Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial)

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Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya

<p>Abstract</p> <p>Background</p> <p>Understanding the origin and spread of mutations associated with drug resistance, especially in the context of combination therapy, will help guide strategies to halt and prevent the emergence of resistance. Unfortunately, studies have assessed these complex processes when resistance is already highly prevalent. Even further, information on the evolutionary dynamics leading to multidrug-resistant parasites is scattered and limited to areas with low or seasonal malaria transmission. This study describes the dynamics of strong selection for mutations conferring resistance against sulphadoxine-pyrimethamine (SP), a combination therapy, in western Kenya between 1992 and 1999, just before SP became first-line therapy (1999). Importantly, the study is based on longitudinal data, which allows for a comprehensive analysis that contrasts with previous cross-sectional studies carried out in other endemic regions.</p> <p>Methods</p> <p>This study used 236 blood samples collected between 1992 and 1999 in the Asembo Bay area of Kenya. Pyrosequencing was used to determine the alleles of dihydrofolate reductase (<it>dhfr</it>) and dihydropterote synthase <it>(dhps) </it>genes. Microsatellite alleles spanning 138 kb around <it>dhfr </it>and <it>dhps</it>, as well as, neutral markers spanning approximately 100 kb on chromosomes 2 and 3 were characterized.</p> <p>Results</p> <p>By 1992, the South-Asian <it>dhfr </it>triple mutant was already spreading, albeit in low frequency, in this holoendemic Kenyan population, prior to the use of SP as a first-line therapy. Additionally, <it>dhfr </it>triple mutant alleles that originated independently from the predominant Southeast Asian lineage were present in the sample set. Likewise, <it>dhps </it>double mutants were already present as early as 1992. There is evidence for soft selective sweeps of two <it>dhfr </it>mutant alleles and the possible emergence of a selective sweep of double mutant <it>dhps </it>alleles between 1992 and 1997. The longitudinal structure of the dataset allowed estimation of selection pressures on various <it>dhfr </it>and <it>dhps </it>mutants relative to each other based on a theoretical model tailored to <it>P. falciparum</it>. The data indicate that drug selection acted differently on the resistant alleles of <it>dhfr </it>and <it>dhps</it>, as evidenced by fitness differences. Thus a combination drug therapy such as SP, by itself, does not appear to select for "multidrug"-resistant parasites in areas with high recombination rate.</p> <p>Conclusions</p> <p>The complexity of these observations emphasizes the importance of population-based studies to evaluate the effects of strong drug selection on <it>Plasmodium falciparum </it>populations.</p

Gains in awareness, ownership and use of insecticide-treated nets in Nigeria, Senegal, Uganda and Zambia

Abstract Background In April 2000, the Roll Back Malaria (RBM) "Abuja Summit" set a target of having at least 60% of pregnant women and children under five use insecticide-treated nets (ITNs). Thereafter, programmes were implemented to create demand, reduce taxes and tariffs, spur the commercial market, and reach vulnerable populations with subsidized ITNs. Using national ITN monitoring data from the USAID-sponsored AED/NetMark project, this article examines the extent to which these activities were successful in increasing awareness, ownership, and use of nets and ITNs. Methods A series of surveys with standardized sampling and measurement methods was used to compare four countries at two points in time. Surveys were conducted in 2000 and again in 2004 (Nigeria, Senegal, Zambia) or 2006 (Uganda). They contained questions permitting classification of each net as untreated, ever-treated or currently-treated (an ITN). Household members as well as nets owned were enumerated so that households, household members, and nets could be used as units of analysis. Several measures of net/ITN ownership, plus RBM ITN use indicators, were calculated. The results show the impact of ITN activities before the launch of massive free net distribution programmes. Results In 2000, treated nets were just being introduced to the public, but four to six years later the awareness of ITNs was nearly universal in all countries but Nigeria, where awareness increased from 7% to 60%. By any measure, there were large increases in ownership of nets, especially treated nets, in all countries. All countries but Nigeria made commensurate gains in the proportion of under-fives sleeping under a net/ITN, and in all countries the proportion of pregnant women sleeping under a net/ITN increased greatly. Conclusion A mix of demand creation, a strengthened commercial sector, reduced taxes and tariffs, and programmes making ITNs available at reduced prices resulted in impressive gains in awareness, ownership, and use of nets and ITNs in Nigeria, Senegal, Zambia, and Uganda between 2000 and 2004–2006. None of the countries reached the ambitious Abuja targets for ITN use, but they made substantial progress towards them.</p

A Randomized Placebo-Controlled Trial of Intermittent Preventive Treatment in Pregnant Women in the Context of Insecticide Treated Nets Delivered through the Antenatal Clinic

Background:Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets(ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of theircombined use.Methods:1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC)visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess thesafety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight.Findings:Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence atdelivery (RR, 0.92 [95% CI, 0.79-1.08]), low birth weight (RR, 0.99 [95% CI, 0.70-1.39]), or overall placental infection(p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40-61.20]; p = 0.020) in the incidence of clinicalmalaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p,0.001), and ofactively infected placentas (7.04% vs 13.60%) (p = 0.002). There was a reduction in severe anaemia at delivery of borderlinestatistical significance (p = 0.055). These effects were not modified by gravidity or HIV status. Reported ITN's use was morethan 90% in both groups.Conclusions:Two-dose SP was associated with a reduction in some indicators, but these were not translated to significantimprovement in other maternal or birth outcomes. The use of ITNs during pregnancy may reduce the need to administerIPTp. ITNs should be part of the ANC package in sub-Saharan Afric

Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report

BACKGROUND: Convenient once-a-week dosing has made mefloquine a popular choice as malaria prophylaxis for travel to countries with chloroquine-resistant malaria. However, the increased use of mefloquine over the past decade has resulted in reports of rare, but severe, neuropsychiatric adverse reactions, such as anxiety, depression, hallucinations and psychosis. A direct causality between mefloquine and severe reactions among travelers has been partly confounded by factors associated with foreign travel and, in the case of therapeutic doses of mefloquine, the central nervous system manifestations of Plasmodium infection itself. The present case provides a unique natural history of mefloquine-induced neuropsychiatric toxicity and revisits its dose-dependent nature. CASE PRESENTATION: This report describes an acute exacerbation of neuropsychiatric symptoms after an unwarranted therapeutic dose (1250 mg) of mefloquine in a 37-year-old male previously on a once-a-week prophylactic regimen. Neuropsychiatric symptoms began as dizziness and insomnia of several days duration, which was followed by one week of escalating anxiety and subtle alterations in behaviour. The patient's anxiety culminated into a panic episode with profound sympathetic activation. One week later, he was hospitalized after developing frank psychosis with psychomotor agitation and paranoid delusions. His psychosis remitted with low-dose quetiapine. CONCLUSION: This report suggests that an overt mefloquine-induced psychosis can be preceded by a prodromal phase of moderate symptoms such as dizziness, insomnia, and generalized anxiety. It is important that physicians advise patients taking mefloquine prophylaxis and their relatives to recognize such symptoms, especially when they are accompanied by abrupt, but subtle, changes in behaviour. Patients with a history of psychiatric illness, however minor, may be at increased risk for a mefloquine-induced neuropsychiatric toxicity. Physicians must explicitly caution patients not to self-medicate with a therapeutic course of mefloquine when a malaria diagnosis has not been confirmed

How antimalarial drug resistance affects post-treatment prophylaxis

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base

Maternal Malaria and Perinatal HIV Transmission, Western Kenya1,2

To determine whether maternal placental malaria is associated with an increased risk for perinatal mother-to-child HIV transmission (MTCT), we studied HIV-positive women in western Kenya. We enrolled 512 mother-infant pairs; 128 (25.0%) women had malaria, and 102 (19.9%) infants acquired HIV perinatally. Log10 HIV viral load and episiotomy or perineal tear were associated with increased perinatal HIV transmission, whereas low-density malaria (<10,000 parasites/μL) was associated with reduced risk (adjusted relative risk [ARR] 0.4). Among women dually infected with malaria and HIV, high-density malaria (>10,000 parasites/μL) was associated with increased risk for perinatal MTCT (ARR 2.0), compared to low-density malaria. The interaction between placental malaria and MTCT appears to be variable and complex: placental malaria that is controlled at low density may cause an increase in broad-based immune responses that protect against MTCT; uncontrolled, high-density malaria may simultaneously disrupt placental architecture and generate substantial antigen stimulus to HIV replication and increase risk for MTCT