[Show abstract][Hide abstract] ABSTRACT: Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).
Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in
included studies was evaluated based on study design, methodology and missing data.
Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 %
(95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting
(AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).
Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.
BMC Medicine 09/2015; 13:212. · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholera is caused by Vibrio cholerae, and is transmitted through fecal-oral contact. Infection occurs after the ingestion of the bacteria and is usually asymptomatic. In a minority of cases, it causes acute diarrhea and vomiting, which can lead to potentially fatal severe dehydration, especially in the absence of appropriate medical care. Immunity occurs after infection and typically lasts 6-36 months.
[Show abstract][Hide abstract] ABSTRACT: Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded. Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking. The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.
In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded. Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program. Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.
This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.
[Show abstract][Hide abstract] ABSTRACT: Background:
Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination
therapies (ACTs) to t
malaria in Africa. We investigated the impact of
different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.
Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance
Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression
model with shared frailty across study sites.
Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%)
treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with
e of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a
non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%)
with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median
dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated
with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25
(median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg
[IQR: 27-39.0]. After adjusting for rei
nfections, the corrected antimalarial efficacy on day 28 after treatment
was similar for co-blistered NFDC (97.9% [95% confiden
ce interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI:
= 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30
(95.0% [95% CI: 94.1%-95.9%]) (
< 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and
region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted
hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12],
< 0.001) compared to FDC, and treatment with loose NFDC-30 was
associated with a higher risk of recrudescence at only three sites.
There was substantial variation in the total dose of amodiaquine administered in different AS-AQ
combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial
treatment efficacy than the loose individual tablets in all age categories.
[Show abstract][Hide abstract] ABSTRACT: In 2010 and 2011, Haiti was heavily affected by a large cholera outbreak that spread throughout the country. Although national health structure-based cholera surveillance was rapidly initiated, a substantial number of community cases might have been missed, particularly in remote areas. We conducted a community-based survey in a large rural, mountainous area across four districts of the Nord department including areas with good versus poor accessibility by road, and rapid versus delayed response to the outbreak to document the true cholera burden and assess geographic distribution and risk factors for cholera mortality.
A two-stage, household-based cluster survey was conducted in 138 clusters of 23 households in four districts of the Nord Department from April 22nd to May 13th 2011. A total of 3,187 households and 16,900 individuals were included in the survey, of whom 2,034 (12.0%) reported at least one episode of watery diarrhea since the beginning of the outbreak. The two more remote districts, Borgne and Pilate were most affected with attack rates up to 16.2%, and case fatality rates up to 15.2% as compared to the two more accessible districts. Care seeking was also less frequent in the more remote areas with as low as 61.6% of reported patients seeking care. Living in remote areas was found as a risk factor for mortality together with older age, greater severity of illness and not seeking care.
These results highlight important geographical disparities and demonstrate that the epidemic caused the highest burden both in terms of cases and deaths in the most remote areas, where up to 5% of the population may have died during the first months of the epidemic. Adapted strategies are needed to rapidly provide treatment as well as prevention measures in remote communities.
[Show abstract][Hide abstract] ABSTRACT: SUMMARY Two community-based density case-control studies were performed to assess risk factors for cholera transmission during inter-peak periods of the ongoing epidemic in two Haitian urban settings, Gonaives and Carrefour. The strongest associations were: close contact with cholera patients (sharing latrines, visiting cholera patients, helping someone with diarrhoea), eating food from street vendors and washing dishes with untreated water. Protective factors were: drinking chlorinated water, receiving prevention messages via television, church or training sessions, and high household socioeconomic level. These findings suggest that, in addition to contaminated water, factors related to direct and indirect inter-human contact play an important role in cholera transmission during inter-peak periods. In order to reduce cholera transmission in Haiti intensive preventive measures such as hygiene promotion and awareness campaigns should be implemented during inter-peak lulls, when prevention activities are typically scaled back.
Epidemiology and Infection 10/2013; 142(8):1-11. DOI:10.1017/S0950268813002562 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malaria is a major public health problem, especially for children. However, recent reports suggest a decline in the malaria burden. The aim of this study was to assess the change in the prevalence of malaria infection among children below five years of age between 2004 and 2010 in a mesoendemic area of Uganda and to analyse the risk factors of malaria infection.
Two cross-sectional surveys were conducted in 2004 and in 2010 at the end of the rainy and dry seasons to measure the prevalence of P. falciparum infection among children less than five years of age. Rapid diagnostic tests and blood smears were used to diagnose malaria infection. In 2010, sampling was stratified by urban and rural areas. In each selected household, knowledge of malaria and bed nets, and bed net ownership and use, were assessed.
In 2004 and 2010, respectively, a total of 527 and 2,320 (999 in the urban area and 1,321 in rural areas) children less than five years old were enrolled. Prevalence of malaria infection declined from 43% (95% CI: 34-52) in 2004, to 23% (95% CI: 17-30) in rural areas in 2010 and 3% (95% CI: 2-5) in the urban area in 2010. From the rainy to dry season in 2010, prevalence decreased from 23% to 10% (95% CI: 6-14) in rural areas (P = 0.001) and remained stable from 3% to 4% (95% CI: 1-7) in the urban area (P = 0.9). The proportion of households reporting ownership and use of at least one bed net increased from 22.9% in 2004 to 64.7% in the urban area and 44.5% in rural areas in 2010 (P < 0.001). In 2010, the risk of malaria infection was consistently associated with child age and household wealth. In rural areas, malaria infection was also associated with geographic factors.
This study reports a significant drop in the prevalence of malaria infection among children below five years of age, paralleled by an uptake in bed-net use. However, prevalence remains unacceptably high in rural areas and is strongly associated with poverty.