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1.  Assessing Antimalarial Efficacy in a Time of Change to Artemisinin-Based Combination Therapies: The Role of Médecins Sans Frontières 
PLoS Medicine  2008;5(8):e169.
Jean-Paul Guthmann and colleagues describe the output of MSF's work in antimalarial efficacy assessment during the last decade.
doi:10.1371/journal.pmed.0050169
PMCID: PMC2494566  PMID: 18684011
2.  Death Rates from Malaria Epidemics, Burundi and Ethiopia 
Emerging Infectious Diseases  2007;13(1):140-143.
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.
doi:10.3201/eid1301.060546
PMCID: PMC2725810  PMID: 17370530
Malaria; Plasmodium falciparum; epidemic; mortality; Burundi; Ethiopia; dispatch
3.  Efficacy of three artemisinin combination therapies for the treatmentof uncomplicated Plasmodium falciparum malaria in the Republic of Congo 
Malaria Journal  2006;5:113.
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.
doi:10.1186/1475-2875-5-113
PMCID: PMC1697822  PMID: 17125496
4.  Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda 
Malaria Journal  2006;5:59.
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.
doi:10.1186/1475-2875-5-59
PMCID: PMC1543643  PMID: 16854236
5.  Vaccine knowledge in students in Paris, France, and surrounding regions 
For young adults living in France, the transition to becoming responsible for their own vaccination records at 18 years of age may result in missed opportunities for vaccination due to a lack of knowledge among this population. Accordingly, the authors of this study aimed to assess vaccine-related knowledge among individuals between 18 and 25 years of age by conducting a survey that was completed by 583 students.
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.
PMCID: PMC4173975  PMID: 25285109
General practitioner; Students; Tetanus; Vaccine knowledge; Young adults
6.  Incidence of H1N1 2009 Virus Infection through the Analysis of Paired Plasma Specimens among Blood Donors, France 
PLoS ONE  2012;7(3):e33056.
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.
doi:10.1371/journal.pone.0033056
PMCID: PMC3310844  PMID: 22457734
7.  Susceptibility of Health Care Students to Measles, Paris, France 
Emerging Infectious Diseases  2011;17(9):1766-1767.
doi:10.3201/eid1709.110141
PMCID: PMC3322083  PMID: 21888820
health care students; measles; virus; vaccination; Paris; France; letter
8.  Influenza vaccination coverage against seasonal and pandemic influenza and their determinants in France: a cross-sectional survey 
BMC Public Health  2011;11:30.
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.
doi:10.1186/1471-2458-11-30
PMCID: PMC3025842  PMID: 21226919
9.  Influenza vaccination coverage of healthcare workers and residents and their determinants in nursing homes for elderly people in France: a cross-sectional survey 
BMC Public Health  2010;10:159.
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.
doi:10.1186/1471-2458-10-159
PMCID: PMC2850345  PMID: 20338028
10.  Outbreak of Hepatitis E Virus Infection in Darfur, Sudan: Effectiveness of Real-Time Reverse Transcription-PCR Analysis of Dried Blood Spots ▿  
Journal of Clinical Microbiology  2009;47(6):1931-1933.
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.
doi:10.1128/JCM.02245-08
PMCID: PMC2691126  PMID: 19339474
11.  Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis 
Malaria Journal  2009;8:203.
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.
doi:10.1186/1475-2875-8-203
PMCID: PMC2745424  PMID: 19698172
12.  Varying efficacy of artesunate+amodiaquine and artesunate+sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in the Democratic Republic of Congo: a report of two in-vivo studies 
Malaria Journal  2009;8:192.
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.
doi:10.1186/1475-2875-8-192
PMCID: PMC2734861  PMID: 19664280
13.  Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria 
PLoS Medicine  2009;6(4):e1000055.
Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa.
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.
Editors' Summary
Background
Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year, mostly in sub-Saharan Africa. People become infected with P. falciparum when they are bitten by a mosquito that has acquired the parasite in a blood meal taken from an infected person. P. falciparum malaria, which is characterized by recurring fevers and chills, anemia (loss of red blood cells), and damage to vital organs, can be fatal within hours of symptom onset if untreated. Until recently, treatment in Africa relied on chloroquine and sulfadoxine–pyrimethamine. Unfortunately, parasites resistant to both these antimalarial drugs is now widespread. Consequently, the World Health Organization currently recommends artemisinin combination therapy for the treatment of P. falciparum malaria in Africa and other places where drug-resistant malaria is common. In this therapy, artemisinin derivatives (new fast-acting antimalarial agents) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug.
Why Was This Study Done?
P. falciparum becomes resistant to antimalarial drugs by acquiring “resistance mutations,” genetic changes that prevent these drugs from killing the parasite. A mutation in the gene encoding a protein called the chloroquine resistance transporter causes resistance to chloroquine, a specific group of mutations in the dihydrofolate reductase gene causes resistance to pyrimethamine, and several mutations in dhps, the gene that encodes dihydropteroate synthase, are associated with resistance to sulfadoxine. Scientists have discovered that the mutations causing chloroquine and pyrimethamine resistance originated in Asia and spread into Africa (probably multiple times) in the late 1970s and mid-1980s, respectively. These Asian-derived mutations are now common throughout Africa and, consequently, it is not possible to determine how they spread across the continent. Information of this sort would, however, help experts design effective measures to control the spread of drug-resistant P. falciparum. Because the mutations in dhps that cause sulfadoxine resistance only began to emerge in the mid-1990s, they haven't spread evenly across Africa yet. In this study, therefore, the researchers use genetic methods to characterize the geographical origins and contemporary distribution of dhps resistance mutations in Africa.
What Did the Researchers Do and Find?
The researchers analyzed dhps mutations in P. falciparum DNA from blood samples collected from patients with malaria in various African countries and searched the scientific literature for other similar studies. Together, these data show that five major variant dhps sequences (three of which contain mutations that confer various degrees of resistance to sulphadoxine in laboratory tests) are currently present in Africa, each with a unique geographical distribution. In particular, the data show that P. falciparum parasites in east and west Africa carry different resistance mutations. Next, the researchers looked for microsatellite variants in the DNA flanking the dhps gene. Microsatellites are DNA regions that contain short, repeated sequences of nucleotides. Because the number of repeats can vary and because microsatellites are inherited together with nearby genes, the ancestry of various resistance mutations can be worked out by examining the microsatellites flanking different mutant dhps genes. This analysis revealed five regional clusters in which the same resistance lineage was present at all the sites examined within the region and also showed that the resistance mutations in east and west Africa have a different ancestry.
What Do These Findings Mean?
These findings show that sulfadoxine-resistant P. falciparum has recently emerged independently at multiple sites in Africa and that the molecular basis for sulfadoxine resistance is different in east and west Africa. This latter result may have clinical implications because it suggests that the effectiveness of sulfadoxine as an antimalarial drug may vary across the continent. Finally, although many more samples need to be analyzed to build a complete picture of the spread of antimalarial resistance across Africa, these findings suggest that economic and transport infrastructures may have played a role in governing recent parasite dispersal across this continent by affecting human migration. Thus, coordinated malaria control campaigns across socioeconomically linked areas in Africa may reduce the African malaria burden more effectively than campaigns that are confined to national territories.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000055.
This study is further discussed in a PLoS Medicine Perspective by Tim Anderson
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in several languages) and on drug-resistant malaria
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria, and on malaria control efforts in specific parts of the world
The WorldWide Antimalarial Resistance Network is creating an international database about antimalarial drug resistance
doi:10.1371/journal.pmed.1000055
PMCID: PMC2661256  PMID: 19365539
14.  Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children 
Malaria Journal  2008;7:154.
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.
doi:10.1186/1475-2875-7-154
PMCID: PMC2527011  PMID: 18691429
15.  The relationship between the haemoglobin concentration and the haematocrit in Plasmodium falciparum malaria 
Malaria Journal  2008;7:149.
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.
doi:10.1186/1475-2875-7-149
PMCID: PMC2515851  PMID: 18673575
16.  Community coverage of an antimalarial combination of artesunate and amodiaquine in Makamba Province, Burundi, nine months after its introduction 
Malaria Journal  2007;6:94.
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.
doi:10.1186/1475-2875-6-94
PMCID: PMC1948001  PMID: 17640357
17.  Don't spin the pen: two alternative methods for second-stage sampling in urban cluster surveys 
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.
doi:10.1186/1742-7622-4-8
PMCID: PMC1894792  PMID: 17543102
18.  Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré 
Malaria Journal  2007;6:54.
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.
doi:10.1186/1475-2875-6-54
PMCID: PMC1868032  PMID: 17477865
19.  Methodological Issues in the Assessment of Antimalarial Drug Treatment: Analysis of 13 Studies in Eight African Countries from 2001 to 2004▿  
Antimicrobial Agents and Chemotherapy  2006;50(11):3734-3739.
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).
doi:10.1128/AAC.01618-05
PMCID: PMC1635238  PMID: 16954313
20.  Malaria Epidemics and Interventions, Kenya, Burundi, Southern Sudan, and Ethiopia, 1999–2004 
Emerging Infectious Diseases  2006;12(10):1477-1485.
Effectiveness was reduced by delays and other factors.
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.
doi:10.3201/eid1210.060540
PMCID: PMC3290957  PMID: 17176560
Malaria; Plasmodium falciparum; epidemic; intervention; Kenya; Burundi; Sudan; Ethiopia; perspective
21.  Selection strength and hitchhiking around two anti-malarial resistance genes 
Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2–4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34–64 kb (2–4 cM) in Laos on chromosome 4, compared with 98–137 kb (6–8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34–69 kb (2–4 cM) around pfcrt in Laos, but for 195–268 kb (11–16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.
doi:10.1098/rspb.2004.3026
PMCID: PMC1559806  PMID: 16024377
hitchhiking; selection; drug resistance; Plasmodium falciparum; chloroquine; pyrimethamine
22.  In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up 
Antimicrobial Agents and Chemotherapy  2004;48(11):4271-4280.
To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r2 = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
doi:10.1128/AAC.48.11.4271-4280.2004
PMCID: PMC525402  PMID: 15504852

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