Practical Guidelines for Standardised Resolution of Important Protocol Deviations in Clinical Trials Conducted in Sub-Saharan Africa.

A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant's rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.

Stillbirths, Neonatal Morbidity, and Mortality in Health-Facility Deliveries in Urban Gambia.

Background: The Gambia Demographic and Health Survey 2013 data showed that up to 63% of deliveries in the country occur in health facilities. Despite such a high rate, there are few facility-based studies on delivery outcomes in the country. This analysis ancillary to a randomized control trial describes occurrence of poor pregnancy outcomes in a cohort of women and their infants delivering in a government health facility in urban Gambia. Methods: Using clinical information obtained during the trial, we calculated rates of poor pregnancy outcomes including stillbirths, hospitalization and neonatal deaths. Logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) in the risk factors analysis. Results: Between April 2013 and 2014, 829 mothers delivered 843 babies, including 13 stillbirths [15.4 (7.1-23.8)] per 1,000 births. Among 830 live born infants, 7.6% (n = 63) required hospitalization during the 8-week follow-up period. Most of these hospitalizations (74.6%) occurred during the early neonatal period (<7 days of life). Severe clinical infections (i.e., sepsis, meningitis and pneumonia) (n = 27) were the most common diagnoses, followed by birth asphyxia (n = 13), major congenital malformations (n = 10), jaundice (n = 6) and low birth weight (n = 5). There were sixteen neonatal deaths, most of which also occurred during the early neonatal period. Overall, neonatal mortality rate (NMR) and perinatal mortality rate (PMR) were 19.3 (CI: 9.9-28.7) per 1,000 live births and 26.1 (CI: 15.3-36.9) per 1,000 total births, respectively. Severe clinical infections and birth asphyxia accounted for 37 and 31% of neonatal deaths, respectively. The risk of hospitalization was higher among neonates with severe congenital malformations, low birth weight, twin deliveries, and those born by cesarean section. Risk of mortality was higher among neonates with severe congenital malformations and twin deliveries. Conclusion: Neonatal hospitalization and deaths in our cohort were high. Although vertical interventions may reduce specific causes of morbidity and mortality, data indicate the need for a holistic approach to significantly improve the rates of poor pregnancy outcomes. Critically, a focus on decreasing the high rate of stillbirths is warranted. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01800942.

Perceptions, attitudes and practices towards scabies in communities on the Bijagós Islands, Guinea-Bissau.

BACKGROUND: Scabies is highly endemic among impoverished populations and has been recently included in the WHO's list of neglected tropical diseases (NTDs). Community support and behavioural changes are essential for the success of control interventions. This study aimed to explore beliefs, prevention attitudes and healthcare-seeking behaviours towards scabies in the Bijagós Archipelago of Guinea-Bissau. METHODS: Data were collected through two methods. Community key informants (community members, community health workers, healthcare workers and traditional healers) were interviewed using snowball sampling. A questionnaire covering perceptions, attitudes and practices was administered to community members using random cluster sampling. Thematic analysis of qualitative data was applied to identify themes. Descriptive statistics were used for quantitative data analysis. RESULTS: There was a satisfactory awareness about scabies, but perceptions about disease causation and transmission were imprecise. Misconceptions about personal hygiene as the primary measure for scabies prevention were recurrent. Some participants recognised the importance of early treatment to interrupt transmission. Treatment of close contacts was not considered important. Costs were the main determining factor for treatment choice between traditional healer and the local health centre. Late presentation and delayed treatment were common and associated with poverty and stigmatisation. Scabies impaired quality of life by affecting social interactions, health, fitness to work and school attendance. CONCLUSIONS: There is a need to improve education, recognition, management and affordable access to treatment. Community education, healthcare workers' training and skin NTD integrated control programmes should address the challenges highlighted in this study.

Effects of Weekly Iron and Folic Acid Supplements on Malaria Risk in Nulliparous Women in Burkina Faso: A Periconceptional, Double-Blind, Randomized Controlled Noninferiority Trial.

Background: The safety of iron supplementation for young women is uncertain in malaria-endemic settings. Methods: This was a double-blind, randomized controlled noninferiority trial in rural Burkina Faso. Results: A total of 1959 nulliparae were assigned to weekly supplementation (60 mg iron and 2.8 mg folic acid) (n = 980) or 2.8 mg folic acid (n = 979) until first antenatal visit (ANC1), or 18 months if remaining nonpregnant. Three hundred fifteen women attended ANC1, and 916 remained nonpregnant. There was no difference at ANC1 in parasitemia prevalence (iron, 53.4% [95% confidence interval {CI}, 45.7%-61.0%]; control, 55.3% [95% CI, 47.3%-62.9%]; prevalence ratio, 0.97 [95% CI, .79-1.18]; P = .82), anemia (adjusted effect, 0.96 [95% CI, .83-1.10]; P = .52), iron deficiency (adjusted risk ratio [aRR], 0.84 [95% CI, .46-1.54]; P = .58), or plasma iron biomarkers. Outcomes in nonpregnant women were parasitemia (iron, 42.9% [95% CI, 38.3%-47.5%]; control, 39.2% [95% CI, 34.9%-43.7%]; prevalence ratio, 1.09 [95% CI, .93-1.28]; P = .282); anemia (aRR, 0.90 [95% CI, .78-1.05]; P = .17), and iron deficiency (aRR, 0.99 [95% CI, .77-1.28]; P = .96), with no iron biomarker differences. Conclusions: Weekly iron supplementation did not increase malaria risk, improve iron status, or reduce anemia in young, mostly adolescent menstruating women, nor in early pregnancy. World Health Organization Guidelines for universal supplementation for young nulliparous women may need reassessment. Clinical Trials Registration: NCT01210040.

Long-term Impact of Oral Azithromycin Taken by Gambian Women During Labor on Prevalence and Antibiotic Susceptibility of Streptococcus pneumoniae and Staphylococcus aureus in Their Infants: Follow-up of a Randomized Clinical Trial.

Background: Oral azithromycin given to women in labor decreases maternal and neonatal bacterial carriage but increases azithromycin-resistant bacteria during at least 4 weeks following the intervention. We assessed the prevalence of bacterial carriage and azithromycin resistance 12 months after treatment among study infants. Methods: Nasopharyngeal swabs (NPSs) were collected between November 2014 and May 2015 from children aged 11-13 months whose mothers had received azithromycin or placebo during labor. Streptococcus pneumoniae and Staphylococcus aureus were isolated using conventional microbiological methods. Antibiotic susceptibility was determined by disk diffusion and confirmed by Etest or VITEK-2. Results: NPSs were collected from 461 children. The prevalence of S. pneumoniae and S. aureus was similar between children from the azithromycin and placebo arms (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval {CI}, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Prevalence of azithromycin-resistant S. pneumoniae was similar in both arms (1.8% vs 0.9% in children from the azithromycin and placebo arms, respectively; OR, 2.10 [95% CI, .30-23.38]); resistance to other antibiotics was also similar between arms. For S. aureus, there was no difference in azithromycin resistance between children in the azithromycin (3.1%) and placebo (2.6%) arms (OR, 1.22 [95% CI, .35-4.47]) or resistance to any other antibiotics. Conclusions: The higher prevalence of S. aureus azithromycin resistance observed among women treated during labor and their babies 4 weeks after treatment had waned 12 months after delivery. Azithromycin intervention did not induce other antibiotic resistance to S. pneumoniae or S. aureus. Clinical Trials Registration: NCT01800942.

Malaria and Iron Load at the First Antenatal Visit in the Rural South Kivu, Democratic Republic of the Congo: Is Iron Supplementation Safe or Could It Be Harmful?

We investigated the relationship between malaria infection and iron status in 531 pregnant women in South Kivu, Democratic Republic of the Congo. Sociodemographic data, information on morbidity, and clinical data were collected. A blood sample was collected at the first antenatal visit to diagnose malaria and measure serum ferritin (SF), soluble transferrin receptor, C-reactive protein, and α1-acid-glycoprotein. Malaria prevalence was 7.5%. Median (interquartile range) SF (adjusted for inflammation) was significantly higher in malaria-infected (82.9 µg/L [56.3-130.4]) than in non-infected (39.8 µg/L [23.6-60.8]) women (P < 0.001). Similarly, estimated mean body iron store was higher in malaria-infected women (P < 0.001). Malaria was significantly and independently associated with high levels of SF. Efforts to improve malaria prevention while correcting iron deficiency and anemia during pregnancy are warranted.

Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants.

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.).

Effects of long-term weekly iron and folic acid supplementation on lower genital tract infection - a double blind, randomised controlled trial in Burkina Faso.

BACKGROUND: Provision of routine iron supplements to prevent anaemia could increase the risk for lower genital tract infections as virulence of some pathogens depends on iron availability. This trial in Burkina Faso assessed whether weekly periconceptional iron supplementation increased the risk of lower genital tract infection in young non-pregnant and pregnant women. METHODS: Genital tract infections were assessed within a double blind, controlled, non-inferiority trial of malaria risk among nulliparous women, randomised to receive either iron and folic acid or folic acid alone, weekly, under direct observation for 18 months. Women conceiving during this period entered the pregnancy cohort. End assessment (FIN) for women remaining non-pregnant was at 18 months. For the pregnancy cohort, end assessment was at the first scheduled antenatal visit (ANC1). Infection markers included Nugent scores for abnormal flora and bacterial vaginosis (BV), T. vaginalis PCR, vaginal microbiota, reported signs and symptoms, and antibiotic and anti-fungal prescriptions. Iron biomarkers were assessed at baseline, FIN and ANC1. Analysis compared outcomes by intention to treat and in iron replete/deficient categories. RESULTS: A total of 1954 women (mean 16.8 years) were followed and 478 (24.5%) became pregnant. Median supplement adherence was 79% (IQR 59-90%). Baseline BV prevalence was 12.3%. At FIN and ANC1 prevalence was 12.8% and 7.0%, respectively (P < 0.011). T. vaginalis prevalence was 4.9% at FIN and 12.9% at ANC1 (P < 0.001). BV and T. vaginalis prevalence and microbiota profiles did not differ at trial end-points. Iron-supplemented non-pregnant women received more antibiotic treatments for non-genital infections (P = 0.014; mainly gastrointestinal infections (P = 0.005), anti-fungal treatments for genital infections (P = 0.014) and analgesics (P = 0.008). Weekly iron did not significantly reduce iron deficiency prevalence. At baseline, iron-deficient women were more likely to have normal vaginal flora (P = 0.016). CONCLUSIONS: Periconceptional weekly iron supplementation of young women did not increase the risk of lower genital tract infections but did increase general morbidity in the non-pregnant cohort. Unabsorbed gut iron due to malaria could induce enteric infections, accounting for the increased administration of antibiotics and antifungals in the iron-supplemented arm. This finding reinforces concerns about routine iron supplementation in highly malarious areas. TRIAL REGISTRATION: Trial registration number NCT01210040 . Registered with Clinicaltrials.gov on 27 September 2010.

An outbreak of pneumococcal meningitis among older children (≥5 years) and adults after the implementation of an infant vaccination programme with the 13-valent pneumococcal conjugate vaccine in Ghana.

BACKGROUND: An outbreak of pneumococcal meningitis among non-infant children and adults occurred in the Brong-Ahafo region of Ghana between December 2015 and April 2016 despite the recent nationwide implementation of a vaccination programme for infants with the 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Cerebrospinal fluid (CSF) specimens were collected from patients with suspected meningitis in the Brong-Ahafo region. CSF specimens were subjected to Gram staining, culture and rapid antigen testing. Quantitative PCR was performed to identify pneumococcus, meningococcus and Haemophilus influenzae. Latex agglutination and molecular serotyping were performed on samples. Antibiogram and whole genome sequencing were performed on pneumococcal isolates. RESULTS: Eight hundred eighty six patients were reported with suspected meningitis in the Brong-Ahafo region during the period of the outbreak. In the epicenter district, the prevalence was as high as 363 suspected cases per 100,000 people. Over 95 % of suspected cases occurred in non-infant children and adults, with a median age of 20 years. Bacterial meningitis was confirmed in just under a quarter of CSF specimens tested. Pneumococcus, meningococcus and Group B Streptococcus accounted for 77 %, 22 % and 1 % of confirmed cases respectively. The vast majority of serotyped pneumococci (80 %) belonged to serotype 1. Most of the pneumococcal isolates tested were susceptible to a broad range of antibiotics, with the exception of two pneumococcal serotype 1 strains that were resistant to both penicillin and trimethoprim-sulfamethoxazole. All sequenced pneumococcal serotype 1 strains belong to Sequence Type (ST) 303 in the hypervirulent ST217 clonal complex. CONCLUSION: The occurrence of a pneumococcal serotype 1 meningitis outbreak three years after the introduction of PCV13 is alarming and calls for strengthening of meningitis surveillance and a re-evaluation of the current vaccination programme in high risk countries.

Perspectives on the design and methodology of periconceptional nutrient supplementation trials.

Periconceptional supplementation could extend the period over which maternal and fetal nutrition is improved, but there are many challenges facing early-life intervention studies. Periconceptional trials differ from pregnancy supplementation trials, not only because of the very early or pre-gestational timing of nutrient exposure but also because they generate subsidiary information on participants who remain non-pregnant. The methodological challenges are more complex although, if well designed, they provide opportunities to evaluate concurrent hypotheses related to the health of non-pregnant women, especially nulliparous adolescents. This review examines the framework of published and ongoing randomised trial designs. Four cohorts typically arise from the periconceptional trial design--two of which are non-pregnant and two are pregnant--and this structure provides assessment options related to pre-pregnant, maternal, pregnancy and fetal outcomes. Conceptually the initial decision for single or micronutrient intervention is central--as is the choice of dosage and content--in order to establish a comparative framework across trials, improve standardisation, and facilitate interpretation of mechanistic hypotheses. Other trial features considered in the review include: measurement options for baseline and outcome assessments; adherence to long-term supplementation; sample size considerations in relation to duration of nutrient supplementation; cohort size for non-pregnant and pregnant cohorts as the latter is influenced by parity selection; integrating qualitative studies and data management issues. Emphasis is given to low resource settings where high infection rates and the possibility of nutrient-infection interactions may require appropriate safety monitoring. The focus is on pragmatic issues that may help investigators planning a periconceptional trial.

Foul wind, spirits and witchcraft: illness conceptions and health-seeking behaviour for malaria in the Gambia.

BACKGROUND: As the disease burden in the Gambia has reduced considerably over the last decade, heterogeneity in malaria transmission has become more marked, with infected but asymptomatic individuals maintaining the reservoir. The identification, timely diagnosis and treatment of malaria-infected individuals are crucial to further reduce or eliminate the human parasite reservoir. This ethnographic study focused on the relationship between local beliefs of the cause of malaria and treatment itineraries of suspected cases. METHODS: An ethnographic qualitative study was conducted in twelve rural communities in the Upper River Region and the Central River Region in the Gambia. The data collection methods included in-depth interviews, participant observation, informal conversations, and focus group discussions. RESULTS: While at first glance, the majority of people seek biomedical treatment for 'malaria', there are several constraints to seeking treatment at health centres. Certain folk illnesses, such as Jontinooje and Kajeje, translated and interpreted as 'malaria' by healthcare professionals, are often not considered to be malaria by local populations but rather as self-limiting febrile illnesses--consequently not leading to seeking care in the biomedical sector. Furthermore, respondents reported delaying treatment at a health centre while seeking financial resources, and consequently relying on herbal treatments. In addition, when malaria cases present symptoms, such as convulsions, hallucinations and/or loss of consciousness, the illness is often interpreted as having a supernatural aetiology, leading to diagnosis and treatment by traditional healers. CONCLUSION: Although malaria diagnostics and treatment-seeking in the biomedical sector has been reported to be relatively high in the Gambia compared to other sub-Saharan African countries, local symptom interpretation and illness conceptions can delay or stop people from seeking timely biomedical treatment, which may contribute to maintaining a parasite reservoir of undiagnosed and untreated malaria patients.

Doctors and vampires in sub-Saharan Africa: ethical challenges in clinical trial research.

Collecting blood samples from individuals recruited into clinical research projects in sub-Saharan Africa can be challenging. Strikingly, one of the reasons for participant reticence is the occurrence of local rumors surrounding "blood stealing" or "blood selling." Such fears can potentially have dire effects on the success of research projects--for example, high dropout rates that would invalidate the trial's results--and have ethical implications related to cultural sensitivity and informed consent. Though commonly considered as a manifestation of the local population's ignorance, these rumors represent a social diagnosis and a logical attempt to make sense of sickness and health. Born from historical antecedents, they reflect implicit contemporary structural inequalities and the social distance between communities and public health institutions. We aim at illustrating the underlying logic governing patients' fear and argue that the management of these beliefs should become an intrinsic component of clinical research.

Prenatal lipid-based nutrient supplements increase cord leptin concentration in pregnant women from rural Burkina Faso.

In developing countries, prenatal lipid-based nutrient supplements (LNSs) were shown to increase birth size; however, the mechanism of this effect remains unknown. Cord blood hormone concentrations are strongly associated with birth size. Therefore, we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development. We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a randomized, controlled design including 197 pregnant women from rural Burkina Faso. Insulin-like growth factors (IGF) I and II, their binding proteins IGFBP-1 and IGFBP-3, leptin, cortisol, and insulin were quantified in cord sera using immunoassays. LNS was associated with higher cord blood leptin mainly in primigravidae (+57%; P = 0.02) and women from the highest tertile of BMI at study inclusion (+41%; P = 0.02). We did not find any significant LNS effects on other measured cord hormones. The observed increase in cord leptin was associated with a significantly higher birth weight. Cord sera from small-for-gestational age newborns had lower median IGF-I (-9 µg/L; P = 0.003), IGF-II (-79 µg/L; P = 0.003), IGFBP-3 (-0.7 µg/L; P = 0.007), and leptin (-1.0 µg/L; P = 0.016) concentrations but higher median cortisol (+18 µg/L; P = 0.037) concentrations compared with normally grown newborns. Prenatal LNS resulted in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion. The elevated leptin concentrations could point toward a higher neonatal fat mass.

Improving malaria control in West Africa: interruption of transmission as a paradigm shift.

With the paradigm shift from the reduction of morbidity and mortality to the interruption of transmission, the focus of malaria control broadens from symptomatic infections in children ≤5 years of age to include asymptomatic infections in older children and adults. In addition, as control efforts intensify and the number of interventions increases, there will be decreases in prevalence, incidence and transmission with additional decreases in morbidity and mortality. Expected secondary consequences of these changes include upward shifts in the peak ages for infection (parasitemia) and disease, increases in the ages for acquisition of antiparasite humoral and cellular immune responses and increases in false-negative blood smears and rapid diagnostic tests. Strategies to monitor these changes must include: (1) studies of the entire population (that are not restricted to children ≤5 or ≤10 years of age), (2) study sites in both cities and rural areas (because of increasing urbanization across sub-Saharan Africa) and (3) innovative strategies for surveillance as the prevalence of infection decreases and the frequency of false-negative smears and rapid diagnostic tests increases.

Randomized controlled trial of 2 prenatal iron supplements: is there a dose-response relation with maternal hemoglobin?

BACKGROUND: The most appropriate dose of iron to prevent maternal anemia is still unclear. OBJECTIVE: We assessed the dose-response relation between maternal hemoglobin and 2 prenatal iron supplements. DESIGN: An intention-to-treat, double-blind, randomized controlled trial compared 30 mg Fe + folic acid and 13 other micronutrients (UNIMMAP; UNICEF/WHO/UNU multiple micronutrient supplement for pregnant and lactating women) with 60 mg Fe + folic acid (IFA) only in rural Burkina Faso. Home visitors directly observed tablet intake. Mixed-effects models were used for the data analysis. RESULTS: At inclusion, 43.2% of the 1268 participants were anemic. On average, the hemoglobin concentration decreased over gestation by 0.019 g/dL (95% CI: 0.012, 0.025 g/dL) per week in the IFA and UNIMMAP groups. An increment in hemoglobin concentration per micronutrient tablet [ß (±SE) = 0.006 ± 0.001 g/dL; P < 0001] was observed only in women who were anemic at inclusion, whereas a decrease was observed in the other mothers (-0.003 ± 0.001 g/dL; P = 0.002, P for interaction < 0.0001); the finding was similar in both the IFA and UNIMMAP groups. Women with baseline anemia achieved the same hemoglobin concentration (mean ± SD: 11.1 ± 0.64 g/dL) as their counterparts who received ±180 tablets of either UNIMMAP or IFA. Despite this, micronutrient intake did not significantly prevent anemia (51.0% in the third trimester). It was, however, a risk factor for hemoconcentration (odds ratio per tertile of tablet intake: 2.10; 95% CI: 1.12, 3.94), independently of supplement type or initial hemoglobin concentration. CONCLUSIONS: UNIMMAP triggered the same hemoglobin dose response with half the amount of iron as provided by IFA treatment. The benefit of iron supplements in nonanemic women is unclear. Despite micronutrient supplementation, anemia remained highly prevalent during gestation, partly because of physiologic hemodilution. This trial was registered at clinicaltrials.gov as NCT00642408.

Trends in pregnancy outcomes in Malawian adolescents receiving antimalarial and hematinic supplements.

OBJECTIVE: To describe pregnancy outcomes of adolescent and adult primigravidae receiving antimalarials and hematinic supplementation and compare findings with a survey in this area a decade earlier. DESIGN: Cross-sectional surveys in intervention and control sites. SETTING: Community, antenatal and delivery facilities in Chikwawa, Malawi. A rural area with year round malaria transmission. METHODS: Data on antenatal attendance, uptake of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP), birthweight, malaria, anaemia, for 2,152 primigravidae. OUTCOME MEASURES: Place of delivery, anaemia, malaria, birthweight. RESULTS: Fewer adolescent than adult primigravidae received >or=2 IPTp-SP doses (66 vs. 77.2%, p < 0.001), although more attended for two or more antenatal visits (92.0 vs. 76.7%, p < 0.001). Only 24.1% of adolescent primigravidae attended for hospital delivery. Women resident in intervention sites receiving IPTp-SP community distribution were more likely to choose a community delivery (p < 0.01), and have higher uptake of IPTp-SP (p = 0.036) than women not resident in these villages. Postnatal malaria prevalence was low and did not differ by age or place of delivery. Postnatal anaemia and low birthweight prevalence were higher in adolescents with community deliveries. Maternal anaemia and low birthweight prevalence were lower amongst adolescents in this study compared to estimates from the same population a decade previously. CONCLUSIONS: Adolescents had higher anaemia risk, lower IPTp-SP uptake than adults and under a quarter had a hospital delivery. Pregnancy outcomes improved compared to the survey a decade earlier. Monitoring and surveillance is required to reinforce to policy makers the need to improve adolescent coverage for available interventions.

Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa.

BACKGROUND: Benin has recently shifted its national antimalarial drug policy from monotherapies to combinations containing artemisinin derivatives. When this decision was taken, the available information on alternatives to chloroquine and sulphadoxine-pyrimethamine, the first- and second-line treatment, was sparse. METHODS: In 2003 - 2005, before the drug policy change, a randomized, open-label, clinical trial was carried out on the efficacy of chloroquine, and sulphadoxine-pyrimethamine alone or combined with artesunate, with the aim of providing policy makers with the information needed to formulate a new antimalarial drug policy. Children between six and 59 months of age, with uncomplicated malaria and living in the lagoon costal area in southern Benin, were randomly allocated to one of the three study arms and followed up for 28 days. RESULTS: Treatment failure (PCR corrected) was significantly lower in the artesunate + sulphadoxine-pyrimethamine group (4/77, 5.3%) than in chloroquine group(51/71, 71.8%) or the sulphadoxine-pyrimethamine alone group (30/70, 44.1%) (p < 0.001). Despite high sulphadoxine-pyrimethamine failure, its combination with artesunate greatly improved treatment efficacy. CONCLUSION: In Benin, artesunate + sulphadoxine-pyrimethamine is efficacious and could be used when the recommended artemisinin-based combinations (artemether-lumefantrine and amodiaquine-artesunate) are not available. However, because sulphadoxine-pyrimethamine is also used in pregnant women as intermittent preventive treatment, its combination with artesunate should not be widely employed in malaria patients as this may compromise the efficacy of intermittent preventive treatment.

A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru.

BACKGROUND: Multi-drug resistant falciparum malaria is an important health problem in the Peruvian Amazon region. We carried out a randomised open label clinical trial comparing mefloquine-artesunate, the current first line treatment in this region, with dihydroartemisinin-piperaquine. METHODS AND FINDINGS: Between July 2003 and July 2005, 522 patients with P. falciparum uncomplicated malaria were recruited, randomized (260 with mefloquine-artesunate and 262 with dihydroartemisinin-piperaquine), treated and followed up for 63 days. PCR-adjusted adequate clinical and parasitological response, estimated by Kaplan Meier survival and Per Protocol analysis, was extremely high for both drugs (99.6% for mefloquine-artesunate and 98.4% and for dihydroartemisinin-piperaquine) (RR: 0.99, 95%CI [0.97-1.01], Fisher Exact p = 0.21). All recrudescences were late parasitological failures. Overall, gametocytes were cleared faster in the mefloquine-artesunate group (28 vs 35 days) and new gametocytes tended to appear more frequently in patients treated with dihydroartemisinin-piperaquine (day 7: 8 (3.6%) vs 2 (0.9%), RR: 3.84, 95%CI [0.82-17.87]). Adverse events such as anxiety and insomnia were significantly more frequent in the mefloquine-artesunate group, both in adults and children. CONCLUSION: Dihydroartemisinin-piperaquine is as effective as mefloquine-artesunate in treating uncomplicated P. falciparum malaria but it is better tolerated and more affordable than mefloquine-artesunate (US$1.0 versus US$18.65 on the local market). Therefore, it should be considered as a potential candidate for the first line treatment of P. falciparum malaria in Peru. TRIAL REGISTRATION: ClinicalTrials.gov NCT00373607.

Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children.

In Rwanda, amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) is the current first-line treatment for malaria, introduced in 2001 as an interim strategy before the future deployment of an artemisinin-based combination treatment (ACT). Dihydroartemisinin/piperaquine (DHA-PQP) is a new co-formulated and well tolerated ACT increasingly used in Southeast Asia where it has proved to be highly effective against Plasmodium falciparum malaria. We tested the efficacy, safety and tolerability of DHA-PQP in children with uncomplicated P. falciparum malaria. A randomised, open trial was carried out in 2003-2004. Seven hundred and sixty-two children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to one of the following treatments: amodiaquine+artesunate; AQ+SP; or DHA-PQP. Patients were followed-up until Day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Children treated with DHA-PQP or AQ+AS had a significantly higher cure rate compared with those treated with amodiaquine+sulfadoxine/pyrimethamine (95.2% and 92.0% vs. 84.7%, respectively). Parasite clearance was significantly faster in children treated with DHA-PQP and AQ+AS compared with those treated with amodiaquine+sulfadoxine/pyrimethamine. The frequency of adverse events was significantly lower in patients treated with DHA-PQP than in those treated with combinations containing amodiaquine. A 3-day treatment with DHA-PQP proved to be efficacious with a good safety and tolerability profile and could be a good candidate for the next first-line treatment.