Showing papers by "Philippe J Guerin published in 2012"

Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review--terra incognita impairing treatment policies.

Abstract: Background An increasing use of point of care diagnostic tests that exclude malaria, coupled with a declining malaria burden in many endemic countries, is highlighting the lack of ability of many health systems to manage other causes of febrile disease. A lack of knowledge of distribution of these pathogens, and a lack of screening and point-of-care diagnostics to identify them, prevents effective management of these generally treatable contributors to disease burden. While prospective data collection is vital, an untapped body of knowledge already exists in the published health literature.

Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems

Abstract: Summary Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and has been detected in western Thailand The situation is ominously reminiscent of the emergence of resistance to chloroquine and to sulfadoxine–pyrimethamine several decades ago Artemisinin resistance is a major threat to global public health, with the most severe potential effects in sub-Saharan Africa, where the disease burden is highest and systems for monitoring and containment of resistance are inadequate The mechanisms that underlie artemisinin resistance are not fully understood The main phenotypic trait associated with resistance is a substantial delay in parasite clearance, so far reported in southeast Asia but not in Africa One of the pillars of the WHO global plan for artemisinin resistance containment is to increase monitoring and surveillance In this Personal View, we propose strategies that should be adopted by malaria-endemic countries in Africa: resource mobilisation to reactivate regional surveillance networks, establishment of baseline parasite clearance profiles to serve as benchmarks to track emerging artemisinin resistance, improved data sharing to allow pooled analyses to identify rare events, modelling of risk factors for drug resistance, and development and validation of new approaches to monitor resistance

Evaluation of a Rapid Test for the Diagnosis of Cholera in the Absence of a Gold Standard

Abstract: Background Early detection and confirmation of cholera outbreaks are crucial for rapid implementation of control measures. Because cholera frequently affects regions with limited laboratory resources, rapid diagnostic tests (RDT) designed for field conditions are important to enhance rapid response. Stool culture remains the “gold standard” for cholera diagnosis; however, its lack of sensitivity may lead to underestimation of test specificity. We evaluated the Crystal VC® immunochromatographic test (Span Diagnostics, India) for cholera diagnosis using a modified reference standard that combines culture-dependent and independent assays, or a Bayesian latent class model (LCM) analysis. Methodology/Principal Findings The study was conducted during a cholera epidemic in 2008, in Lubumbashi, Democratic Republic of Congo. Stools collected from 296 patients were used to perform the RDT on site and sent to Institut Pasteur, Paris, for bacterial culture. In comparison with culture as the gold standard, the RDT showed good sensitivity (92.2%; 95% CI: 86.8%–95.9%) but poor specificity when used by a trained laboratory technician (70.6%; 95% CI: 60.7%–79.2%) or by clinicians with no specific test training (60.4%, 95% CI: 50.2%–70.0%). The specificity of the test performed by the laboratory technician increased to 88.6% (95% CI: 78.7–94.9) when PCR was combined with culture results as the reference standard, and to 85.0% (95% CI: 70.4–99.2), when the Bayesian LCM analysis was used for performance evaluation. In both cases, the sensitivity remained high. Conclusion Using an improved reference standard or appropriate statistical methods for diagnostic test evaluations in the absence of a gold standard, we report better performance of the Crystal VC® RDT than previously published. Our results confirm that this test can be used for early outbreak detection or epidemiological surveillance, key components of efficient global cholera control. Our analysis also highlights the importance of improving evaluations of RDT when no reliable gold standard is available.

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Abstract: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

Efficacy of fixed-dose combination artesunate-amodiaquine versus artemether-lumefantrine for uncomplicated childhood Plasmodium falciparum malaria in Democratic Republic of Congo: a randomized non-inferiority trial

Abstract: In 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga. Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed. Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference −0.7%, one sided 95% CI −3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated. Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces. The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

Performance of a Histidine-Rich Protein 2 Rapid Diagnostic Test, Paracheck Pf®, for Detection of Malaria Infections in Ugandan Pregnant Women

Abstract: Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2–based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0–59.2%) and 99.6% (95% CI = 97.7–100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7–54.9%) and 100% (95% CI = 98.3–100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed.

Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake.

Abstract: We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial

Abstract: Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508

Longitudinal study assessing the return of chloroquine susceptibility of Plasmodiun falciparum isolates from travelers returning from West Africa

Abstract: Background From the 1940s up to the 1990s, chloroquine (CQ) was the main malaria therapy worldwide. Following the CQ resistance burden in Africa, most African countries have discontinued CQ during the past 2 decades, and now promote artemisinin-based combination therapy (ACT), as the first-line treatment for uncomplicated malaria. The policy changed in West Africa during the last decade (2002 in Cameroon; 2003 in Senegal and Cote d’ lv oire; 2004 in Mali). The aim of this study is to describe the evolution of CQ resistance in West Africa, through travellers returning from this region. Methods The study was conducted by the Malaria National Reference Centre, France. The database collated in vitro response of reference and clinical isolates for CQ and the pfcrtK76 molecular marker for CQ susceptible Pf malaria from travellers returning from Cameroon, Senegal, Cote d’lvoire and Mali. As a proxy of drug pressure, CQ intake for children under five years of age with fever was extracted from the Demographic Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) for the study period [1,2]. Logistic regression models were used to detect trends in the susceptible isolates proportions. Results From 2000 to 2011, around 700 isolates were genotyped for each country. The frequency of the pfcrt76 wild-type significantly increased for Cameroon (CM) (from 10% to 41%, Slope=0.09, p<10-3), Cote d’lvoire (CI) (from 37% to 63%, Slope = 0.14, p<10-3), and Senegal (SN) (from 22% to 53%, Slope=0.17, p<10-3). The geometric mean of the 50% growth inhibition (IC50) of CQ decreased from 181 nM (95% confidence interval, 87-374) (25% CQ sensitive) to 51 nM (37-71) (63% CQ sensitive) in CM, from 75nM (43-130) (41% CQ sensitive) to 29nM (22-39) (84% CQ sensitive) in CI and from 86nM (51-145) (41% CQ sensitive) to 39nM (26-60) (75% CQ sensitive) in SN. Analyses performed from 2004 to 2011, when most of West African countries have officially discontinued CQ, confirmed previous results and also show a significant increase of the prevalence of pfcrt76 wild-type genotype for Mali (ML) (Slope = 0.07, p=0.02). Meanwhile, CQ use among children with fever significantly decreased during this period. Conclusions An increase of CQ susceptibility following official withdrawal is observed in travellers returning from Cameroon, Cote d’lvoire, Mali and Senegal. The length of time between policy changes and their subsequent implementation, as well as the cross resistance between antimalarial drugs, may affect the time for a significant recovery of CQ sensitivity. This information should be compared to country level CQ efficacy data.

Childhood imported malaria: could we have suppressed risk factors in some children?

Abstract: Background Malaria infection among child travellers need special attention as it rarely occurs in non endemic countries. Most studies dealt with risks in the paediatric population, but there is a need to justify age class choices and its direct implication of analysis for severity risk factors. In this study we demonstrated that analysing the multi factorial and caregiver dependent feedbacks for children 6months had severity risks of OR 3.4 (95% CI: 1.39-8.30) and being born in endemic countries confirmed a protective factor against severity in all 3 groups analysed. However, evaluation of <12 years old, surfaced the risk of severity associated with declaration of chemoprophylaxis intake with OR 3.08 (95%CI: 1.31-7.24), thus not fulfilling its protective role. Declaration of inappropriate doxycycline use <12 years old was also detected. Being <5 years old and being born in France conferred a protective effect of OR 0.15 (95% CI: 0.02-0.97) were both reassuring and a new contribution in understanding imported childhood malaria. Medical services were promptly used by caregivers in France with diagnostic services and treatment initiated within the same day (mean 0.07 days, 95% CI: 0.05-0.95). Caregivers’ response accuracy of providing date of symptoms onset, were validated through an innovative approach.

Optimal sampling designs for accurate estimation of parasite clearance in the context of artemisinin resistance

Abstract: Background The emergence of artemisinin resistance in South East Asia threatens the efficacy of artemisinin derivatives (AD). Since the pharmacodynamic hallmark of AD is rapid parasite clearance, the clinical phenotype of slow clearance characterises resistance. This indicator remains critically important to monitor the extent of the problem in the absence of molecular marker(s) associated with artemisinin resistance and lack of sensitivity of current in vitro tests. Frequent parasite counts are needed to define clearance rate but it is uncertain what sampling frequency is required to ensure reliable estimates.