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From April 2023 to May 2024, an unusual epidemic of parvovirus B19 (B19V) infections occurred in France. The number of B19V IgM-positive serologies was four times higher than in the previous epidemic in 2019. Clinical data from emergency networks corroborated this observation. Morbidity and mortality consequences were observed in children through all data sources. In adults, the increase was only observed in laboratory-confirmed data. Physicians and decisionmakers should be informed in order to better prevent, diagnose and manage at-risk patients.

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Persons fleeing Ukraine since February 2022 have potentially higher risk of tuberculosis (TB) vs all European Union countries. Interest of active TB screening among this population is debated and not widely adopted. In this screening intervention by a network of TB centres in France, the number needed to screen (NNS) was 862 to find one case. This experience shows that this strategy may be relevant for TB control in situations of massive displacement, similar to that following the Russian invasion.

Background : The number of homeless families has increased considerably since the 1990s in France. We aimed to estimate the homeless children vaccination coverage (VC) for diphtheria, tetanus, polio, measles-mumps-rubella and hepatitis B and identify factors associated with insufficient VC according to birthplace. Methods : A cross-sectional survey was conducted among homeless shelter families in the greater Paris area. A nurse conducted face-to-face interviews and collected vaccination records. We analyzed factors associated with insufficient VC, stratified by birthplace and vaccine, using robust Poisson regression. Results : The study included 214 children born in France and 236 born outside France. VC in French-born homeless children was high (>90% at 24 months for most vaccinations) and similar to levels observed in the general population, whereas VC in those born outside France was low (<50% at 24 months for all vaccines). Factors significantly associated with insufficient VC among children born outside France were age, parents with French-language difficulties, and changing residence at least twice in the previous year. Children in contact with the healthcare system at least once in the previous year had significantly higher VC, irrespective of vaccine and birthplace. Conclusion : Special attention should be paid to homeless children born outside France, with recent European and French recommendations confirming the need for catch-up vaccination in children with undocumented VC.

BackgroundSurveillance of tuberculosis (TB) treatment outcome, for which reporting has been mandatory in France since 2007, is a key component of TB control.AimWe aimed to present surveillance data for non-multidrug-resistant (MDR) cases reported between 2008 and 2014, and identify factors associated with potentially unfavourable treatment outcome.MethodsPatients were classified according to their treatment outcome 12 months after beginning treatment. Poisson regression with a robust error variance was used to investigate factors associated with potentially unfavourable treatment outcome. Missing data were handled using multiple imputation.ResultsA total of 22,526 cases were analysed for treatment outcome. Information available on treatment outcome increased between 2008 (60%) and 2014 (71%) (p < 0.001). During this period, 74.1% of cases completed treatment, increasing from 73.0% in 2008 to 76.9% in 2014 (p < 0.001). This proportion was 74.0% in culture-positive pulmonary cases. Overall, 19.8% of cases had a potentially unfavourable outcome, including lost-to-follow-up, transferred out, still on treatment, death related to TB and interrupted treatment. Potentially unfavourable outcome was significantly associated with TB severity, residing in congregate settings, homelessness, being a smear-positive pulmonary case, being born abroad and residing in France for < 2 years, history of previous anti-TB treatment and age > 85 years.ConclusionMonitoring of treatment outcome is improving over time. The increase in treatment completion over time suggests improved case management. However, treatment outcome monitoring needs to be strengthened in cases belonging to population groups where the percentage of unfavourable outcome is the highest and in cases where surveillance data shows poorer documented follow-up.

Background: Since 2011 public concerns about Human Papillomavirus (HPV) vaccination safety and efficacy arose in France. We explored the relevance of using vaccines reimbursement data to assess the impact of those public concerns on vaccination coverage., Methods: We used the Permanent Sample of Beneficiaries which was, at the time of the study, a representative sample of 1/97(th) health insurance beneficiaries of the main Social Security scheme, the General Health Insurance Scheme, covering approximately 77 % of the French resident population. We estimated HPV vaccination coverage among girls born between 1995 and 1999 at their 15(th), 16(th) and 17(th) birthday., Results: The coverage for complete vaccination among 16 years old girls decreased from 26.5 % in the first semester of 2011 to 18.6 % in the first semester of 2014., Conclusions: HPV vaccination coverage was already low in 2011 and continued to decrease thereafter. Vaccines reimbursement data allowed us to reactively monitor the impact of the controversy on vaccination coverage and design counteracting measures.

Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up., Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive., Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007., Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

Background: Artesunate-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., Methods: 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., Results: 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 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 < 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], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites., Conclusions: 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.

Introduction: In France, young adults are legally freed from parental authority at the age of 18 years and are, thus, responsible for their own vaccine record. This young adult population is more frequently exposed to vaccine-preventable infectious diseases., Objective: To determine the factors associated with students' knowledge of the interval between two antitetanus boosters and their report of having up-to-date vaccinations., Methods: In April 2009, a survey was conducted involving a random sample of students between 18 and 25 years of age eating lunch at university dining facilities in Paris and its suburbs (Ile de France)., Results: Among the 677 students approached, 583 agreed to participate. Only 207 (36%) of respondents knew the recommended dosing interval between two doses of tetanus vaccine booster (10 years). The majority of students (69%) reported having up-to-date vaccinations. Declaring having up-to-date vaccinations was significantly associated with having a general practitioner (OR 3.03 [95% CI 1.69 to 5.55]). Health care students were significantly more likely to know the decennial interval between two antitetanus boosters (OR 2 [95% CI 1.28 to 3.25]). Most of responding students (n=519 [89%]) believed that vaccines were very useful., Conclusions: An overall lack of knowledge of vaccines was observed among this student population. Health care providers, such as GPs and university medical practice staff, who interact with these young individuals have an essential role to promote better vaccination coverage in this population.

After withdrawal of multipuncture BCG device from the French market in January 2006, vaccination coverage (VC) with the intradermal device has dropped and since remained sub-optimal in Ile-de-France, the only region of mainland France where BCG is recommended to all children. We conducted a cross-sectional study to identify socio-economic factors associated with BCG VC in children of Paris metropolitan area born after January 2006. Two-stage random sampling was used to include 425 children up to 5 years old from Paris and its suburbs. Information was collected through face-to-face interviews and vaccination status confirmed by a vaccination document. Poisson regression analyzed the association between VC and potential determinants. VC of children from families with the lowest incomes (first quartile of family income/consumption unit (CU) (<883 €) was close to 100% regardless of family origin. In families with higher incomes (≥ 883 €/CU), VC was significantly higher among children born to families from a tuberculosis highly endemic country (98.2%) compared with other children (76.2%) (p=0.004). Children of low socio-economic background as well as those with a family history of immigration, regardless of family income, are correctly identified as being at high risk of tuberculosis and properly vaccinated with BCG in this area., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Healthcare students should comply with the same vaccination recommendations as employed healthcare professionals. Vaccination coverage data for healthcare students are lacking, Materials and Methods: This cross-sectional survey was carried out on medical, nursing and midwifery students in 15 hospitals of the Assistance Publique - Hôpitaux de Paris with a maternity ward. All midwifery students were surveyed, and a subset of medical and nursing students were selected from 10 hospitals by three-stage random sampling. Data were collected by face-to-face interviews and verified from health records., Results: A total of 432 students were included in the study (178 medical, 147 nursing, 107 midwifery), of whom 376 (87%) had proof of vaccination. The confirmed coverage for compulsory vaccinations was 96.9% for the booster dose of diphtheria-tetanus-poliomyelitis vaccine, 93.6% for BCG and 91.8% for at least three doses of hepatitis B. The coverage for recommended vaccinations confirmed by a vaccine booklet was 44% for pertussis (booster at 11-13 or 16-18 years of age), and 79.3% and 49.6% for the first and second doses of measles, respectively. The rate for influenza vaccination was 39.6%, based on self-reported information. Of the 27 students without any history of varicella infection, six had been vaccinated., Discussion: Vaccination coverage of healthcare students is high for compulsory vaccinations, but largely insufficient for recommended vaccinations. Increased awareness regarding the required vaccinations is necessary in this population, as well as stronger enforcement prior to initiating clinical work., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We conducted a national cross-sectional survey to investigate vaccination coverage (VC) in health care personnel (HCP) working in clinics and hospitals in France. We used a two-stage stratified random sampling design to select 1127 persons from 35 health care settings. Data were collected by face-to-face interviews and completed using information gathered from the occupational health doctor. A total of 183 physicians, 110 nurses, 58 nurse-assistants and 101 midwives were included. VC for compulsory vaccinations was 91.7% for hepatitis B, 95.5% for the booster dose of diphtheria-tetanus-polio (DTP), 94.9% for BCG. For non-compulsory vaccinations, coverage was 11.4% for the 10 year booster of the DTP pertussis containing vaccine, 49.7% for at least one dose of measles, 29.9% for varicella and 25.6% for influenza. Hepatitis B VC did not differ neither between HCP working in surgery and HCP in other sectors, nor in surgeons and anaesthesiologists compared to physicians working in medicine. Young HCP were better vaccinated for pertussis and measles (p<0.01), and those working in an obstetric or a paediatric ward were better vaccinated for influenza and pertussis (p<0.01). HCP are overall well covered by compulsory vaccinations, whereas VC for non-compulsory vaccinations is very insufficient. The vaccination policy regarding these latter vaccinations should be reinforced in France., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We report influenza vaccination coverage in target groups for the 2010-2011 influenza season, one year after the A(H1N1) pandemic. Data were collected through a one-stage cross-sectional national random telephone survey conducted in January 2011 among a sample of the population of mainland France connected to a land telephone line. Influenza vaccination coverage was below 75%, ranging from 28% for health professionals to 71% in the "65+" group with an underlying condition. Coverage was higher in the "65+" compared to the "<65" with an underlying condition. It was not significantly lower compared to the previous season. Our results do not suggest that the controversies related to the pandemic vaccination campaign of 2009-2010 have had a negative impact on subsequent seasonal influenza vaccination coverage., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Knowledge of the age-specific prevalence of seroprotection and incidence of seroconversion infection is necessary to complement clinical surveillance data and statistical models. It provides the basis for estimating the future impact of influenza A (H1N1pdm09) and implementing appropriate prevention and response strategies., Methods: Using a cross-sectional design, two-stage stratified sampling and paired plasma samples, we estimated the age-specific prevalence of a protective level of H1N1pdm09 antibodies in the French adult population before and after the 2009/10 pandemic, and the proportion of those susceptible that seroconverted due to infection, from a single sample of 1,936 blood donors aged 20-70 years in mainland France in June 2010. Samples with a haemagglutination inhibition (HI) titre ≥1∶40 were considered seropositive, and seroconversion due to infection was defined as a 4-fold increase in titre in the absence of H1N1pdm09 vaccination or pre-pandemic seropositivity., Results: Out of the 1,936 donors, 1,708 were included in the analysis. Seroprevalence before the pandemic was 6.7% (95% CI 5.0, 8.9) with no significant differences by age-group (p = 0.3). Seroprevalence afterwards was 23.0% (95% CI 17.7, 29.3) with 20-29 year olds having a higher level than older groups (p<0.001). Seroconversion due to infection was 12.2% (95% CI 6.9, 20.5). Younger age-group, vaccination against H1N1 and being seropositive before the pandemic were strongly associated with post-pandemic seropositivity., Conclusions: Before the 2009/2010 winter influenza season, only 6.7% of the French mainland population aged 20-70 had a level of antibodies usually considered protective. During the first pandemic wave, 12.2% of the population seroconverted due to infection and the seroprevalence after the wave rose to 23%, either due to prepandemic seropositivity, infection or vaccination. This relatively low latter figure contributed to an extension of target groups for influenza vaccination for the 2010/2011 season.

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.

A mass vaccination campaign against influenza A/H1N1 was launched in France in October 2009. Vaccination was offered free of charge to the entire population according to a pre-defined order of priority. Demographic data and data on vaccinations given were recorded in a dedicated database. We analysed vaccine uptake by age, sex and region in the overall population and in certain risk groups, including pregnant women. Overall vaccine uptake was 8% and varied by age-group and sex. Vaccine uptake in pregnant women was 22.7%. These low uptakes may reflect controversies around the vaccine and vaccination policy and have important implications for future pandemic vaccination strategies., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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.

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

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.

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.

Biological samples collected in refugee camps during an outbreak of hepatitis E were used to compare the accuracy of hepatitis E virus RNA amplification by real-time reverse transcription-PCR (RT-PCR) for sera and dried blood spots (concordance of 90.6%). Biological profiles (RT-PCR and serology) of asymptomatic individuals were also analyzed.

Background: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution., Methods and Findings: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations., Conclusions: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

In the 1990s and in the absence of data, Médecins sans frontiers (MSF) initiated a series of in vivo clinical studies to measure antimalarial efficacy and optimise treatment strategies within its missions. Between 1996 and 2004, more than 12,000 patients were enrolled in 43 studies in 18 countries of Asia and Africa. These studies were conducted in insecure and difficult-to-access sites, usually conflict-affected countries of sub-Saharan Africa. The data were used by MSF to improve treatments within its missions. In several countries they were considered by health authorities for adapting treatment guidelines at a country level. They had an effect on international policy. The high number of publications in peer-reviewed journals shows that research of high quality can be performed despite the important logistical difficulties encountered in the field. These studies are essential to adapt treatments for MSF programs. They need to be rigorous enough to be scientifically valid but also have to be adapted to specific field conditions. Although this work demonstrates the potential role of medical NGOs (non governmental organisations) such as MSF in collecting scientific data, national malaria programs, WHO and other international disease control partnerships hold the primary responsibility in initiating such studies.

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 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].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.

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.

A study to assess the diagnostic capabilities of three parasite lactate dehydrogenase (pan-pLDH) tests, Vistapan), Carestart and Parabank), was conducted in Uganda. An HRP2 test, Paracheck-Pf), and a Giemsa-stained blood film were performed with the pLDH tests for outpatients with suspected malaria. In total, 460 subjects were recruited: 248 with positive blood films and 212 with negative blood films. Plasmodium falciparum was present in 95% of infections. Sensitivity above 90% was shown by two pLDH tests, Carestart (95.6%) and Vistapan (91.9%), and specificity above 90% by Parabank (94.3%) and Carestart (91.5%). Sensitivity decreased with low parasitaemia (chi(2) trend, P<0.001); however, all tests achieved sensitivity >90% with parasitaemia > or =100/microl. All tests had good inter-reader reliability (kappa>0.95). Two weeks after diagnosis, 4-10% of pLDH tests were still positive compared with 69.7% of the HRP2 tests. All tests had similar ease of use. In conclusion, two pLDH tests performed well in diagnosing P. falciparum malaria, and all pLDH tests became negative after treatment more quickly than the HRP2. Therefore the rapid test of choice for use with artemisinin-combination therapies in this area would be one of these new pLDH tests.

Objective: Parasites may recur asymptomatically after initial clearance by antimalarial treatment. Current guidelines recommend treatment only when patients develop symptoms or at the end of follow-up. We wanted to assess prospectively the probability of becoming symptomatic and the risks of this practice., Methods: We analysed data collected in 13 trials of uncomplicated paediatric malaria conducted in eight sub-Saharan African countries. These studies followed all cases of post-treatment asymptomatic parasitaemia until they developed symptoms or to the end of the 28-day follow-up period, at which time parasite genotypes were compared to pre-treatment isolates to distinguish between recrudescences and new infections., Results: There were 425 asymptomatic recurrences after 2576 treatments with either chloroquine, sulfadoxine/pyrimethamine or amodiaquine, of which 225 occurred by day 14 and 200 between day 15 and day 28. By day 28, 42% developed fever (median time to fever = 5 days) and 30% remained parasitaemic but afebrile, while 23% cleared their parasites (outcome unknown in 4%). Young age, parasitaemia >/=500 parasites/microl; onset of parasitaemia after day 14, and treatment with amodiaquine were the main variables associated with higher risk of developing fever., Conclusion: In areas of moderate to intense transmission, asymptomatic recurrences of malaria after treatment carry a substantial risk of becoming ill within a few days and should be treated as discovered. Young children are at higher risk. The higher risk carried by cases occurring in the second half of follow-up may be explained by falling residual drug levels.

Objective: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar., Methods: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains., Results: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance., Conclusions: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.

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.

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.

Background: In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT), many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS)/sulphadoxine-pyrimethamine (SP) had been used in refugee camps for two years., Methods: In Dabola (central Guinea), 220 children aged 6-59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ) or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea), where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 436, 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively., Results: In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR)-adjusted failure rates were 1.0% (95%CI 0-5.3) for AS/AQ and 1.0% (95%CI 0-5.5) for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2-90.7) patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2-15.9)., Conclusion: Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of implementing ACTs, but cannot predict how long their therapeutic life will be, especially in countries which have chosen drugs also available as monotherapies.

Background: Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites that caused the primary infection., Methods: Paired samples were collected before initiation of antimalarial treatment and at recurrence of parasitemia from 149 patients with vivax malaria in Thailand (n=36), where reinfection could be excluded, and during field studies in Myanmar (n=75) and India (n=38)., Results: Combined genetic data from 2 genotyping approaches showed that novel P. vivax populations were present in the majority of patients with recurrent infection (107 [72%] of 149 patients overall [78% of patients in Thailand, 75% of patients in Myanmar {Burma}, and 63% of patients in India]). In 61% of the Thai and Burmese patients and in 55% of the Indian patients, the recurrent infections contained none of the parasite genotypes that caused the acute infection., Conclusions: The P. vivax populations emerging from hypnozoites commonly differ from the populations that caused the acute episode. Activation of heterologous hypnozoite populations is the most common cause of first relapse in patients with vivax malaria.

Polymerase chain reaction (PCR) genotyping of malaria parasites in drug efficacy trials helps differentiate reinfections from recrudescences. A combination therapy trial of one (n = 115) or three (n = 117) days artesunate (1AS, 3AS 4 mg/kg/day) plus sulphadoxine-pyrimethamine (SP) vs. SP alone (n = 153) was conducted in Mbarara, a mesoendemic area of western Uganda. All paired recurrent Plasmodium falciparum parasitaemias on days 7, 14, 21 and 28 post-treatment were genotyped by PCR amplification and analysis of glutamate-rich protein (glurp) and merozoite surface proteins (msp) 1 and 2 genes to distinguish recrudescent from new infections. A total of 156 (1AS = 61, 3AS = 35, SP alone = 60) of 199 paired recurrent samples were successfully analysed and were resolved as 79 recrudescences (1AS = 32, 3AS = 8, SP = 39) and 77 as new infections (1AS = 29, 3AS = 27, SP = 21). The ratios of proportions of new to recrudescent infections were 0.2, 0.9, 1.4 and 1.9 on days 7, 14, 21 and 28, respectively (P < 0.001, chi(2) test for linear trend). Unexpected high new infection rates were observed early in follow-up on days 7 [5/26 (19.2%)] and 14 [24/51 (47.1%)]. These results impact significantly on resistance monitoring and point to the value of genotyping all recurrent infections in antimalarial trials.

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, depending on site, and accounted for 52% to 78% of total deaths. Earlier detection of malaria and better case management are needed.

The diagnostic capacity of three malaria rapid diagnostic tests (RDTs), NOW-Malaria-ICT, OptiMAL-IT, and Paracheck-Pf, was evaluated against expert microscopy in Colombia. We tested 896 patients, of whom microscopy confirmed 139 P. falciparum, 279 P. vivax, and 13 mixed P.f/P.v infections and 465 negatives. Paracheck-Pf and NOW-malaria-ICT were more accurate in detecting P. falciparum (sensitivities 90.8% and 90.1%, respectively) in comparison with Optimal-IT (83.6%). NOW showed an acceptable Pf detection rate at low densities (< 500/microL), but resulted in a higher proportion of false positives. For P. vivax diagnosis, Optimal-IT had a higher sensitivity than NOW (91.0% and 81.4%, respectively). The choice between the two Pf/Pv detecting RDTs balances P. falciparum and P. vivax detection rates. Considering some degree of P. falciparum overtreatment and failure to detect all P. vivax cases as more acceptable than missing some cases of P. falciparum, we recommend careful implementation of NOW-malaria-ICT in areas where microscopy is lacking. The price is however still a constraint.

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.

The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).

We report the results of an in vivo antimalarial efficacy study with chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) conducted between 2003 and 2004 in Koumantou, southern Mali. A total of 244 children were included in the study; 210 children were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescence from re-infection. Global failure proportions at Day 14, without taking into account re-infections, were 44.2% (95% CI 34.9-53.5%) in the CQ group and 2.0% (95% CI 0.0-4.8%) in the SP group. PCR-adjusted failure proportions at Day 28 were even higher in the CQ group (90.5% (95/105), 95% CI 84.8-96.2%) and relatively low in the SP group (7.0% (7/100), 95% CI 1.9-12.1%). These results show that CQ is no longer efficacious in Koumantou. The use of SP in monotherapy is likely to compromise its efficacy. We recommend the use of artemisinin-based combination therapy as first-line treatment for uncomplicated Plasmodium falciparum malaria in Koumantou.

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, Burundi, 2000-2001; Aweil East, southern Sudan, 2003; Gutten and Damot Gale, Ethiopia, 2003-2004). We highlight possible epidemic risk factors and review delays in epidemic detection and response (up to 20 weeks), essentially due to poor case reporting and analysis or low use of public facilities. Epidemics lasted 15-36 weeks, and patients' age profiles suggested departures from classical notions of epidemic malaria everywhere but Burundi. Although emergency interventions were mounted to expand inpatient and outpatient treatment access, we believe their effects were lessened because of delays, insufficient evaluation of disease burden, lack of evidence on how to increase treatment coverage in emergencies, and use of ineffective drugs.

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.

Objective: In 2004, Sierra Leone adopted artesunate plus amodiaquine as first-line antimalarial treatment. We evaluated the efficacy of this combination in Kailahun, where a previous study had shown 70.2% efficacy of amodiaquine in monotherapy., Methods: Method and outcome classification of the study complied with WHO guidelines. Children 6-59 months with uncomplicated malaria were followed-up for 28 days. PCR genotyping was used to distinguish recrudescence from reinfection. Reinfections were reclassified as cured., Results: Of 172 children who were referred to the study clinic, 126 satisfied inclusion criteria and were enrolled. No early treatment failures were reported. The day 14, efficacy was 98.2% (95% CI: 93.8-99.8). Of 65 recurrent parasitaemias analysed by PCR, 17 were recrudescences. The PCR-adjusted day 28 efficacy was 84.5% (95% CI: 76.4-90.7). All true failures occurred in the last 8 days of follow-up. Of 110 children who completed the 28-day follow-up, 54 (49.1%) experienced a novel infection., Conclusion: The efficacy of this combination was disappointing. The high reinfection rate suggested little prophylactic effect. In Kailahun a more efficacious combination might be necessary in the future. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone.

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.

In April 2004, 137 children 6-59 months of age with uncomplicated Plasmodium falciparum (Pf) malaria (Caala, Central Angola) were randomized to receive either artemether-lumefantrine (Coartem) or artesunate + amodiaquine (ASAQ). After 28 days of follow-up, there were 2/61 (3.2%) recurrent parasitemias in the Coartem group and 4/64 (6.2%) in the ASAQ group (P = 0.72), all classified as re-infections after PCR genotyping (cure rate = 100% [95%CI: 94-100] in both groups). Only one patient (ASAQ group) had gametocytes on day 28 versus five (Coartem) and three (ASAQ) at baseline. Compared with baseline, anemia was significantly improved after 28 days of follow-up in both groups (Coartem: from 54.1% to 13.4%; ASAQ: from 53.1% to 15.9%). Our findings are in favor of a high efficacy of both combinations in Caala. Now that Coartem has been chosen as the new first-line anti-malarial, the challenge is to insure that this drug is available and adequately used.

Background: Hepatitis E virus (HEV) causes acute onset of jaundice and a high case-fatality ratio in pregnant women. We provide a clinical description of hospitalized case patients and assess the specific impact on pregnant women during a large epidemic of HEV infection in a displaced population in Mornay camp (78,800 inhabitants), western Darfur, Sudan., Methods: We reviewed hospital records. A sample of 20 clinical cases underwent laboratory confirmation. These patients were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody to HEV (serum) and for amplification of the HEV genome (serum and stool). We performed a cross-sectional survey in the community to determine the attack rate and case-fatality ratio in pregnant women., Results: Over 6 months, 253 HEV cases were recorded at the hospital, of which 61 (24.1%) were in pregnant women. A total of 72 cases (39.1% of those for whom clinical records were available) had a diagnosis of hepatic encephalopathy. Of the 45 who died (case-fatality ratio, 17.8%), 19 were pregnant women (specific case-fatality ratio, 31.1%). Acute hepatitis E was confirmed in 95% (19/20) of cases sampled; 18 case-patients were positive for IgG (optical density ratio > or =3), for IgM (optical density ratio >2 ), or for both, whereas 1 was negative for IgG and IgM but positive for HEV RNA in serum. The survey identified 220 jaundiced women among the 1133 pregnant women recorded over 3 months (attack rate, 19.4%). A total of 18 deaths were recorded among these jaundiced pregnant women (specific case-fatality ratio, 8.2%)., Conclusions: This large epidemic of HEV infection illustrates the dramatic impact of this disease on pregnant women. Timely interventions and a vaccine are urgently needed to prevent mortality in this special group.

Background: The conflict in Darfur, Sudan, was responsible for the displacement of 1.8 million civilians. We investigated a large outbreak of hepatitis E virus (HEV) infection in Mornay camp (78,800 inhabitants) in western Darfur., Methods: To describe the outbreak, we used clinical and demographic information from cases recorded at the camp between 26 July and 31 December 2004. We conducted a case-cohort study and a retrospective cohort study to identify risk factors for clinical and asymptomatic hepatitis E, respectively. We collected stool and serum samples from animals and performed a bacteriological analysis of water samples. Human samples were tested for immunoglobulin G and immunoglobulin M antibody to HEV (for serum samples) and for amplification of the HEV genome (for serum and stool samples)., Results: In 6 months, 2621 hepatitis E cases were recorded (attack rate, 3.3%), with a case-fatality rate of 1.7% (45 deaths, 19 of which involved were pregnant women). Risk factors for clinical HEV infection included age of 15-45 years (odds ratio, 2.13; 95% confidence interval, 1.02-4.46) and drinking chlorinated surface water (odds ratio, 2.49; 95% confidence interval, 1.22-5.08). Both factors were also suggestive of increased risk for asymptomatic HEV infection, although this was not found to be statistically significant. HEV RNA was positively identified in serum samples obtained from 2 donkeys. No bacteria were identified from any sample of chlorinated water tested., Conclusions: Current recommendations to ensure a safe water supply may have been insufficient to inactivate HEV and control this epidemic. This research highlights the need to evaluate current water treatment methods and to identify alternative solutions adapted to complex emergencies.

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.

Objective: To compare the cost-effectiveness of malaria treatment based on presumptive diagnosis with that of malaria treatment based on rapid diagnostic tests (RDTs)., Methods: We calculated direct costs (based on experience from Ethiopia and southern Sudan) and effectiveness (in terms of reduced over-treatment) of a free, decentralised treatment programme using artesunate plus amodiaquine (AS + AQ) or artemether-lumefantrine (ART-LUM) in a Plasmodium falciparum epidemic. Our main cost-effectiveness measure was the incremental cost per false positive treatment averted by RDTs., Results: As malaria prevalence increases, the difference in cost between presumptive and RDT-based treatment rises. The threshold prevalence above which the RDT-based strategy becomes more expensive is 21% in the AS + AQ scenario and 55% in the ART-LUM scenario, but these thresholds increase to 58 and 70%, respectively, if the financing body tolerates an incremental cost of 1 euro per false positive averted. However, even at a high (90%) prevalence of malaria consistent with an epidemic peak, an RDT-based strategy would only cost moderately more than the presumptive strategy: +29.9% in the AS + AQ scenario and +19.4% in the ART-LUM scenario. The treatment comparison is insensitive to the age and pregnancy distribution of febrile cases, but is strongly affected by variation in non-biomedical costs. If their unit price were halved, RDTs would be more cost-effective at a malaria prevalence up to 45% in case of AS + AQ treatment and at a prevalence up to 68% in case of ART-LUM treatment., Conclusion: In most epidemic prevalence scenarios, RDTs would considerably reduce over-treatment for only a moderate increase in costs over presumptive diagnosis. A substantial decrease in RDT unit price would greatly increase their cost-effectiveness, and should thus be advocated. A tolerated incremental cost of 1 euro is probably justified given overall public health and financial benefits. The RDTs should be considered for malaria epidemics if logistics and human resources allow.