In vivo study of Plasmodium falciparum chloroquine susceptibility in three departments of Haiti.

BACKGROUND: Malaria is considered a public health priority in Haiti, with a goal to eliminate by year 2020. Chloroquine is the first-line treatment recommended by the Ministry of Public Health and Population. In order to verify the suitability of chloroquine for uncomplicated malaria treatment, an in vivo study of susceptibility of Plasmodium falciparum to chloroquine was conducted from January 2013 to March 2015 in six localities in the south of Haiti. RESULTS: Sixty-one patients who presented with confirmed P. falciparum malaria were included in the study and followed until day 28 after having taken 25 mg/kg of chloroquine orally over 3 days. The sample included 28 children under the age of 10, 9 adolescents aged 10-19 years, and 24 adults aged 20 years and over. Among them, 30 were monitored on day 3 (49%) and 33 on day 28 (59%). Clinical and parasitological monitoring was carried out on day 7 on 28 subjects, on day 14 on 13 subjects and on day 21 on 18 subjects. Residual parasitaemia with presence of trophozoites was found in 7 of 30 subjects on day 3 (23%), and in 6 of 28 subjects on day 7 (21%) who had a temperature less than 37.5 °C. These patients can be considered as late parasitological failures. All monitoring performed on day 28 was negative. Gametocytes were found in 3 patients (9%) despite the use of primaquine. The continuing low parasitaemia on day 3 and 7 in more than one fifth of cases raises the question of the efficacy of chloroquine in southern Haiti. CONCLUSIONS: Results suggest a decrease of chloroquine susceptibility for treatment of P. falciparum malaria cases in southern Haiti. Consequently, there is a need to strengthen malaria treatment surveillance and to study the effectiveness of chloroquine in Haiti by monitoring patients after treatment.

Malaria elimination in Haiti by the year 2020: an achievable goal?

Haiti and the Dominican Republic, which share the island of Hispaniola, are the last locations in the Caribbean where malaria still persists. Malaria is an important public health concern in Haiti with 17,094 reported cases in 2014. Further, on January 12, 2010, a record earthquake devastated densely populated areas in Haiti including many healthcare and laboratory facilities. Weakened infrastructure provided fertile reservoirs for uncontrolled transmission of infectious pathogens. This situation results in unique challenges for malaria epidemiology and elimination efforts. To help Haiti achieve its malaria elimination goals by year 2020, the Laboratoire National de Santé Publique and Henry Ford Health System, in close collaboration with the Direction d'Épidémiologie, de Laboratoire et de Recherches and the Programme National de Contrôle de la Malaria, hosted a scientific meeting on "Elimination Strategies for Malaria in Haiti" on January 29-30, 2015 at the National Laboratory in Port-au-Prince, Haiti. The meeting brought together laboratory personnel, researchers, clinicians, academics, public health professionals, and other stakeholders to discuss main stakes and perspectives on malaria elimination. Several themes and recommendations emerged during discussions at this meeting. First, more information and research on malaria transmission in Haiti are needed including information from active surveillance of cases and vectors. Second, many healthcare personnel need additional training and critical resources on how to properly identify malaria cases so as to improve accurate and timely case reporting. Third, it is necessary to continue studies genotyping strains of Plasmodium falciparum in different sites with active transmission to evaluate for drug resistance and impacts on health. Fourth, elimination strategies outlined in this report will continue to incorporate use of primaquine in addition to chloroquine and active surveillance of cases. Elimination of malaria in Haiti will require collaborative multidisciplinary approaches, sound strategic planning, and strong ownership of strategies by the Haiti Ministère de la Santé Publique et de la Population.

Assessing drivers of full adoption of test and treat policy for malaria in Senegal.

Malaria treatment policy has changed from presumptive treatment to targeted "test and treat" (T&T) with malaria rapid diagnostic tests (RDTs) and artemisinin combination therapy (ACT). This transition involves changing behavior among health providers, meaning delays between introduction and full implementation are recorded in almost every instance. We investigated factors affecting successful transition, and suggest approaches for accelerating uptake of T&T. Records from 2000 to 2011 from health clinics in Senegal where malaria is mesoendemic were examined (96,166 cases). The study period encompassed the implementation of national T&T policy in 2006. Analysis showed that adherence to test results is the first indicator of T&T adoption and is dependent on accumulation of experience with positive RDTs (odds ratio [OR]: 0.55 [P ≤ 0.001], 95% confidence interval [CI]: 0.53-0.58). Reliance on tests for malaria diagnosis (rather than presumptive diagnosis) followed after test adherence is achieved, and was also associated with increased experience with positive RDTs (OR: 0.60 [P ≤ 0.001], 95% CI: 0.58-0.62). Logistic models suggest that full adoption of T&T clinical practices can occur within 2 years, that monitoring these behavioral responses rather than RDT or ACT consumption will improve evaluation of T&T uptake, and that accelerating T&T uptake by focusing training on adherence to test results will reduce overdiagnosis and associated health and economic costs in mesoendemic regions.

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Mansonelliasis, a neglected parasitic disease in Haiti.

Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting-midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised.

Mansonelliasis, a neglected parasitic disease in Haiti

Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting-midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised.

Epidemiologic survey of Mansonella ozzardi in Corail, Haiti.

An epidemiologic (cross-sectional study) survey on 462 inhabitants in Corail, Haiti showed that 16.5% were infected with Mansonella ozzardi. This finding was determined from a single 20-µL sample of finger prick blood from each person. Among children, < 2% had a detectable microfilaremia. In persons > 15 years of age, the prevalence of infection for males and females was 23% and 21%, respectively. In general, the microfilaremias were low and 70% of positive persons had < 10 microfilariae per 20 µL of blood; only 5% had > 50 microfilariae. This study shows that persons living near mangrove marshes that are breeding sites for Culicoides furens and C. barbosai biting midges, which are recognized vectors of M. ozzardi in Haiti, are consequently more frequently infected than those living in downtown area of Corail or inland.

Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999-2009.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene METHODS: Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis. RESULTS: Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3.In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 µL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) - 6.135, r(2) = 0.94) in ASAQ recipients was 31 hours. CONCLUSION: Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes.

Influence of ionic strength and soil characteristics on the behavior of Cryptosporidium oocysts in saturated porous media.

The physico-chemical behavior of Cryptosporidium oocysts was investigated during their transfer through an alluvial formation from Les Cayes (Haiti) via batch tests. Five approximately 3 kg soil samples were collected and combined prior to batch tests from the alluvial formations. The experiments were carried out at soil pH by equilibrating different ranges of pure oocysts concentrations and soil samples with 3mM CaCl2 and 1mM NaBr as electrolyte. We used the Debye-Hückel equation describing ion activity in a solution for a given ionic strength. The equilibrium adsorption mechanism is used to enumerate the oocysts in the soil. The results suggest that the oocysts behavior in porous media depends on soil characteristics such as soil pH, the nature of the mineral and organic constituents of the soil and the ionic strength and activities in solution. These results show that a total transfer in batch containing NaBr solutions against a partial one in batch containing CaCl2 solutions depends on the oocysts media concentration. To confirm the oocysts number retained in soil, confocal microscopy was successfully used and the images demonstrate that the majority of oocysts were retained at the range of concentrations tested. The findings from this study demonstrated that the retention of C. Parvum in soils may be influenced by chemical conditions and soils characteristics, which are important for groundwater risk assessment.

Surveillance of travellers: an additional tool for tracking antimalarial drug resistance in endemic countries.

INTRODUCTION: There are growing concerns about the emergence of resistance to artemisinin-based combination therapies (ACTs). Since the widespread adoption of ACTs, there has been a decrease in the systematic surveillance of antimalarial drug resistance in many malaria-endemic countries. The aim of this work was to test whether data on travellers returning from Africa with malaria could serve as an additional surveillance system of local information sources for the emergence of drug resistance in endemic-countries. METHODOLOGY: Data were collected from travellers with symptomatic Plasmodium falciparum malaria returning from Senegal (n = 1,993), Mali (n = 2,372), Cote d'Ivoire (n = 4,778) or Cameroon (n = 3,272) and recorded in the French Malaria Reference Centre during the period 1996-2011. Temporal trends of the proportion of parasite isolates that carried the mutant genotype, pfcrt 76T, a marker of resistance to chloroquine (CQ) and pfdhfr 108N, a marker of resistance to pyrimethamine, were compared for travellers and within-country surveys that were identified through a literature review in PubMed. The in vitro response to CQ was also compared between these two groups for parasites from Senegal. RESULTS: The trends in the proportion of parasites that carried pfcrt 76T, and pfdhfr 108N, were compared for parasites from travellers and patients within-country using the slopes of the curves over time; no significant differences in the trends were found for any of the 4 countries. These results were supported by in vitro analysis of parasites from the field in Senegal and travellers returning to France, where the trends were also not significantly different. CONCLUSION: The results have not shown different trends in resistance between parasites derived from travellers or from parasites within-country. This work highlights the value of an international database of drug responses in travellers as an additional tool to assess the emergence of drug resistance in endemic areas where information is limited.

Use of a colorimetric (DELI) test for the evaluation of chemoresistance of Plasmodium falciparum and Plasmodium vivax to commonly used anti-plasmodial drugs in the Brazilian Amazon.

BACKGROUND: The emergence and spread of Plasmodium falciparum and Plasmodium vivax resistance to available anti-malarial drugs represents a major drawback in the control of malaria and its associated morbidity and mortality. The aim of this study was to evaluate the chemoresistance profile of P. falciparum and P. vivax to commonly used anti-plasmodial drugs in a malaria-endemic area in the Brazilian Amazon. METHODS: The study was carried out in Manaus (Amazonas state), in the Brazilian Amazon. A total of 88 P. falciparum and 178 P. vivax isolates was collected from 2004 to 2007. The sensitivity of P. falciparum isolates was determined to chloroquine, quinine, mefloquine and artesunate and the sensitivity of P. vivax isolates was determined to chloroquine and mefloquine, by using the colorimetric DELI test. RESULTS: As expected, a high prevalence of P. falciparum isolates resistant to chloroquine (78.1%) was observed. The prevalence of isolates with profile of resistance or decreased sensitivity for quinine, mefloquine and artesunate was 12.7, 21.2 and 11.7%, respectively. In the case of P. vivax, the prevalence of isolates with profile of resistance for chloroquine and mefloquine was 9.8 and 28%, respectively. No differences in the frequencies of isolates with profile of resistance or geometric mean IC50s were seen when comparing the data obtained in 2004, 2005, 2006 and 2007, for all tested anti-malarials. CONCLUSIONS: The great majority of P. falciparum isolates in the Brazilian malaria-endemic area remain resistant to chloroquine, and the decreased sensitivity to quinine, mefloquine and artesunate observed in 10-20% of the isolates must be taken with concern, especially for artesunate. Plasmodium vivax isolates also showed a significant proportion of isolates with decreased sensitivity to chloroquine (first-line drug) and mainly to mefloquine. The data presented here also confirm the usefulness of the DELI test to generate results able to impact on public health policies.

Probabilistic record linkage for monitoring the safety of artemisinin-based combination therapy in the first trimester of pregnancy in Senegal.

BACKGROUND: There are insufficient data on the safety in early pregnancy of the artemisinins, a new class of antimalarials. Assessment of drug teratogenicity requires large sample sizes for an adequate risk-benefit assessment. There is currently limited pharmacovigilance infrastructure in malaria-endemic countries. Monitoring drug safety in early pregnancy is especially challenging, as it requires early pregnancy detection to assess any potential increased risk of miscarriage, prospective follow-up to reduce recall and survival biases, and accurate data on gestational age assessment. Record linkage approaches for pregnancy pharmacovigilance using routinely generated health records could be a pragmatic and cost-effective approach for pharmacovigilance in early pregnancy, but has not been evaluated in resource-poor settings. OBJECTIVE: Our objective was to assess the feasibility of record linkage using routinely collected healthcare data as a pragmatic means of monitoring the safety in early pregnancy of artemisinin-based combination therapies (ACTs) in Senegal. METHODS: Data (2004-2008) from paper-based registers from outpatient clinics, antenatal care services (ANC) and the delivery unit from the St Joseph dispensary in Mlomp, south-western Senegal, were entered into databases. Record linkage based on a probabilistic matching approach was used to identify pregnancies exposed to ACTs in the first trimester of pregnancy. Two record linkage software packages (Link-Plus and FRIL) were compared and output data were reviewed independently by two investigators. RESULTS: Information on 685 pregnancies was extracted, 536 of which were from the geographic catchment area and eligible for record linkage; 94.6 % of them resulted in live births, 2.6 % in stillbirths and 2.8 % in miscarriages. Major congenital malformations were identified in 1.6 % of births. Seventy-three and 75 true matches between pregnancy outcome and the outpatient treatment registers were identified by two different record linkage software packages, respectively. Record linkage identified seven exposures to ACTs in the first trimester, all of which resulted in normal live-births. CONCLUSION: Probabilistic record linkage is a potentially cost-effective method to assess the safety of antimalarials in early pregnancy in resource-constrained settings to assess increased risk of overall birth defects, and stillbirths in settings with good existing health records and well defined target populations.

Artesunate-amodiaquine efficacy in Congolese children with acute uncomplicated falciparum malaria in Brazzaville.

BACKGROUND: Congo-Brazzaville adopted artemisinin-based combination therapy (ACT) in 2006. Artesunate-amodiaquine (AS + AQ) and artemether-lumefantrine are the first-line and second-line anti-malarial drugs to treat uncomplicated Plasmodium falciparum malaria, respectively. The baseline efficacy of AS + AQ was evaluated from February to August 2005 in patients living in Brazzaville, the capital city of the Republic of Congo. METHODS: One hundred and ninety-seven patients (96 ≤ 5 years old and 101 >5 years old, including adults) were recruited in a non-randomized study, treated under supervision with AS + AQ, and were followed up for 28 days in accordance with the 2003 World Health Organization protocol. Plasmodium falciparum recrudescent isolates from day 7 to day 28 were compared to pretreatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. RESULTS: The overall efficacy of AS + AQ after PCR correction on day 28 was 94.4%. An adequate clinical and parasitological response was observed in 94.3% and 94.4% of children aged ≤ 5 years old and those aged >5 years old (including adults), respectively. The main reported adverse events were dizziness, vomiting, diarrhoea, pruritus, headache, anorexia, and abdominal pain. CONCLUSION: This study has shown the high efficacy of AS + AQ in Congolese patients of all ages with acute uncomplicated falciparum malaria and serves as the baseline efficacy and tolerance of this ACT in Brazzaville.

Anti-malarial drug safety information obtained through routine monitoring in a rural district of South-Western Senegal.

BACKGROUND: Knowing the safety profile of anti-malarial treatments in routine use is essential; millions of patients receive now artemisinin combination therapy (ACT) annually, but the return on information through current systems is as yet inadequate. Cohort event monitoring (CEM) is a WHO (World Health Organization)-recommended practice; testing its performance and feasibility in routine practice in malaria-endemic is important. METHODS: A nine-year CEM-based study of the safety of artesunate-amodiaquine (ASAQ) at five peripheral health facilities in a rural district of South-western Senegal. Staff (nurses, health workers) were trained to collect actively and systematically information on the patient, treatment and events on a purposely designed questionnaire. The occurrence and severity of events was collected before, during and after treatment up to 28 days in order to generate information on all adverse events (AEs) as well as treatment-emerging signs/symptoms (TESS). Laboratory tests (haematology, liver and renal) was planned for at least 10% of cases. RESULTS: During 2001-2009, 3,708 parasitologically-confirmed malaria cases (mean age = 16.0 ± 12.7 years) were enrolled (26% and 52% of all and parasitologically-confirmed ASAQ treatments, respectively). Treatment was supervised in 96% of cases. Products changed over time: 49% were a loose combination of individually-packaged products (available 2001-03), 42% co-blistered products (2004-09) and 9% a fixed-dose co-formulation (2006-09); dosing was age-based for 42%, weight-based for 58%. AS and AQ were correctly dosed in 97% and 82% of cases with the loose and 93% and 86% with the fixed combination, but only 50% and 42% with the co-blistered product.Thirty-three per cent (33%) of patients had at least one sign/symptom pre-treatment, 12% had at least one AE and 9% a TESS (total events 3,914, 1,144 and 693, respectively). AEs overestimated TESS by 1.2-2 fold (average 1.7). Changes in laboratory value were insignificant. Over-dosing more than doubled the risk of TESS, though statistical significance was reached only during 2003-2007. The incidence of serious events (including death) was five per thousand. CONCLUSIONS: The study was successful in quantifying and characterizing known reactions and has benchmarking value. Health staff performance varied. Investments in training, motivating and providing a quality control system would be needed. The study proved that a CEM-based system is feasible in this setting but more research is needed to assess whether it is sustainable and what conditions would make it cost-effective, including the amount and quality of data generated, and the use thereof for decision-making.

Changing patterns of malaria during 1996-2010 in an area of moderate transmission in southern Senegal.

BACKGROUND: Malaria is reportedly receding in different epidemiological settings, but local long-term surveys are limited. At Mlomp dispensary in south-western Senegal, an area of moderate malaria transmission, year-round, clinically-suspected malaria was treated with monotherapy as per WHO and national policy in the 1990s. Since 2000, there has been a staggered deployment of artesunate-amodiaquine after parasitological confirmation; this was adopted nationally in 2006. METHODS: Data were extracted from clinic registers for the period between January 1996 and December 2010, analysed and modelled. RESULTS: Over the 15-year study period, the risk of malaria decreased about 32-times (from 0.4 to 0.012 episodes person-year), while anti-malarial treatments decreased 13-times (from 0.9 to 0.07 treatments person-year) and consultations for fever decreased 3-times (from 1.8 to 0.6 visits person-year). This was paralleled by changes in the age profile of malaria patients so that the risk of malaria is now almost uniformly distributed throughout life, while in the past malaria used to concern more children below 16 years of age. CONCLUSIONS: This study provides direct evidence of malaria risk receding between 1996-2010 and becoming equal throughout life where transmission used to be moderate. Infection rates are no longer enough to sustain immunity. Temporally, this coincides with deploying artemisinin combinations on parasitological confirmation, but other contributing causes are unclear.

Cryptosporidium contamination of surface and water supplies in Haiti.

Cryptosporidiosis is one of the most frequent causes of diarrhea in Haiti. Transmission in children less than five years-old, HIV-infected individuals, and people living in low socio-economic conditions is frequently due to consumption of water or food contaminated by Cryptosporidium oocysts. This study examined the circulation of Cryptosporidium oocysts in surface waters and in public water supplies in the district of Port-au-Prince. Data were gathered from December 2000 to June 2002 in 37 sites. In the district of Port-au-Prince, 24/37 samples of water collected (65%) were contaminated by Cryptosporidium oocysts and 10/11 (91%) of those collected in reservoirs used by people living in peripheral areas. The rate of contamination was 7/13 (54%) in water from public standpipes provided by the public company of water distribution. All surface water (4/4) collected was highly contaminated.

Understanding human-Plasmodium falciparum immune interactions uncovers the immunological role of worms.

BACKGROUND: Former studies have pointed to a monocyte-dependent effect of antibodies in protection against malaria and thereby to cytophilic antibodies IgG1 and IgG3, which trigger monocyte receptors. Field investigations have further documented that a switch from non-cytophilic to cytophilic classes of antimalarial antibodies was associated with protection. The hypothesis that the non-cytophilic isotype imbalance could be related to concomittant helminthic infections was supported by several interventions and case-control studies. METHODS AND FINDINGS: We investigated here the hypothesis that the delayed acquisition of immunity to malaria could be related to a worm-induced Th2 drive on antimalarial immune responses. IgG1 to IgG4 responses against 6 different parasite-derived antigens were analyzed in sera from 203 Senegalese children, half carrying intestinal worms, presenting 421 clinical malaria attacks over 51 months. Results show a significant correlation between the occurrence of malaria attacks, worm carriage (particularly that of hookworms) and a decrease in cytophilic IgG1 and IgG3 responses and an increase in non-cytophilic IgG4 response to the merozoite stage protein 3 (MSP3) vaccine candidate. CONCLUSION: The results confirm the association with protection of anti-MSP3 cytophilic responses, confirm in one additional setting that worms increase malaria morbidity and show a Th2 worm-driven pattern of anti-malarial immune responses. They document why large anthelminthic mass treatments may be worth being assessed as malaria control policies.

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.

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.

Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. METHODS: A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. RESULTS: Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. CONCLUSION: The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. TRIAL REGISTRATION: The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

Implementation of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine (IPTp-SP) at a district health centre in rural Senegal.

BACKGROUND: Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) is recommended for reducing the risk of malaria in pregnancy and its consequences on mothers and babies (IPTp-SP). Indicators of implementation and effects of IPTp-SP were collected in a rural clinic in Southern Senegal. METHODS: Women seen routinely at the antenatal clinic (ANC) of a rural dispensary during 2000-2007. Deployment of IPTp-SP started in January 2004. Inspection of antenatal and outpatient clinic registries of the corresponding period. RESULTS: Between 1st January 2000 and 30th April 2007, 1,781 women of all gravitidities and parities attended the ANC with 965 deliveries (606 and 398 respectively since 1st January 2004, when IPTp-SP was started.) 69% of women were seen > or = 3 times; 95% received at least one dose and 70% two doses of SP (from 61% in 2004 to 86% in 2007). The first visit, first and second dose of SP occurred at a median week 20, 22 and 31. The probability of receiving two doses was > 80% with > or = 3 antenatal visits and a first dose of SP by week 20.The prevalence of maternal malaria was low and similar pre- (0.7%) and during IPTp (0.8%). Effects on of low birth weight (LBW, < 2.5 kg) were non-statistically significant. The prevalence of LBW was 10.8% pre- and 7.7% during IPTp deployment (29% risk reduction, p = 0.12).Unfavourable pregnancy outcomes numbered 72 (7.5% of pregnancies with known outcome), including 30 abortions and 42 later deaths (late foetal deaths, stillbirth, peri-natal) of which 13 with one or more malformations (1.35% of all recorded deliveries). CONCLUSION: The implementation of IPTp-SP was high. Early attendance to ANC favours completion of IPTp-SP. The record keeping system in place is amenable to data extraction and linkage. A model was developed that predicts optimal compliance to two SP doses, and could be tested in other settings. Maternal malaria was infrequent and unaffected by IPTp-SP. The risk of LBW was lower during IPT implementation but the difference was non-significant and could have other explanations.