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BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual 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.ResultsForty-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 a non-fixed dose combination with an AQ target dose 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 reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 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%]) (P

Abstract Background Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. Methods An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. Results A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6–77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2–94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. Conclusion AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

During the 1990s, high levels of Plasmodium falciparum (Pf) resistance to common antimalarials were reported from malaria-endemic countries, raising questions about the efficacy of chloroquine (CQ), then the mainstay of [...]

Death rates exceeded emergency thresholds at 4 sites during epidemics of Plasmodium falciparum malaria in Burundi (2000-2001) and in Ethiopia (2003-2004). Deaths likely from malaria ranged from 1,000 to 8,900, [...]

Quantitative data on the onset and evolution of malaria epidemics are scarce. We review case studies from recent African Plasmodium falciparum epidemics (Kisii and Gucha Districts, Kenya, 1999; Kayanza Province, [...]

Abstract Background Following the emergence of the influenza A(H1N1)2009 virus, the French ministry of health decided to offer free vaccination against pandemic influenza to the entire French population. Groups of people were defined and prioritised for vaccination. Methods We took a random sample of the population of mainland France and conducted a retrospective cross-sectional telephone survey to estimate vaccination coverage against seasonal and pandemic influenza and to identify determinants of these vaccinations. Results 10,091 people were included in the survey. Overall seasonal influenza vaccination coverage (IVC) remained stable in the population from the 2008-2009 season to the 2009-2010 season reaching 20.6% and 20.8% respectively. Overall pandemic IVC in the French population is estimated to be 11.1% (CI95%: 9.8 - 12.4). The highest pandemic IVC was observed in the 0-4 years age group. For individuals with health conditions associated with higher risk of influenza, pandemic IVC was estimated to be 12.2% (CI95%: 9.8 - 15.1). The main determinants associated with pandemic influenza vaccine uptake were: living in a household with a child < 5 years ORadj: 2.0 (CI95%: 1.3 - 3.1) or with two children < 5 years or more, ORadj: 2.7 (CI95%: 1.4 - 5.1), living in a household where the head of the family is university graduate (>2 years), ORadj: 2.5 (CI95%: 1.5 - 4.1), or has a higher professional and managerial occupation, ORadj: 3.0 (CI95%: 1.5 - 5.5) and being vaccinated against seasonal influenza, ORadj: 7.1 (CI95%: 5.1 - 10.0). Being an individual with higher risk for influenza was not a determinant for pandemic influenza vaccine uptake. These determinants are not the same as those for seasonal influenza vaccination. Conclusions Overall A(H1N1)2009 influenza vaccine uptake remained low, particularly among individuals with higher risk for influenza and was lower than that observed for seasonal influenza. The reasons behind people's reluctance to be vaccinated need to be investigated further.

Abstract Background Nursing home residents bear a substantial burden of influenza morbidity and mortality. Vaccination of residents and healthcare workers (HCWs) is the main strategy for prevention. Despite recommendations, influenza vaccination coverage among HCWs remains generally low. Methods During the 2007-2008 influenza season, we conducted a nationwide survey to estimate influenza vaccination coverage of HCWs and residents in nursing homes for elderly people in France and to identify determinants of vaccination rates. Multivariate analysis were performed with a negative binomial regression. Results Influenza vaccination coverage rates were 33.6% (95% CI: 31.9-35.4) for HCWs and 91% (95% CI: 90-92) for residents. Influenza vaccination uptake of HCWs varied by occupational category. Higher vaccination coverage was found in private elderly care residences, when free vaccination was offered (RR: 1.89, 1.35-2.64), in small nursing homes (RR: 1.54, 1.31-1.81) and when training sessions and staff meetings on influenza were organized (RR: 1.20, 1.11-1.29). The analysis by occupational category showed that some determinants were shared by all categories of professionals (type of nursing homes, organization of training and staff meetings on influenza). Higher influenza vaccination coverage was found when free vaccination was offered to recreational, cleaning, administrative staff, nurses and nurse assistants, but not for physicians. Conclusions This nationwide study assessed for the first time the rate of influenza vaccination among residents and HCWs in nursing homes for elderly in France. Better communication on the current recommendations regarding influenza vaccination is needed to increase compliance of HCWs. Vaccination programmes should include free vaccination and education campaigns targeting in priority nurses and nurse assistants.

Abstract Background Very few data on anti-malarial efficacy are available from the Democratic Republic of Congo (DRC). DRC changed its anti-malarial treatment policy to amodiaquine (AQ) and artesunate (AS) in 2005. Methods The results of two in vivo efficacy studies, which tested AQ and sulphadoxine-pyrimethamine (SP) monotherapies and AS+SP and AS+AQ combinations in Boende (Equatorial province), and AS+SP, AS+AQ and SP in Kabalo (Katanga province), between 2003 and 2004 are presented. The methodology followed the WHO 2003 protocol for assessing the efficacy of anti-malarials in areas of high transmission. Results Out of 394 included patients in Boende, the failure rates on day 28 after PCR-genotyping adjustment of AS+SP and AS+AQ were estimated as 24.6% [95% CI: 16.6–35.5] and 15.1% [95% CI: 8.6–25.7], respectively. For the monotherapies, failure rates were 35.9% [95% CI: 27.0–46.7] for SP and 18.3% [95% CI: 11.6–28.1] for AQ. Out of 207 patients enrolled in Kabalo, the failure rate on day 28 after PCR-genotyping adjustment was 0 [1-sided 95% CI: 5.8] for AS+SP and AS+AQ [1-sided 95% CI: 6.2]. It was 19.6% [95% CI: 11.4–32.7] for SP monotherapy. Conclusion The finding of varying efficacy of the same combinations at two sites in one country highlights one difficulty of implementing a uniform national treatment policy in a large country. The poor efficacy of AS+AQ in Boende should alert the national programme to foci of resistance and emphasizes the need for systems for the prospective monitoring of treatment efficacy at sentinel sites in the country.

Abstract Background Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. Methods An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. Results A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6–77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2–94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. Conclusion AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

Abstract Background Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. Methods Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/haematocrit relationship at different time points in malaria. Using a linear random effects model, a conversion equation for haematocrit was derived based on 3,254 measurements from various time points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold conversion. Results A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average, haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference (± SD) of -0.69 (± 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients). Conclusion Based on this large data set, an accurate and robust conversion factor both in acute malaria and in convalescence was obtained. The commonly used threefold conversion is also valid.

Abstract Background Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. Methods Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. Results Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518). Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to24.8], (ii) method 2a = 1.1% [0 to21.5], and (iii) method 2b = 0% [-38 to19.3]. The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. Conclusion The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

Abstract Background In 2003, artesunate-amodiaquine (AS+AQ) was introduced as the new first-line treatment for uncomplicated malaria in Burundi. After confirmed diagnosis, treatment was delivered at subsidized prices in public health centres. Nine months after its implementation a study was carried out to assess whether children below five years of age with uncomplicated malaria were actually receiving AS+AQ. Methods A community-based study was conducted in Makamba province. Randomly selected households containing one or more children under five with reported fever onset within fourteen days before the study date were eligible. Case-management information was collected based on caregiver recall. A case definition of symptomatic malaria from observations of children presenting a confirmed malaria episode on the day of the survey was developed. Based on this definition, those children who had probable malaria among those with fever onset in the 14 days prior to the study were identified retrospectively. Treatment coverage with AS+AQ was then estimated among these probable malaria cases. Results Out of 195 children with fever on the day of the study, 92 were confirmed as true malaria cases and 103 tested negative. The combination of 'loss of appetite', 'sweating', 'shivering' and 'intermittent fever' yielded the highest possible positive predictive value, and was chosen as the case definition of malaria. Out of 526 children who had had fever 14 days prior to the survey, 165 (31.4%) were defined as probable malaria cases using this definition. Among them, 20 (14.1%) had been treated with AS+AQ, 10 with quinine (5%), 68 (41%) received non-malaria treatments, and 67 got traditional treatment or nothing (39.9%). Most people sought treatment from public health centres (23/99) followed by private clinics (15/99, 14.1%). The median price paid for AS+AQ was 0.5 US$. Conclusion AS+AQ was the most common treatment for patients with probable malaria at public health centres, but coverage was low due to low health centre utilisation and apparently inappropriate prescribing. In addition, AS+AQ was given to patients at a price ten times higher than the subsidized price. The availability and proper use of ACTs should be monitored and maximized after their introduction in order to have a significant impact on the burden of malaria.

Abstract In two-stage cluster surveys, the traditional method used in second-stage sampling (in which the first household in a cluster is selected) is time-consuming and may result in biased estimates of the indicator of interest. Firstly, a random direction from the center of the cluster is selected, usually by spinning a pen. The houses along that direction are then counted out to the boundary of the cluster, and one is then selected at random to be the first household surveyed. This process favors households towards the center of the cluster, but it could easily be improved. During a recent meningitis vaccination coverage survey in Maradi, Niger, we compared this method of first household selection to two alternatives in urban zones: 1) using a superimposed grid on the map of the cluster area and randomly selecting an intersection; and 2) drawing the perimeter of the cluster area using a Global Positioning System (GPS) and randomly selecting one point within the perimeter. Although we only compared a limited number of clusters using each method, we found the sampling grid method to be the fastest and easiest for field survey teams, although it does require a map of the area. Selecting a random GPS point was also found to be a good method, once adequate training can be provided. Spinning the pen and counting households to the boundary was the most complicated and time-consuming. The two methods tested here represent simpler, quicker and potentially more robust alternatives to spinning the pen for cluster surveys in urban areas. However, in rural areas, these alternatives would favor initial household selection from lower density (or even potentially empty) areas. Bearing in mind these limitations, as well as available resources and feasibility, investigators should choose the most appropriate method for their particular survey context.

Abstract Background Presented here are the results of a comparative trial on the efficacy of three artemisinin-based combinations conducted from May to October 2004, in Pool Province, Republic of Congo. Methods The main outcome was the proportion of cases of true treatment success at day 28. Recrudescences were distinguished from re-infections by PCR analysis. A total of 298 children of 6–59 months were randomized to receive either artesunate + SP (AS+SP), artesunate + amodiaquine (AS+AQ) or artemether + lumefantrine (AL), of which 15 (5%) were lost to follow-up. Results After 28 days, there were 21/85 (25%) recurrent parasitaemias in the AS+SP group, 31/97 (32%) in the AS+AQ group and 13/100 (13%) in the AL group. The 28-day PCR-corrected cure rate was 90.1% [95% CI 80.7–95.9] for AS+SP, 98.5% [95% CI 92.0–100] for AS+AQ and 100% [95.8–100] for AL, thereby revealing a weaker response to AS+SP than to AL (p = 0.003) and to AS+AQ (p = 0.06). A potential bias was the fact that children treated with AL were slightly older and in better clinical condition, but logistic regression did not identify these as relevant factors. There was no significant difference between groups in fever and parasite clearance time, improvement of anaemia and gametocyte carriage at day 28. No serious adverse events were reported. Conclusion Considering the higher efficacy of AL as compared to AS+SP and the relatively high proportion of cases with re-infections in the AS+AQ group, we conclude that AL is clinically more effective than AS+SP and AS+AQ in this area of the Republic of Congo. Implementation of the recently chosen new national first-line AS+AQ should be monitored closely.

Abstract 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.