receiving the intervention in 2016. There is evidence of its overall benefit in routine implementation settings, and a meta-analysis of clinical trial data showed a 75% decrease in clinical malaria compared to placebo. SMC is not free of shortcomings. Its target zone includes many hard-to-reach areas, both because of poor infrastructure and because of political instability. Treatment adherence to a 3-day course of preventive treatment has not been fully documented, and could prove challenging. As SMC is scaled up, integration into a broader, community-based paradigm which includes other preventive and curative activities may prove beneficial, both for health systems and for recipients.
    • Selection of Plasmodium Falciparum pfcrt and pfmdr1 Polymorphisms After Treatment with Artesunate-Amodiaquine Fixed Dose Combination or Artemether-Lumefantrine in Liberia

      Otienoburu, SD; Maïga-Ascofaré, O; Schramm, B; Jullien, V; Jones, JJ; Zolia, YM; Houzé, P; Ashley, EA; Kiechel, JR; Guérin, PJ; et al. (BioMed Central (Springer Science), 2016-09-05)
      Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.
    • Selection strength and hitchhiking around two anti-malarial resistance genes.

      Nash, D; Nair, S; Mayxay, M; Newton, P N; Guthmann, J P; Nosten, F; Anderson, T J C; Southwest Foundation for Biomedical Research (SFBR), San Antonio, TX 78245, USA. (2005-06-07)
      Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34-64 kb (2-4 cM) in Laos on chromosome 4, compared with 98-137 kb (6-8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34-69 kb (2-4 cM) around pfcrt in Laos, but for 195-268 kb (11-16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.
    • Severe acute malnutrition results in lower lumefantrine exposure in children treated with artemether-lumefantrine for uncomplicated malaria

      Chotsiri, P; Denoeud-Ndam, L; Baudin, E; Guindo, O; Diawara, H; Attaher, O; Smit, M; Guerin, PJ; Duombo, OK; Weisner, L; et al. (American Society for Clinical Pharmacology and Therapeutics, 2019-06-01)
      Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub‐Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic‐pharmacodynamic study included 131 SAM and 266 non‐SAM children administered artemether‐lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit‐absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the pharmacokinetic model. Mid‐upper arm circumference (MUAC) was associated with decreased absorption of lumefantrine (25.4% decrease per 1 cm reduction). Risk of recurrent malaria episodes (i.e. reinfection) were characterised by an interval‐censored time‐to‐event model with a sigmoid EMAX‐model describing the effect of lumefantrine. SAM children were at risk of under‐exposure to lumefantrine and an increased risk of malaria reinfection compared to well‐nourished children. Research on optimised regimens should be considered for malaria treatment in malnourished children.
    • Short Report: Association Between Chloroquine and Amodiaquine Resistance and Allelic Variation in the Plasmodium Falciparum Multiple Drug Resistance 1 Gene and the Chloroquine Resistance Transporter Gene in Isolates from the Upper Nile in Southern Sudan.

      Ochong, E; van den Broek, I; Keus, K; Nzila, A; Kenya Medical Research Institute, Wellcome Trust Collaborative Program, Médecins sans Frontières-Holland, South Sudan Section, Nairobi, Kenya. (Published by: American Society of Tropical Medicine and Hygiene, 2003-08)
      Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.
    • Short report: molecular markers associated with Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in the Democratic Republic of Congo.

      Cohuet, S; Bonnet, M; Van Herp, M; Van Overmeir, C; D'Alessandro, U; Guthmann, J P; Epicentre, Paris, France; Médecins Sans Frontières, Brussels, Belgium; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium. (2006-07)
      Sulfadoxine-pyrimethamine (SP) is the first line antimalarial treatment in the Democratic Republic of Congo. Using polymerase chain reaction, we assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulfadoxine, respectively. Four hundred seventy-four patients were sampled in Kilwa (N = 138), Kisangani (N = 112), Boende (N = 106), and Basankusu (N = 118). The proportion of triple mutations dhfr varied between sites but was always > 50%. The proportion of dhps double mutations was < 20%, with some sites as low as 0.9%. A quintuple mutation was present in 12.8% (16/125) samples in Kilwa; 11.9% (13/109) in Kisangani, 2.9% (3/102) in Boende, and 0.9% (1/112) in Basankusu. These results suggest high resistance to pyrimethamine alone or combined with sulfadoxine. Adding artesunate to SP does not seem a valid alternative to the current monotherapy.
    • A significant increase in kdr in Anopheles gambiae is associated with an intensive vector control intervention in Burundi highlands.

      Protopopoff, N; Verhaeghen, K; Van Bortel, W; Roelants, P; Marcotty, T; Baza, D; D'Alessandro, U; Coosemans, M; Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium. nprotopopoff@itg.be (2008-12)
      OBJECTIVES AND METHODS: In Burundi, the occurrence of the knock down resistance (kdr) mutation in Anopheles gambiae sensu lato (s.l.) was determined for six consecutive years within the framework of a vector control programme. Findings were also linked with the insecticide resistance status observed with bioassay in An. gambiae s.l. and An. funestus. RESULTS: The proportion of An. gambiae s.l. carrying the East Leu-Ser kdr mutation was 1% before the spraying intervention in 2002; by 2007 it was 86% in sprayed valleys and 67% in untreated valleys. Multivariate analysis showed that increased risk of carrying the kdr mutation is associated with spraying interventions, location and time. In bioassays conducted between 2005 and 2007 at five sites, An. funestus was susceptible to permethrin, deltamethrin and DDT. Anopheles gambiae s.l. remained susceptible or tolerant to deltamethrin and resistant to DDT and permethrin, but only when kdr allele carriers reached 90% of the population. CONCLUSIONS: The cross-resistance against DDT and permethrin in Karuzi suggests a possible kdr resistance mechanism. Nevertheless, the homozygous resistant genotype alone does not entirely explain the bioassay results, and other mechanisms conferring resistance cannot be ruled out. After exposure to all three insecticides, homozygote individuals for the kdr allele dominate among the surviving An. gambiae s.l. This confirms the potential selection pressure of pyrethroids on kdr mutation. However, the high occurrence of the kdr mutation, even at sites far from the sprayed areas, suggests a selection pressure other than that exerted by the vector control programme.
    • Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa

      Taylor, WR; Naw, HK; Maitland, K; Williams, TN; Kapulu, M; D'Alessandro, U; Berkley, JA; Bejon, P; Okebe, J; Achan, J; et al. (BioMed Central, 2018-01-18)
      In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa.
    • Sociocultural and Structural Factors Contributing to Delays in Treatment for Children with Severe Malaria: A Qualitative Study in Southwestern Uganda

      Sundararajan, Radhika; Mwanga-Amumpaire, Juliet; Adrama, Harriet; Tumuhairwe, Jackline; Mbabazi, Sheilla; Mworozi, Kenneth; Carroll, Ryan; Bangsberg, David; Boum, Yap; Ware, Norma C (American Society of Tropical Medicine and Hygiene, 2015-03-23)
      Malaria is a leading cause of pediatric mortality, and Uganda has the highest incidences in the world. Increased morbidity and mortality are associated with delays to care. This qualitative study sought to characterize barriers to prompt allopathic care for children hospitalized with severe malaria in the endemic region of southwestern Uganda. Minimally structured, qualitative interviews were conducted with guardians of children admitted to a regional hospital with severe malaria. Using an inductive and content analytic approach, transcripts were analyzed to identify and define categories that explain delayed care. These categories represented two broad themes: sociocultural and structural factors. Sociocultural factors were 1) interviewee's distinctions of "traditional" versus "hospital" illnesses, which were mutually exclusive and 2) generational conflict, where deference to one's elders, who recommended traditional medicine, was expected. Structural factors were 1) inadequate distribution of health-care resources, 2) impoverishment limiting escalation of care, and 3) financial impact of illness on household economies. These factors perpetuate a cycle of illness, debt, and poverty consistent with a model of structural violence. Our findings inform a number of potential interventions that could alleviate the burden of this preventable, but often fatal, illness. Such interventions could be beneficial in similarly endemic, low-resource settings.
    • Spatial targeted vector control in the highlands of Burundi and its impact on malaria transmission.

      Protopopoff, N; Van Bortel, W; Marcotty, T; Van Herp, M; Maes, P; Baza, D; D'Alessandro, U; Coosemans, M; Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium. nprotopopoff@itg.be (BMC, 2007)
      BACKGROUND: Prevention of malaria epidemics is a priority for African countries. The 2000 malaria epidemic in Burundi prompted the government to implement measures for preventing future outbreaks. Case management with artemisinin-based combination therapy and malaria surveillance were nationally improved. A vector control programme was initiated in one of the most affected highland provinces. The focal distribution of malaria vectors in the highlands was the starting point for designing a targeted vector control strategy. The objective of this study was to present the results of this strategy on malaria transmission in an African highland region. METHODS: In Karuzi, in 2002-2005, vector control activities combining indoor residual spraying and long-lasting insecticidal nets were implemented. The interventions were done before the expected malaria transmission period and targeted the valleys between hills, with the expectation that this would also protect the populations living at higher altitudes. The impact on the Anopheles population and on malaria transmission was determined by nine cross-sectional surveys carried out at regular intervals throughout the study period. RESULTS: Anopheles gambiae s.l. and Anopheles funestus represented 95% of the collected anopheline species. In the valleys, where the vector control activities were implemented, Anopheles density was reduced by 82% (95% CI: 69-90). Similarly, transmission was decreased by 90% (95% CI: 63%-97%, p = 0.001). In the sprayed valleys, Anopheles density was further reduced by 79.5% (95% CI: 51.7-91.3, p < 0.001) in the houses with nets as compared to houses without them. No significant impact on vector density and malaria transmission was observed in the hill tops. However, the intervention focused on the high risk areas near the valley floor, where 93% of the vectors are found and 90% of the transmission occurs. CONCLUSION: Spatial targeted vector control effectively reduced Anopheles density and transmission in this highland district. Bed nets have an additional effect on Anopheles density though this did not translate in an additional impact on transmission. Though no impact was observed in the hilltops, the programme successfully covered the areas most at risk. Such a targeted strategy could prevent the emergence and spread of an epidemic from these high risk foci.
    • Spatial targeted vector control is able to reduce malaria prevalence in the highlands of Burundi.

      Protopopoff, N; Van Bortel, W; Marcotty, T; Van Herp, M; Maes, P; Baza, D; D'Alessandro, U; Coosemans, M; Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium. nprotopopoff@itg.be (American Society of Tropical Medicine and Hygiene, 2008-07)
      In a highland province of Burundi, indoor residual spraying and long-lasting insecticidal net distribution were targeted in the valley, aiming also to protect the population living on the hilltops. The impact on malaria indicators was assessed, and the potential additional effect of nets evaluated. After the intervention--and compared with the control valleys--children 1-9 years old in the treated valleys had lower risks of malaria infection (odds ratio, OR: 0.55), high parasite density (OR: 0.48), and clinical malaria (OR: 0.57). The impact on malaria prevalence was even higher in infants (OR: 0.14). Using nets did not confer an additional protective effect to spraying. Targeted vector control had a major impact on malaria in the high-risk valleys but not in the less-exposed hilltops. Investment in targeted and regular control measures associated with effective case management should be able to control malaria in the highlands.
    • Successful introduction of artesunate combination therapy is not enough to fight malaria: results from an adherence study in Sierra Leone.

      Gerstl, Sibylle; Dunkley, Sophie; Mukhtar, Ahmed; Baker, Samuel; Maikere, Jacob; Médecins Sans Frontières (MSF) UK, 67-74 Saffron Hill, London EC1N 8QX, UK. (2010-02-01)
      A study to measure adherence to artesunate and amodiaquine (AS+AQ) therapy in patients treated for uncomplicated malaria in community health centres (CHC) was conducted in Sierra Leone. Patients/caretakers were interviewed and remaining AS+AQ tablets at home after the last treatment dose were counted. Persons leaving CHCs with an AS+AQ prescription were also interviewed (exit interviews). In total, 118 patients were visited at home: 27 (22.9%) had one or more tablets left and were classed as certainly non-adherent; 34 (28.8%) were probably non-adherent [reported incorrect (n=27) or incomplete (n=7) intake]; and 57 (48.3%) were probably adherent. The main reasons for incomplete intake were sickness after one dose of AS+AQ, no food available for drug intake and forgetting to take them. For incorrect intake, reasons were vomiting after drug intake and incorrect instructions given by the CHC. Eighty-one percent of probably adherent patients reported following instructions given to them. In exit interviews, 82% of patients or caretakers of patients were able to repeat AS+AQ intake instructions correctly. Adherence to antimalarial treatment should not be taken for granted. Instructions on correct AS+AQ use should include discussion of disease symptoms as well as possible treatment side effects and how to manage them. Other factors are more difficult to influence, such as patients forgetting to take the treatment.
    • Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda.

      Checchi, F; Piola, P; Fogg, C; Bajunirwe, F; Biraro, S; Grandesso, F; Ruzagira, E; Babigumira, J; Kigozi, I; Kiguli, J; et al. (BioMed Central, 2006)
      BACKGROUND: A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. METHODS: Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. RESULTS: C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). CONCLUSION: Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.
    • Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial.

      Piola, P; Fogg, C; Bajunirwe, F; Biraro, S; Grandesso, F; Ruzagira, E; Babigumira, J; Kigozi, I; Kiguli, J; Kyomuhendo, J; et al. (Elsevier, 2005-04-23)
      BACKGROUND: The six-dose regimen of artemether-lumefantrine is effective and is among combination therapies prioritised to replace antimalarials that no longer work in Africa. However, its effectiveness has not been assessed in the field, and could be compromised by poor adherence, incorrect timing of doses, and insufficient intake of fatty foods with every dose. Our aim, therefore, was to assess the effectiveness of artemether-lumefantrine prescribed under routine outpatient conditions, compared with its efficacy when given under supervision to inpatients with acute uncomplicated falciparum malaria. METHODS: We did a randomised trial to compare the efficacy, safety, and pharmacokinetics of artemether-lumefantrine when given in a supervised (all doses observed with fatty-food intake; n=313) or unsupervised (first dose supervised followed by outpatient treatment with nutritional advice; n=644) setting to patients of all ages (weight >10 kg) with acute, uncomplicated falciparum malaria in Mbarara, Uganda. Our primary endpoint was 28 day, PCR-adjusted, parasitological cure rate. Analysis was by intention to treat and evaluability analysis. FINDINGS: 38 patients were lost to follow-up and one withdrew consent. Day-28 cure rates were 97.7% (296 of 303) and 98.0% (603 of 615) in the supervised and unsupervised groups, respectively. We recorded 15 non-severe, drug-related adverse events, all of which resolved. INTERPRETATION: Artemether-lumefantrine has a high cure rate irrespective of whether given under supervision with food or under conditions of routine clinic practice. If used as first-line treatment, artemether-lumefantrine could make a substantial contribution to malaria control in Africa, though cost is an issue.
    • Suppression of circulating IgD+CD27+ memory B cells in infants living in a malaria-endemic region of Kenya

      Asito, Amolo S; Piriou, Erwan; Jura, Walter GZO; Ouma, Collins; Odada, Peter S; Ogola, Sidney; Fiore, Nancy; Rochford, Rosemary; Maseno University, Maseno, Kenya; Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya; SUNY Upstate Medical University, Syracuse, NY; Medecins Sans Frontieres-Operational Centre Amsterdam, Amsterdam, The Netherlands (BioMed Central, 2011-12-13)
      Background: Plasmodium falciparum infection leads to alterations in B cell subset distribution. During infancy, development of peripheral B cell subsets is also occurring. However, it is unknown if infants living a malaria endemic region have alterations in B cell subsets that is independent of an age effect. Methods: To evaluate the impact of exposure to P. falciparum on B cell development in infants, flow cytometry was used to analyse the distribution and phenotypic characteristic of B cell subsets in infant cohorts prospectively followed at 12, 18 and 24 months from two geographically proximate regions in western Kenya with divergent malaria exposure i.e. Kisumu (malaria-endemic, n = 24) and Nandi (unstable malaria transmission, n = 21). Results: There was significantly higher frequency and absolute cell numbers of CD19+ B cells in Kisumu relative to Nandi at 12(p = 0.0440), 18(p = 0.0210) and 24 months (p = 0.0493). No differences were observed between the infants from the two sites in frequencies of naïve B cells (IgD+CD27-) or classical memory B cells (IgD-CD27+). However, immature transitional B cells (CD19+CD10+CD34-) were higher in Kisumu relative to Nandi at all three ages. In contrast, the levels of non-class switched memory B cells (CD19+IgD+CD27+) were significantly lower overall in Kisumu relative to Nandi at significantly at 12 (p = 0.0144), 18 (p = 0.0013) and 24 months (p = 0.0129). Conclusions: These data suggest that infants living in malaria endemic regions have altered B cell subset distribution. Further studies are needed to understand the functional significance of these changes and long-term impact on ability of these infants to develop antibody responses to P. falciparum and heterologous infections.
    • The Efficacy of Chloroquine for the Treatment of Acute, Uncomplicated, Plasmodium Falciparum Malaria in Laos.

      Guthmann, J P; Kasparian, S; Phetsouvanh, R; Nathan, N; Garcia, M; Phompida, S; Brockman, A; Gastellu-Etchegorry, M; Legros, D; Epicentre, 8 rue Saint Sabin, 75011 Paris, France. jguthmann@epicentre.msf.org (Published by: Maney Publishing, 2002-09)
      To assess the local efficacy of chloroquine for the treatment of acute, uncomplicated, Plasmodium falciparum malaria, children and adults from Sekong province (an area of Laos with a low intensity of transmission) were tested in a 28-day, in-vivo study. Complete data were collected from 88 of the 102 subjects enrolled between October 1999 and September 2000. After genotypic analysis to distinguish recrudescing infections from re-infections, 35 (39.7%, with a 95% confidence interval of 29.5%-50.7%) of these 88 patients were considered treatment failures. These results seriously question the use of chloroquine as the first-line treatment for P. falciparum malaria in the study area.
    • Timing of Malaria in Pregnancy and Impact on Infant Growth and Morbidity: a Cohort Study in Uganda

      De Beaudrap, P; Turyakira, E; Nabasumba, C; Tumwebaze, B; Piola, P; Boum Ii, Y; McGready, R (BioMed Central, 2016-02-16)
      Malaria in pregnancy (MiP) is a major cause of fetal growth restriction and low birth weight in endemic areas of sub-Saharan Africa. Understanding of the impact of MiP on infant growth and infant risk of malaria or morbidity is poorly characterized. The objective of this study was to describe the impact of MIP on subsequent infant growth, malaria and morbidity.
    • Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

      Schramm, Birgit; Valeh, Parastou; Baudin, Elisabeth; Mazinda, Charles S; Smith, Richard; Pinoges, Loretxu; Sundaygar, Timothy; Zolia, Yah M; Jones, Joel J; Comte, Eric; et al. (BioMed Central, 2013-07-17)
      Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.