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Background The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Patients and methods Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. Results A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). Conclusions This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F

Background\ud \ud Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and parasite resistance to the standard treatment (chloroquine) is now high in some parts of Oceania. This review aims to assess the current treatment options in the light of increasing chloroquine resistance.\ud \ud Objectives\ud \ud To compare artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P. vivax malaria.\ud \ud Search methods\ud \ud We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and the metaRegister of Controlled Trials (mRCT) up to 28 March 2013 using “vivax” and “arte* OR dihydroarte*” as search terms.\ud \ud Selection criteria\ud \ud Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria.\ud \ud Data collection and analysis\ud \ud Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We used recurrent parasitaemia prior to day 28 as a proxy for effective treatment of the blood stage parasite, and compared drug treatments using risk ratios (RR) and 95% confidence intervals (CIs). We used trials following patients for longer than 28 days to assess the duration of the post-treatment prophylactic effect of ACTs. We assessed the quality of the evidence using the GRADE approach.\ud \ud Main results\ud \ud We included 14 trials, that enrolled 2592 participants, and were all conducted in Asia and Oceania between 2002 and 2011.\ud \ud ACTs versus chloroquine\ud \ud ACTs clear parasites from the peripheral blood quicker than chloroquine monotherapy (parasitaemia after 24 hours of treatment: RR 0.42, 95% CI 0.36 to 0.50, four trials, 1652 participants, high quality evidence).\ud \ud In settings where chloroquine remains effective, ACTs are as effective as chloroquine at preventing recurrent parasitaemias before day 28 (RR 0.58, 95% CI 0.18 to 1.90, five trials, 1622 participants, high quality evidence). In four of these trials, recurrent parasitaemias before day 28 were very low following treatment with both chloroquine and ACTs. The fifth trial, from Thailand in 2011, found increased recurrent parasitaemias following treatment with chloroquine (9%), while they remained low following ACT (2%) (RR 0.25, 95% CI 0.09 to 0.66, one trial, 437 participants).\ud \ud ACT combinations with long half-lives probably also provide a longer prophylactic effect after treatment, with significantly fewer recurrent parasitaemias between day 28 and day 42 or day 63 (RR 0.57, 95% CI 0.40 to 0.82, three trials, 1066 participants, moderate quality evidence). One trial, from Cambodia, Thailand, India and Indonesia, gave additional primaquine to both treatment groups to reduce the risk of spontaneous relapses. Recurrent parasitaemias after day 28 were lower than seen in the trials that did not give primaquine, but the ACT still appeared to have an advantage (RR 0.27, 95% CI 0.08 to 0.94, one trial, 376 participants, low quality evidence).\ud \ud ACTs versus alternative ACTs\ud \ud In high transmission settings, dihydroartemisinin-piperaquine is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitaemias before day 28 (RR 0.20, 95% CI 0.08 to 0.49, three trials, 334 participants, moderate quality evidence).\ud \ud Dihydroartemisinin-piperaquine may also have an improved post-treatment prophylactic effect lasting for up to six weeks, and this effect may be present even when primaquine is also given to achieve radical cure (RR 0.21, 95% CI 0.10 to 0.46, two trials, 179 participants, low quality evidence).\ud \ud The data available from low transmission settings is too limited to reliably assess the relative effectiveness of ACTs.\ud \ud Authors' conclusions\ud \ud ACTs appear at least equivalent to chloroquine at effectively treating the blood stage of P. vivax infection. Even in areas where chloroquine remains effective, this finding may allow for simplified protocols for treating all forms of malaria with ACTs. In areas where chloroquine no longer cures the infection, ACTs offer an effective alternative.\ud \ud Dihydroartemisinin-piperaquine is the most studied ACT. It may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine. This effect may be clinically important in high transmission settings whether primaquine is also given or not.

Background\ud \ud Rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria use antibodies to detect either HRP-2 antigen or pLDH antigen, and can improve access to diagnostics in developing countries.\ud \ud Objectives\ud \ud To assess the diagnostic accuracy of RDTs for detecting P. falciparum parasitaemia in persons living in endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria by type and brand.\ud \ud Search strategy\ud \ud We undertook a comprehensive search of the following databases:Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; IndMED; to January 14, 2010.\ud \ud Selection criteria\ud \ud Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in P. falciparum endemic areas.\ud \ud Data collection and analysis\ud \ud For each study, a standard set of data was extracted independently by two authors, using a tailored data extraction form. Comparisons were grouped hierarchically by target antigen, and type and brand of RDT, and combined in meta-analysis where appropriate.\ud \ud Main results\ud \ud We identified 74 unique studies as eligible for this review and categorized them according to the antigens they detected. Types 1 to 3 include HRP-2 (from P. falciparum) either by itself or with other antigens. Types 4 and 5 included pLDH (from P. falciparum) either by itself or with other antigens. In comparisons with microscopy, we identified 71 evaluations of Type 1 tests, eight evaluations of Type 2 tests and five evaluations of Type 3 tests. In meta-analyses, average sensitivities and specificities (95% CI) were 94.8% (93.1% to 96.1%) and 95.2% (93.2% to 96.7%) for Type 1 tests, 96.0% (94.0% to 97.3%) and 95.3% (87.3% to 98.3%) for Type 2 tests, and\ud 99.5% (71.0% to 100.0%) and 90.6% (80.5% to 95.7%) for Type 3 tests, respectively.\ud \ud Overall for HRP-2, the meta-analytical average sensitivity and specificity (95% CI) were 95.0% (93.5% to 96.2%) and 95.2% (93.4% to 99.4%), respectively.\ud \ud For pLDH antibody-based RDTs verified with microscopy, we identified 17 evaluations of Type 4 RDTs and three evaluations of Type 5 RDTs. In meta-analyses, average sensitivity for Type 4 tests was 91.5% (84.7% to 95.3%) and average specificity was 98.7% (96.9% to 99.5%). For Type 5 tests, average sensitivity was 98.4% (95.1% to 99.5%) and average specificity was 97.5% (93.5% to 99.1%).\ud \ud Overall for pLDH, the meta-analytical average sensitivity and specificity (95% CI) were 93.2% (88.0% to 96.2%) and 98.5% (96.7% to 99.4%), respectively.\ud \ud For both categories of test, there was substantial heterogeneity in study results. Quality of the microscopy reference standard could only be assessed in 40% of studies due to inadequate reporting, but results did not seem to be influenced by the reporting quality.\ud \ud Overall, HRP-2 antibody-based tests (such as the Type 1 tests) tended to be more sensitive and were significantly less specific than pLDH-based tests (such as the Type 4 tests). If the point estimates for Type 1 and Type 4 tests are applied to a hypothetical cohort of 1000 patients where 30% of those presenting with symptoms have P. falciparum, Type 1 tests will miss 16 cases, and Type 4 tests will miss 26 cases. The number of people wrongly diagnosed with P. falciparum would be 34 with Type 1 tests, and nine with Type 4 tests.\ud \ud Authors’ conclusions\ud \ud The sensitivity and specificity of all RDTs is such that they can replace or extend the access of diagnostic services for uncomplicated P. falciparum malaria. HRP-2 antibody types may be more sensitive but are less specific than pLDH antibody-based tests, but the differences are small. The HRP-2 antigen persists even after effective treatment and so is not useful for detecting treatment failures.

BACKGROUND: Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested. METHODS: A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety. RESULTS: Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients. CONCLUSION: Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07576538.

Background The control of schistosomiasis emphasizes preventive chemotherapy with praziquantel, which aims at decreasing infection intensity and thus morbidity in individuals, as well as transmission in communities. Standardizing methods to assess treatment efficacy is important to compare trial outcomes across settings, and to monitor program effectiveness consistently. We compared customary methods and looked at possible complementary approaches in order to derive suggestions for standardizing outcome measures. Methodology/Principal Findings We analyzed data from 24 studies conducted at African, Asian, and Latin American sites, enrolling overall 4,740 individuals infected with Schistosoma mansoni, S. haematobium, or S. japonicum, and treated with praziquantel at doses of 40–80 mg/kg. We found that group-based arithmetic and geometric means can be used interchangeably to express egg reduction rates (ERR) only if treatment efficacy is high (>95%). For lower levels of efficacy, ERR estimates are higher with geometric than arithmetic means. Using the distribution of individual responses in egg excretion, 6.3%, 1.7% and 4.3% of the subjects treated for S. haematobium, S. japonicum and S. mansoni infection, respectively, had no reduction in their egg counts (ERR = 0). The 5th, 10th, and 25th centiles of the subjects treated for S. haematobium had individual ERRs of 0%, 49.3%, and 96.5%; the corresponding values for S. japonicum were 75%, 99%, and 99%; and for S. mansoni 18.2%, 65.3%, and 99.8%. Using a single rather than quadruplicate Kato-Katz thick smear excluded 19% of S. mansoni-infected individuals. Whilst the effect on estimating ERR was negligible by individual studies, ERR estimates by arithmetic means were 8% lower with a single measurement. Conclusions/Significance Arithmetic mean calculations of Schistosoma ERR are more sensitive and therefore more appropriate to monitor drug performance than geometric means. However, neither are satisfactory to identify poor responders. Group-based response estimated by arithmetic mean and the distribution of individual ERRs are correlated, but the latter appears to be more apt to detect the presence and to quantitate the magnitude of suboptimal responses to praziquantel., Author Summary To identify whether a person is infected with parasitic worms, stool or urine samples are examined for worm eggs. The drug praziquantel is used against the parasitic disease schistosomiasis. However, there is no definitive agreement as to how the efficacy of praziquantel is best expressed. We put together a database from various studies of the efficacy of praziquantel against schistosomiasis. Efficacy was measured using customary methods: cure rate (CR: percentage of people with eggs in their stool/urine before treatment who became egg-negative after treatment); and egg reduction rate (ERR; percentage reduction in the number of eggs in the stool/urine after treatment, where the mean number of eggs from all people treated is calculated using either geometric or arithmetic means). We found that arithmetic and geometric means can be used interchangeably only if treatment efficacy is very high; arithmetic means are more sensitive to capture drops in efficacy expressed by ERR. A valid complement for drug efficacy monitoring is to study the distribution of individual responses in egg excretion that allows identifying in a single measure both those who had an adequate response to treatment and those who respond less well; e.g., the 5% of the patients with the lowest ERRs.

Background: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Patients and methods: Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. Results: A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration–time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life(407 versus 566 h) and T.MIC (766 versus 893 h). Conclusions: This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration–time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F. Refereed/Peer-reviewed

Background: Classified among the neglected tropical diseases (NTDs), schistosomiasis remains one of the most important parasitic diseases in the tropics and subtropics, and constitutes a major public health problem. Following World Health Assembly (WHA) resolution 54.19, put forth in May 2001, several control programmes have emerged in schistosomiasis-endemic countries with the objective to reduce morbidity due to schistosomiasis and soil-transmitted helminthiasis by regularly treating at least 75% and up to 100% of all school-aged children who are at risk by 2010. By focusing treatment upon the school-aged population, WHA resolution 54.19 neglects preschool-aged children, thus preventing them from benefiting from preventive chemotherapy targeted to their older peers, and hence creating a potential health inequity. Root causes include the belief that very young children would not yet be exposed to infected freshwater bodies, thus an insufficient understanding and documentation of the extent and severity of schistosomiasis in this age class, and a paucity of pharmacokinetic safety data of praziquantel among young children. However, in endemic zones, women are frequently accompanied by their children, even at young age, when they go to ponds, rivers or irrigation canals, all of which may be contaminated with cercariae, the infective stage to humans. Recent studies carried out in East and West Africa showed that intestinal and urogenital schistosomiasis can indeed occur in very early childhood. Pathology due to chronic infection with Schistosoma mansoni includes hepatic perisinusoidal egg granulomas, Symmers’ pipe-stem periportal fibrosis, portal hypertension and, occasionally, embolic egg granulomas in the brain or spinal cord. Schistosoma haematobium infection may cause haematuria, scarring, calcification, squamous cell carcinoma and, occasionally, embolic egg granulomas in the brain or spinal cord. Goal and specific objectives: The overarching goal of this Ph.D. thesis is to deepen our understanding of the epidemiology of schistosomiasis in preschool-aged children. The thesis pursued five specific objectives in Azaguié district, south Côte d’Ivoire. First, to characterize intestinal parasitic infections at the Azaguié district level. Second, to assess the accuracy of a commercially available urine circulating cathodic antigen (CCA) cassette test (CCA-A) and an experimental formulation (CCA-B) for the diagnosis of S. mansoni among school-aged children in different endemicity settings. Third, to assess the accuracy of CCA-A for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. Fourth, to study the epidemiology and risk factors for schistosomiasis in preschool-aged children. Fifth, to assess the efficacy and safety of crushed praziquantel tablets in preschool-aged children in a co-endemic setting of S. mansoni and S. haematobium. Methods: The fieldwork for this Ph.D. thesis was split into two parts. In order to address the first two objectives, in mid-2010, a cross-sectional study was carried out in seven schools from four locations of Azaguié district, including more than 600 schoolchildren. Multiple stool and urine samples were collected from each schoolchild over three consecutive days. Stool samples were examined with the Kato-Katz technique for the diagnosis of S. mansoni and soil-transmitted helminths (Trichuris trichiura, Ascaris lumbricoides and hookworm). Stool samples from the first day of collection were preserved in sodium acetate-acetic acid-formalin (SAF) and examined one month later using an ether-concentration method for the diagnosis of intestinal protozoa. Urine samples were examined with CCA tests (CCA-A on three days and CCA-B once) for the diagnosis of S. mansoni. In addition, urine samples were analysed with the urine filtration technique and reagent strips for the diagnosis of S. haematobium. In order to address objectives 3-5, a cross-sectional study was implemented as a baseline survey in 2011 in two villages of Azaguié district, namely Azaguié Makouguié and Azaguié M’Bromé, where S. mansoni and S. haematobium coexist. About 300 preschool-aged children (

Schistosomiasis is a chronic helminthic disease caused by fluke worms of the genus Schistosoma spp. The disease belongs to the so-called neglected tropical diseases (NTDs) and is endemic in approximately 78 countries of the world, but mainly in sub-Saharan Africa. It has been estimated that more than 207 million people worldwide are infected, the annual mortality rate in sub-Saharan Africa might be as high as 280,000. Overall, there are five schistosome species parasitizing humans, with Schistosoma haematobium, S. mansoni and S. japonicum being the three main species with the widest geographical distribution. The disease is transmitted by contact with infested fresh water, containing the infectious stage of the parasites, the cercariae, which were released by infected aquatic snails and penetrate human skin. Chronic pathology is not due to the worms itself, but due to inflammatory reactions provoked by the eggs. The WHO recommended strategy for control of schistosomiasis is morbidity control through regular treatment with praziquantel. Praziquantel is active against the adult stages of all five human schistosome species, however, it has only little or no effect on eggs and immature worms. Hence re-treatment is necessary. Overall, treatment is regarded as safe and generally well-tolerated. However, to date praziquantel is the only drug available for treatment and control of schistosomiasis. The dependence on only one drug for such an important disease and the massive use of praziquantel is a risk factor for the development of praziquantel resistant schistosome strains. Furthermore, to date no vaccines against schistosomiasis are available. Therefore there is a need to develop new drugs against schistosomiasis. Recently the antimalarial drug mefloquine was found to have interesting antischistosomal activities in vitro and in the mouse model. For example, single oral doses of 200 or 400 mg/kg mefloquine administered to mice infected with S. mansoni and S. japonicum resulted in high or complete total and female worm burden reduction. A clinical trial conducted with school children in Côte d´Ivoire showed that a mefloquine/artesunate combination cured 11 out of 18 children infected with S. haematobium. Based on these findings, the aim of my PhD thesis was to further assess the newly discovered antischistosomal properties of the antimalarial drug mefloquine and to get a first insight into the mode of action and the pharmacodynamics of mefloquine in schistosomes. Therefore different in vitro and in vivo studies, including drug target discovery studies, were conducted with S. mansoni. By assessing the time-dependent drug effect of mefloquine on schistosomes we showed that mefloquine has a rapid onset of action on newly transformed schistosomula (NTS; artificially produced, non hematophagous) and a slightly slower onset of action on adult worms (recovered from infected mice) in vitro: 10 µg/ml killed adult worms within 24 h of incubation (LC50= 1.9 µg/mL). In the presence of hemin drug activities against adult S. mansoni were enhanced. In vivo 72 h post treatment more than 90% of schistosomes were shifted to the liver, a criterion for drug activity, which shows how quick after drug treatment worms are forced to migrate from the mesenteric veins to the liver (ED50= 62 mg/kg). With scanning electron microscopy (SEM) studies, we confirmed our previous observations and the differences in the onset of action between in vitro and in vivo studies: SEM revealed extensive tegumental damages including blebbing, shrinking and sloughing on the tegument of NTS and adult worms, in particular following in vitro incubation and on the tegument of female worms. Conducting a structure-activity relationship study we showed that the optical isomers and the racemic forms of the chiral drug mefloquine have only moderate stereoselectivity, in particular in vivo, since prominent activities were observed with all derivates in the S. mansoni mouse model. To evaluate the potential of a mefloquine/praziquantel drug combination against S. mansoni we conducted combination studies and achieved encouraging results, since synergistic effects in vitro and in the S. mansoni mouse model were seen, when both drugs were given simultaneously or when praziquantel treatment followed mefloquine. The latter administration regime achieved the best results. Finally, to get a better knowledge about the mechanism of action of mefloquine in schistosomes, we launched drug target discovery studies using affinity chromatography. We identified enolase, a glycolytic enzyme, as a major mefloquine- binding protein in S. mansoni schistosomula and we demonstrated that mefloquine interacts with glycolysis in schistosomula. To strengthen the field of antischistosomal drug discovery we assessed a new technique, isothermal microcalorimetry (IMC), to examine in vitro drug effects against S. mansoni. Results were compared to microscopic readouts, the actual “gold standard”. Both methods showed a good correlation, however, IMC identified drug effects that were not visible by microscopic evaluation and precisely determined the onset of action of the test drugs. Furthermore, we compared drug effects on NTS and adult schistosomes, because NTS are increasingly used in antischistosomal drug screening assays. In conclusion, my work has confirmed that mefloquine possesses excellent antischistosomal properties and that the drug might be an interesting partner drug in combination chemotherapy. We demonstrated that IMC is a useful tool for antischistosomal drug discovery and should therefore be assessed also for studying drug effects against other helminths. In addition, our data support the use of NTS in in vitro antischistosomal drug assays, since we observed similar drug sensitivities on both stages.