Jean-François Faucher

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 – 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36–17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Comparison of Sulfadoxine‐Pyrimethamine, Unsupervised Artemether‐Lumefantrine, and Unsupervised Artesunate‐Amodiaquine Fixed‐Dose Formulation for Uncomplicated Plasmodium falciparum Malaria in Benin: A Randomized Effectiveness Noninferiority Trial

BACKGROUND We compared sulfadoxine-pyrimethamine (SP) with unsupervised artemether-lumefantrine (AL) and unsupervised amodiaquine-artesunate (ASAQ) fixed-dose formulation for the treatment of uncomplicated malaria in children in Benin. METHODS This open-label, noninferiority comparative trial included children aged 6-60 months. The follow-up period was 6 weeks, and the primary objective was a comparison of polymerase chain reaction (PCR)-adjusted effectiveness rates at day 28. RESULTS The study included 240 children (48 received SP, and 96 each received AL and ASAQ). The intention-to-treat analysis showed effectiveness rates on day 28 of 20.8%, 78.1%, and 70.5% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 27.1%, 83.3%, and 87.4%, respectively. The per-protocol analysis (217 patients) showed effectiveness rates on day 28 of 21.7%, 88.0%, and 76.1% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 28.3%, 94.0%, and 93.2%, respectively. SP was less effective than the other drugs in the PCR-adjusted analysis, whereas AL and ASAQ were equally effective. The rate of new infection was higher among children treated with ASAQ than among those treated with AL. CONCLUSIONS This was the first trial, to our knowledge, to compare unsupervised AL with unsupervised ASAQ fixed-dose formulation; both treatments provided high PCR-adjusted day 28 effectiveness rates. Efficacy rates for SP were surprisingly low. Clinical trials registration. NCT00460369.

PfHRP2 and PfLDH antigen detection for monitoring the efficacy of artemisinin-based combination therapy (ACT) in the treatment of uncomplicated falciparum malaria

BackgroundAn assessment of the accuracy of two malaria rapid diagnostic tests (RDT) for the detection of Plasmodium falciparum histidine-rich protein 2 (Pf HRP2) or Pf lactate dehydrogenase (Pf LDH) was undertaken in children aged between six and 59 months included in an anti-malarial efficacy study in Benin.MethodsIn Allada (Benin), 205 children aged 6-59 months with falciparum malaria received either artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL), or sulphadoxine-pyrimethamine (SP). Children included in the study were simultaneously followed by both RDT and high-quality microscopy for up to 42 days.ResultsAt the time of inclusion, Pf HRP2-based tests were positive in 203 children (99%) and Pf LDH-based tests were positive in 204 (99.5%). During follow-up, independent of the treatment received, only 17.3% (28/162) of children effectively cured were negative with the Pf HRP2 RDT at day 3, with a gradual increase in specificity until day 42. The specificity of antigen detection with the Pf LDH test was 87% (141/162) on day 3, and between 92% and 100% on days 7 to 42. A statistical difference was observed between the persistence of Pf HRP2 and Pf LDH antigenaemia during follow-up in children treated with artemisinin-based combination therapy (ACT) but not with SP.ConclusionAlthough both RDTs are as sensitive as microscopy in detecting true malaria cases, the Pf HRP2 RDT had very low specificity during follow-up until day 28. On the other hand, the Pf LDH test could be used to detect failures and, therefore, to assess anti-malarial efficacy.

The management of leptospirosis.

How to quickly identify patients who should be treated for leptospirosis is a challenge. The interest of polymerase chain reaction (PCR) assays is currently being evaluated and rapid tests which can be used outside of the specialised laboratory, have recently been developed. Leptospires are sensitive to many antibiotics and few clinical studies have been made to compare different treatment options. Doxycycline is standard therapy in early leptospirosis treatment and chemoprophylaxis. Intravenous penicillin has been considered the drug of choice in late and severe disease, although it is now challenged by ceftriaxone, which use is easier. Ciprofloxacin may be combined with standard therapy in uveitis. Adjunctive therapies proposed in the management of severe forms of leptospirosis and Jarisch–Herxheimer reactions, are reviewed.

Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

ABSTRACT Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex vivo, molecular, and pharmacological data is warranted.

Can treatment of malaria be restricted to parasitologically confirmed malaria? A school-based study in Benin in children with and without fever

BackgroundApplying the switch from presumptive treatment of malaria to new policies of anti-malarial prescriptions restricted to parasitologically-confirmed cases is a still unsolved challenge. Pragmatic studies can provide data on consequences of such a switch. In order to assess whether restricting anti-malarials to rapid diagnostic test (RDT)-confirmed cases in children of between five and 15 years of age is consistent with an adequate management of fevers, a school-based study was performed in Allada, Benin.MethodsChildren in the index group (with fever and a negative RDT) and the matched control group (without fever and a negative RDT) were not prescribed anti-malarials and actively followed-up during 14 days. Blood smears were collected at each assessment. Self-medication with chloroquine and quinine was assessed with blood spots. Malaria attacks during the follow-up were defined by persistent or recurrent fever concomitant to a positive malaria test.Results484 children were followed-up (242 in each group). At day 3, fever had disappeared in 94% of children from the index group. The incidence of malaria was similar (five cases in the index group and seven cases in the control group) between groups. Self-medication with chloroquine and quinine in this cohort was uncommon.ConclusionsApplying a policy of restricting anti-malarials to RDT-confirmed cases is consistent with an adequate management of fevers in this population. Further studies on the management of fever in younger children are of upmost importance.

Brill-Zinsser disease in Moroccan man, France, 2011.

To the Editor: Epidemic typhus is caused by Rickettsia prowazekii and transmitted by human body lice. For centuries, it has been associated with overcrowding, cold weather, and poor hygiene. Brill-Zinsser disease is a recurrent form of epidemic typhus that is unrelated to louse infestation and develops sporadically years after the primary illness. Clinical features are similar to, but milder than, those of epidemic typhus (1). We report a case of Brill-Zinsser disease in a patient who was born in Morocco and had no history of epidemic typhus. A 69-year-old man living in France sought care from his general practitioner on March 7, 2011, after 2 days of high-grade fever (40°C) associated with headache, myalgia, fatigue, and mild cough. Amoxicillin was prescribed for a putative diagnosis of acute respiratory infection. He was admitted to hospital on March 9 for persistent fever. Physical examination results were unremarkable. Blood test results were as follows: C-reactive protein 111 mg/L (reference 0–8 mg/L); procalcitonin 0.49 ng/mL (reference 0.1–0.4 ng/mL), lymphocyte count 0.7 × 103 cells/μL (reference 1–4 × 103 cells/μL), platelet count 92 × 103 cells/μL (reference 150–450 × 103 cells/μL), and lactate dehydrogenase 376 U/L (reference 94–246 U/L). Chest radiograph results were normal. Results of 5 blood cultures and a urine culture were negative. Stupor developed on March 11. Cerebrospinal fluid test results were normal. Because the patient lived near a goat farm, Q fever and tularemia were considered plausible hypotheses, and oral doxycycline was introduced on March 13. The patient became afebrile on March 15, and he was discharged from the hospital and remained well. On the basis of serologic results, the following diagnoses could be ruled out: viral infections (HIV, cytomegalovirus, Epstein-Barr virus); tularemia; Q fever; leptospirosis; salmonellosis; and Legionella, Mycoplasma, and Chlamydia spp. infections. Acute-phase and convalescent-phase serum samples were positive for typhus-group rickettsiae by the microimmunofluorescence assay at the World Health Organization Collaborative Center for Rickettsioses and Other Arthropod-Borne Bacterial Diseases (Marseille, France). A microimmunofluorescence assay showed titers of 100 for IgM and 6,400 for IgG. Western blot analyses and cross-adsorption studies strongly suggested R. prowazekii as the cause of the man’s illness. Quantitative PCR result on DNA extracted from the acute-phase serum was negative (2). The patient had been raised in Morocco. At 19 years of age, he emigrated to France, where he lived in a urban area. He subsequently traveled every 3 years to Morocco for 1-month summer holidays, always in urban areas. He had most recently traveled to Morocco in 2008. He denied any history of hospitalization for a severe febrile illness and any exposure to louse bites. In the weeks before disease onset, he had not taken any new drug. He had no immunoglobulin deficiency. On the basis of serologic analysis with Western blot, we confirmed R. prowazekii infection in a patient with no recent travel and no contact with lice or flying squirrels. R. prowazekii infection may occur rarely in France; it was found in Marseille in 2002 in an asymptomatic homeless person (3). In contrast, the patient in our report was living in a hygienic environment, and an autochthonous infection is therefore highly unlikely. Epidemic typhus was endemic to North Africa until the 1970s (4). Subsequently, this region was thought to be free from epidemic typhus, but 2 cases have been reported since 1999 in Algeria, where 1 case of Brill-Zinsser disease was observed in a man who had had epidemic typhus in 1960 during the Algerian civil war (5–7). Few published data exist about the seroprevalence of R. prowazekii infections in North Africa (4). In Tunisia, no epidemic typhus was found in 2005 among 47 febrile patients (8). However, a seroepidemiologic survey performed in blood donors and hospitalized patients in the Aures, Algeria, found a prevalence of 2% (4). This finding suggests that R. prowazekii infection might have occurred in this population more often than suspected. No recent published data are available from Morocco. Since 1970, reports of only 8 cases of Brill-Zinsser disease have been published (9,10). In all cases, known risk factors were present (overcrowding, poor hygiene, or contact with flying squirrels). Brill and Zinsser described that stress or waning immunity could reactivate R. prowazekii infection (2). Corticosteroids can trigger recurrence of R. prowazekii in mice (2), but no such observations were made in humans. In the case presented here, we found no stress factor, no immunosuppression, and no medical history of epidemic typhus. Brill-Zinsser disease can develop >40 years after acute infection. The mechanism of R. prowazekii latency has not been established. A recently explored reservoir for silent forms of R. prowazekii infection is adipose tissue because it contains endothelial cells, which are the target cells for R. prowazekii infection, and because of its wide distribution throughout the body (2). Brill-Zinsser disease should be considered as a possible diagnosis for acute fever in any patient who has lived in an area where epidemic typhus is endemic.

Serum C-reactive protein (CRP) and Procalcitonin (PCT) levels and kinetics in patients with leptospirosis

Leptospirosis is a zoonotic disease of worldwide distribution caused by spirochetes of the genus Leptospira. Leptospirosis clinical presentation ranges from subclinical infections to severe multiorgan-dysfunction syndromes. There are similarities between clinical and pathophysiological features encountered in leptospirosis and those of severe sepsis due to gram negative bacteria. However, the low endotoxic potency of leptospiral lipopolysaccharides could explain why severe manifestations of leptospirosis occur later after the onset of disease, compared to severe manifestations of gram negative basteria sepsis [1]. In previous studies, we found elevated plasma triglycerides and TNF α levels [2], which may translate into a systemic inflammatory response syndrome (SIRS) in patients with leptospirosis. The C-reactive protein (CRP) and procalcitonin (PCT) levels are elevated in SIRS, and these biomarkers are available in routine practice. The aim of this retrospective study was to report on the levels and kinetics of the CRP and PCT in patients with non-severe and severe leptospirosis.

What would PCR assessment change in the management of fevers in a malaria endemic area? A school-based study in Benin in children with and without fever

BackgroundA recent school-based study in Benin showed that applying a policy of anti-malarial prescriptions restricted to parasitologically-confirmed cases on the management of fever is safe and feasible. Additional PCR data were analysed in order to touch patho-physiological issues, such as the usefulness of PCR in the management of malaria in an endemic area or the triggering of a malaria attack in children with submicroscopic malaria.MethodsPCR data were prospectively collected in the setting of an exposed (with fever)/non exposed (without fever) study design. All children had a negative malaria rapid diagnostic test (RDT) at baseline, were followed up to day 14 and did not receive drugs with anti-malarial activity. The index group was defined by children with fever at baseline and the control group by children without fever at baseline. Children with submicroscopic malaria in these two groups were defined by a positive PCR at baseline.ResultsPCR was positive in 66 (27%) children of the index group and in 104 (44%) children of the control group respectively. The only significant factor positively related to PCR positivity at baseline was the clinical status (control group). When definition of malaria attacks included PCR results, no difference of malaria incidence was observed between the index and control groups, neither in the whole cohort, nor in children with submicroscopic malaria. The rate of undiagnosed malaria at baseline was estimated to 3.7% at baseline in the index group.ConclusionsTreating all children with fever and a positive PCR would have led to a significant increase of anti-malarial consumption, with few benefits in terms of clinical events. Non malarial fevers do not or do not frequently trigger malaria attacks in children with submicroscopic malaria.